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11:00 PM|Felix, Klaus; Hauck, Oliver; Schnölzer, Martina; Kempf, Tore; Warnken, Uwe; Schneider, Kathrin; Bergmann, Frank; Fritz, Stefan; Werner, Jens|Pancreas - Current Issue|Labels: pancreatic cancer
imageObjectives: The lack of specific biochemical markers is a major drawback for the diagnosis of autoimmune pancreatitis (AIP). The aims were to characterize the autoantibody profiles in AIP and pancreatic ductal adenocarcinoma (PDAC) and to identify circulating autoantibodies that could be diagnostic markers differentiating PDAC and the AIP subtypes. Methods: Tissue lysates obtained from the resected pancreas of patients with AIP and patients with PDAC were separated by 2-dimensional polyacrylamide gel electrophoresis subsequently immunoblotted with autologous sera. The immunoreactive spots were subjected to nanoscale liquid chromatography–electrospray ionization tandem mass spectrometry to identify serum autoantibodies to tissue-derived autoantigens associated with AIP and PDAC. Autoantibody concentrations for selected autoantigens were assessed by enzyme-linked immunosorbent assays. Results: A total of 115 immunoreactive spots were identified by 2-dimensional polyacrylamide gel electrophoresis/immunobloting. Nanoscale liquid chromatography–electrospray ionization tandem mass spectrometry–based analysis revealed 68 autoantigens in AIP, 26 in PDAC, and 21 present in both diseases. Assessment of 13 selected AIP autoantibody serum levels revealed that 7 of them had significantly higher titers in AIP versus PDAC. IgG-directed against transaldolase could significantly differentiate between the 2 AIP subtypes. Conclusions: The novel panel of AIP autoantibodies is promising to supplement the predictive tests for AIP of the currently known autoantigens and represent a basis for a combined blood test to differentiate AIP from PDAC in the future.
imageObjective: This study aimed to assess the presence of pancreatic hyperenzymemia in patients with pancreatic cystic lesions as compared to other chronic diseases of the pancreas. Methods: Ninety-one patients were studied: 32 had mucinous cystic lesions, 35 had chronic pancreatitis (CP), and 24 had pancreatic ductal adenocarcinoma (PDAC). Surgery was carried out in 10 of the 32 patients with mucinous cystic lesion (7 of them had severe dysplasia), in 5 patients with CP, and in 9 patients with PDAC. Results: Abnormally high serum pancreatic isoamylase activity was present in 11 (34.4%) patients with mucinous cystic lesions, in 14 (40.0%) patients with CP, and none in patients with PDAC (P = 0.002); whereas serum lipase activity was abnormally high in 8 (25.0%) patients with mucinous cystic lesion, in 17 (48.6%) patients with CP, and in 3 (12.5%) patients with PDAC (P = 0.009). In 7 patients with mucinous cystic lesions and histologically confirmed severe dysplasia, abnormally high levels of both serum pancreatic amylase and lipase were present in 3 (42.9%) patients. Conclusions: High serum concentrations of pancreatic amylase and lipase were found in no more than half of the patients with mucinous cystic lesions. High levels of pancreatic enzymes were not associated with a greater risk of malignancy.
12:46 AM|Current Molecular Pharmacology (Volume 9 - Issue 3)|Labels: pancreatic cancer
Pancreatic adenocarcinoma is highly lethal, and until prevention of this disease is possible, various treatments including the recently developed immunotherapy to improve patients’ survival and quality of life are desperately needed. The objectives of this article are to examine the role of tumor-associated immunosuppression in pancreatic cancer development, dissect the cellular and molecular basis of the immunotherapeutic approaches, and discuss the current status and emerging strategies of immunotherapy in this malignant disease. Animal models and experimental evidence have shown that pancreatic tumor-associated stroma produces an immunosuppressive microenvironment, which promotes development and progression of pancreatic tumor. This results from dynamic interactions among pancreatic cancer cells and the immune effector cells through the actions of multiple cytokines and binding of immunomodulatory molecules. Various immunotherapeutic approaches have been developed in attempt to stimulate immune response by cytokine- or tumor-associated antigen-based vaccines, adoptive transfer of immunotoxins or antigen-primed immune cells, or antibodies directed against immune regulators. Results of these clinical studies show that these treatments are generally well tolerated without major serious complications, and demonstrate potential efficacy of immune-based therapies in pancreatic cancer. Strategies to improve the efficacy of immunotherapy may be accomplished by combining it with the conventionally used chemotherapy or targeted agents. Combinatorial approach using molecular profiling and bioinformatics may help identify predictive biomarkers of treatment response as well as identifying potential targets for personalized cancer vaccines. Hopefully, this article will stimulate further research interests and collaborative efforts to optimize therapy for patients with this devastating disease.
10:47 AM|Heid, I., Steiger, K., Trajkovic-Arsic, M., Settles, M., Esswein, M. R., Erkan, M., Kleeff, J., Jäger, C., Friess, H., Haller, B., Steingötter, A., Schmid, R. M., Schwaiger, M., Rummeny, E. J., Esposito, I., Siveke, J. T., Braren, R.|Clinical Cancer Research Online First Articles|Labels: pancreatic cancer

Purpose: Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e. amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or e.g. the recently reported protective role of tumor stroma, we aimed at the non-invasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histological differences in PDAC tissue composition are detectable by the non-invasive diffusion weighted- (DW-) MRI derived apparent diffusion coefficient (ADC) parameter. Experimental design: PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients. Results: Histological analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAClow=21.93 versus PDACmed=12.7 months, Log rank P<0.001, HR=2.23, CI=1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker (P=0.034, HR=1.73, CI=1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine (r=-0.84, CI=-0.90- -0.75) and human (r=-0.79, CI=-0.90- -0.56) PDAC and high pre-operative ADC values correlated with prolonged survival (ADChigh=41.7 months; ADClow=14.77 months, Log rank, P=0.040) in PDAC patients. Conclusion: This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the non-invasive identification of PDAC groups.

Thursday, September 22, 2016 6:00 PM|Jiguang Ma|Public Health & Healthcare|Labels: pancreatic cancer
Resveratrol, a natural polyphenol present in most plants, inhibits the growth of numerous cancers both in vitro and in vivo. Aberrant expression of YAP has been reported to activate multiple growth-regulatory pathways and confer anti-apoptotic abilities to many cancer cells. However, the role of resveratrol in YES-activated protein (YAP) expression and that of YAP in pancreatic cancer cells’ response to gemcitabine resistance remain elusive. In this study, we found that resveratrol suppressed the proliferation and cloning ability and induced the apoptosis of pancreatic cancer cells. These multiple biological effects might result from the activation of AMP-activation protein kinase (AMPK) (Thr172) and, thus, the induction of YAP cytoplasmic retention, Ser127 phosphorylation, and the inhibition of YAP transcriptional activity by resveratrol. YAP silencing by siRNA or resveratrol enhanced the sensitivity of gemcitabine in pancreatic cancer cells. Taken together, these findings demonstrate that resveratrol could increase the sensitivity of pancreatic cancer cells to gemcitabine by inhibiting YAP expression. More importantly, our work reveals that resveratrol is a potential anticancer agent for the treatment of pancreatic cancer, and YAP may serve as a promising target for sensitizing pancreatic cancer cells to chemotherapy.
Thursday, September 22, 2016 8:45 AM|Manikandan Raman|Biotech|Attachments|Labels: PARP, pancreatic cancer, clinical trial

HC Wainwright has started coverage of Oncomed Pharmaceuticals Inc (NASDAQ: OMED) shares with a Buy rating. The firm sees 68 percent potential upside for the pharmaceutical company on upcoming opt-in decisions for its lead drug candidates expected from three partners: Celgene Corporation (NASDAQ: CELG), Bayer AG (ADR) (OTC: BAYRY) and GlaxoSmithKline plc (ADR) (NYSE: GSK).

The brokerage expects OncoMed to share in demcizumab's potential success with Celgene, while OncoMed's co-promotion rights give the company greatest exposure to Celgene partnership.

Redwood City-based OncoMed's lead anti-DLL4 monoclonal antibody demcizumab is actively being evaluated in combination regimens for pancreatic and non-small cell lung cancer (NSCLC).

"We believe a positive readout from the Phase 2 YOSEMITE trial in pancreatic cancer could lead partner Celgene to opt-in to the demcizumab ...

Full story available on Benzinga.com

Wednesday, September 21, 2016 6:00 PM|Gloria M. Petersen|Seminars in Oncology|Labels: CDK, pancreatic cancer
Familial pancreatic cancer (FPC) includes those kindreds that contain at least two first degree relatives with pancreatic ductal adenocarcinoma. At least twelve known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the foremost being BRCA2 and CDKN2A. Research into the identification of mutations in known cancer predisposition genes and through next generation sequencing has revealed extensive heterogeneity. The development of genetic panel testing has enabled genetic risk assessment and predisposition testing to be routinely offered.
Wednesday, September 21, 2016 8:09 AM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: pancreatic cancer

Overexpression of SOX18 correlates with accelerated cell growth and poor prognosis in human pancreatic ductal adenocarcinoma

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: Available online 20 September 2016 Source:Biochemical and Biophysical Research Communications Author(s): Yazhou Wang, Huahu Guo, Dafang Zhang, Xin Yu, Xisheng Leng, Shu Li, Weihua Zhu Transcription factor SOX18 has been proved to play a significant role in carcinogenesis. However, no investigation was performed about the expression of SOX18 in pancreatic ductal adenocarcinoma (PDAC). In our work, we found that the PDAC tissues had higher level of SOX18 mRNA and protein expression than matched non-tumor pancreatic tissues and high level of SOX18 protein indicated poor prognosis for PDAC patients. After knockdown of SOX18 gene in PANC-1 and SW1990 cell lines, which showed higher expression level of SOX18 among five PDAC cell lines, the abilities of proliferation, migration and invasion were inhibited and the tumor growth was suppressed in vivo. In addition, the flow cytometry results indicated that down-regulation of SOX18 induced G1/S phase arrest. Furthermore, we found that the expression of cyclin D1, c-myc and MMP-7, three tumorigenesis promoters, was inhabited with downregulation of SOX18. In conclusion, our study reveals that SOX18 plays a significant role in promoting the growth of PDAC, and might serve as a promising target for PDAC therapy.

Monday, September 19, 2016 7:25 AM|Reuters: Healthcare|Labels: pancreatic cancer, clinical trial
* Mabvax therapeutics reports on interim progress on its programs including the phase i clinical trial for therapeutic antibody treatment of pancreatic cancer
Monday, September 19, 2016 7:05 AM|PR Newswire Association LLC.|PR Newswire: Medical Pharmaceuticals|Attachments|Labels: pancreatic cancer, clinical trial

SAN DIEGO, Sept. 19, 2016 /PRNewswire/ -- MabVax Therapeutics Holdings, Inc. (NASDAQ: MBVX), a clinical stage immuno-oncology drug development company reported on the early progress of its lead therapeutic antibody program, MVT-5873, currently in a phase I clinical trial in patients...


Friday, September 16, 2016 11:13 AM|Zhong, Y., Macgregor-Das, A. M., Saunders, T., Whittle, M., Makohon-Moore, A., Kohutek, Z., Poling, J., Herbst, B., Javier, B., Cope, L., Leach, S. D., Hingorani, S. R., Iacobuzio-Donahue, C. A.|Clinical Cancer Research Online First Articles|Labels: P53, TGF, pancreatic cancer

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated and the frequency and morphology of organ-specific hematogenous metastases compared to that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases. Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs 68%, p<0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases suggesting the ability to colonize is in part developed within the primary site, a phenomenon we refer to as the "Cinderella effect". Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically.

Friday, September 16, 2016 10:23 AM|Yiwei Li, Fazlul H. Sarkar|International Journal of Biological Sciences|Labels: pancreatic cancer

Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer.

Friday, September 16, 2016 10:23 AM|Klaus Felix, Matthias M. Gaida|International Journal of Biological Sciences|Labels: pancreatic cancer

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma.

Friday, September 16, 2016 10:23 AM|Laufey T. Amundadottir|International Journal of Biological Sciences|Labels: pancreatic cancer

Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).

Friday, September 16, 2016 10:23 AM|Junli Guo, Keping Xie, Shaojiang Zheng|International Journal of Biological Sciences|Labels: pancreatic cancer

Lack of early detection and effective interventions is a major reason for the poor prognosis and dismal survival rates for pancreatic cancer. Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor of invasive pancreatic ductal adenocarcinoma (PDAC). Each stage in the progression from PanIN to PDAC is well characterized by multiple significant genetic alterations affecting signaling pathways. Understanding the biological behavior and molecular alterations in the progression from PanIN to PDAC is crucial to the identification of noninvasive biomarkers for early detection and diagnosis and the development of preventive and therapeutic strategies for control of pancreatic cancer progression. This review focuses on molecular biomarkers of PanIN and their important roles in early detection and treatment of pancreatic cancer.

Friday, September 16, 2016 10:23 AM|Jill P. Smith, Lionel K. Fonkoua, Terry W. Moody|International Journal of Biological Sciences|Labels: pancreatic cancer

The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin - responsive tumors.

Friday, September 16, 2016 10:23 AM|Saswati Chand, Kevin O'Hayer, Fernando F. Blanco, Jordan M. Winter, Jonathan R. Brody|International Journal of Biological Sciences|Labels: pancreatic cancer

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.

Friday, September 16, 2016 10:23 AM|S. Perwez Hussain|International Journal of Biological Sciences|Labels: pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the highly lethal malignancies. The highly refractory nature of clinically advanced disease and lack of a reliable biomarker for early detection are major obstructions in improving patient outcome. The recent efforts, however, in understanding the pancreatic tumor biology have resulted in the recognition of novel addictions as well as vulnerabilities of tumor cells and are being assessed for their clinical potential. This special issue highlights some of the recent progress, complexity and challenges towards improving disease outcome in patients with this lethal malignancy.

Thursday, September 15, 2016 6:45 AM|Xiao, Q., Zhou, D., Rucki, A. A., Williams, J., Zhou, J., Mo, G., Murphy, A., Fujiwara, K., Kleponis, J., Salman, B., Wolfgang, C. L., Anders, R. A., Zheng, S., Jaffee, E. M., Zheng, L.|Cancer Research recent issues|Labels: pancreatic cancer
Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor-1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation-dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor–stromal interactions in the TME, which promote malignant growth and progression. Cancer Res; 76(18); 5395–404. ©2016 AACR.
Wednesday, September 14, 2016 6:37 PM|Oncology|Labels: pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, and is known for its extremely poor prognosis. Because of the location and composition of the organ, early symptoms cannot be visualized as easily as in other solid tumors. In the past decades, researchers have been mostly working on the genetic and epigenetic alterations of the cancer cells themselves, and therapies on pancreatic cancer cells alone have failed to significantly improve patient outcome. With the identification of abundant tumor stromal responses, the focus of pancreatic cancer research has begun to change. Increasing evidence has proved that the tumor stroma, especially the cell components (such as pancreatic stellate cells, tumor-associated macrophages, mast cells etc.) plays a key role in the development of PDAC. In this review, we discuss the interactions between cancer cells and several important cell components of the tumor stroma, as well their role in tumor growth, migration, invasion, angiogenesis and immune recognition.
Wednesday, September 14, 2016 5:53 PM|Gao Lu, Maqing Zheng, Yunxia Zhu, Min Sha, Yue Wu, Xiao Han|International Journal of Biological Sciences|Labels: pancreatic cancer, clinical trial

Despite tremendous advances in cancer treatment and survival rates, pancreatic cancer remains one of the most deadly afflictions and the fourth leading cause of cancer deaths in the world. Matrix Metalloproteinases (MMPs) are thought to be involved in cancer progression. Matrix metalloproteinase (MMP)-2 is known to play a pivotal role in tumor invasion, metastasis and angiogenesis, and validated to be the anticancer target. Inhibition of MMP-2 activity is able to reduce the cancer cell invasion and suppress tumor growth in vivo. Two novel peptides, M204C4 and M205C4, which could specially inhibit MMP-2 activity, were identified by a phage display library screening. We showed that M204C4 and M205C4 inhibited the activity of MMP-2 in a dose dependent manner in vitro. Two peptides reduced MMP-2 mediated invasion of the pancreatic cancer cell lines PANC-1 and CFPAC-1, but not affected the expression and release of MMP-2. Furthermore, these two peptides could suppress tumor growth in vivo. Our results indicated that two peptides selected by phase display technology may be used as anticancer drugs in the future.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: EGFR, pancreatic cancer, clinical trial
This phase I/Ib trial studies the side effects and best dose of afatinib dimaleate when given together with capecitabine in treating patients with solid tumors, pancreatic cancer, or biliary cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment and has not responded to previous treatment. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving afatinib dimaleate together with capecitabine may be a better treatment for solid tumors, pancreatic cancer, or biliary cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: pancreatic cancer, clinical trial
This partially randomized phase I/II trial studies the side effects and best dose of pegylated recombinant human hyaluronidase (PEGPH20) when given together with combination chemotherapy and to see how well they work compared with combination chemotherapy alone in treating patients with newly diagnosed pancreatic cancer that has spread to other places in the body. Pegylated recombinant human hyaluronidase may help chemotherapy drugs work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether combination chemotherapy is more effective with or without pegylated recombinant human hyaluronidase in treating pancreatic cancer.
Wednesday, September 14, 2016 7:55 AM|NISHI, K., SUZUKI, K., SAWAMOTO, J., TOKIZAWA, Y., IWASE, Y., YUMITA, N., IKEDA, T.|Anticancer Research recent issues|Labels: pancreatic cancer

Cancer cells tend to have a high requirement for lipids, including fatty acids, cholesterol and triglyceride, because of their rapid proliferative rate compared to normal cells. In this study, we investigated the effects of inhibition of lipid synthesis on the proliferation and viability of human pancreatic cancer cells. Of the inhibitors of lipid synthesis that were tested, 5-(tetradecyloxy)-2-furoic acid (TOFA), which is an inhibitor of acetyl-CoA carboxylase, and the fatty acid synthase (FAS) inhibitors cerulenin and irgasan, significantly suppressed the proliferation of MiaPaCa-2 and AsPC-1 cells. Treatment of MiaPaCa-2 cells with these inhibitors significantly increased the number of apoptotic cells. In addition, TOFA increased caspase-3 activity and induced cleavage of poly (ADP-ribose) polymerase in MiaPaCa-2 cells. Moreover, addition of palmitate to MiaPaCa-2 cells treated with TOFA rescued cells from apoptotic cell death. These results suggest that TOFA induces apoptosis via depletion of fatty acids and that, among the various aspects of lipid metabolism, inhibition of fatty acid synthesis may be a notable target for the treatment of human pancreatic cancer cells.

Wednesday, September 14, 2016 7:55 AM|CEBRIAN, M. J. G., BAUDEN, M., ANDERSSON, R., HOLDENRIEDER, S., ANSARI, D.|Anticancer Research recent issues|Labels: pancreatic cancer

Pancreatic cancer has a dismal prognosis and there is an increasing and unmet need to identify better diagnostic and therapeutic targets in order to ameliorate the course of the disease. HMGB1, a nuclear DNA-binding protein that acts as a transcription factor, is currently in the limelight. HMGB1 exhibits a dual role in pancreatic cancer; when intracellular, it acts as an anti-tumor protein stabilizing the genome, whereas extracellular HMGB1 behaves as a pro-tumor protein with cytokine, chemokine and growth factor functions. Although the exact mechanisms of HMGB1 in pancreatic cancer are still to be elucidated, the significance of this protein for processes, such as autophagy, immunogenic cell death, tumor growth, metastasis and resistance to chemotherapy, have become increasingly clear. In this review, we provide a systematic summary and review of the biological and clinical relevance of HMGB1 in pancreatic cancer.

Tuesday, September 13, 2016 11:38 PM|Seung Tae Kim, Sang Yun Ha, Sujin Lee, Soomin Ahn, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Kyoung-Mee Kim, Young Suk Park|Journal of Cancer|Labels: PD-1/PD-L1, pancreatic cancer

Programmed death-ligand 1 (PD-L1), which is expressed on many cancer cells, interacts with PD1 expressed on the surface of T cells, inhibiting the T cells and blocking the antitumor immune response. Expression of PD-L1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been studied. We investigated the impact of PD-L1 expression in 32 patients with metastatic GEP-NET.

The expression of PD-L1 was evaluated using an anti-PD-L1 immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded (FFPE) tissue samples. The correlation between PD-L1 and clinicopathological data including survival and response to systemic treatments was analyzed.

Primary sites were 24 foregut-derived GEP-NETs, including stomach (n=1), duodenum (n=2), biliary tract (n=7), and pancreas (n=14), and 8 hindgut-derived GEP-NETs of the distal colon and rectum. Among the 32 patients with metastatic GEP-NET analyzed in this study, 7 (21.9%) had expression of PD-L1 in tumor tissues. Expression of PD-L1 was significantly associated with high-grade WHO classification (grade 3) (p=0.008) but not with gender, primary site, and number of metastatic sites (p>0.05). The status of PD-L1 expression was statistically associated with progression-free survival (PFS) for first-line systemic treatment (p=0.047). Moreover, the status of PD-L1 expression could significantly predict overall survival (p=0.037).

The expression of PD-L1 was associated with higher WHO tumor grade (grade 3) in metastatic GEP-NETs. PD-L1 expression had both predictive and prognostic value for survival of patients with metastatic GEP-NETs.

Tuesday, September 13, 2016 11:38 PM|Aino N.E. Salmiheimo, Harri K. Mustonen, Sanna A.A. Vainionpää, Zhanlong Shen, Esko A.J. Kemppainen, Hanna E. Seppänen, Pauli A. Puolakkainen|Journal of Cancer|Labels: pancreatic cancer, IL

Recent studies suggest that pro-inflammatory type M1 macrophages inhibit tumor progression and that anti-inflammatory M2 macrophages enhance it. The aim of this study was to examine the interaction of type M1 and M2 macrophages with pancreatic cancer cells. We studied the migration rate of fluorescein stained pancreatic cancer cells on Matrigel cultured alone or with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) differentiated macrophages or with Macrophage Colony Stimulating Factor (M-CSF) differentiated macrophages, skewing the phenotype towards pro- and anti-inflammatory direction, respectively. Macrophage differentiation was assessed with flow cytometry and the cytokine secretion in cell cultures with cytokine array. Both GM-CSF and M-CSF differentiated macrophages increased the migration rate of primary pancreatic adenocarcinoma cell line (MiaPaCa-2) and metastatic cell line (HPAF-II). Stimulation with IL6 or IL4+LPS reversed the macrophages' increasing effect on the migration rate of MiaPaCa-2 completely and partly of HPAF-II. Co-culture with MiaPaCa-2 reduced the inflammatory cytokine secretion of GM-CSF differentiated macrophages. Co-culture of macrophages with pancreatic cancer cells seem to change the inflammatory cytokine profile of GM-CSF differentiated macrophages and this might explain why also GM-CSF differentiated macrophages promoted the invasion. Adding IL6 or IL4+LPS to the cell culture with MiaPaCa-2 and GM-CSF or M-CSF differentiated macrophages increased the secretion of inflammatory cytokines and this could contribute to the reversion of the macrophage induced increase of cancer cell migration rate.

Tuesday, September 13, 2016 8:19 PM|Yingying Zhao, Yuqiong Wang, Yuefeng Yang, Jingqi Liu, Yang Song, Yan Cao, Xiaoyu Chen, Wenzhuo Yang, Fei Wang, Jun Gao, Zhaoshen Li, Changqing Yang|Journal of Cancer (RSS 2.0)|Labels: pancreatic cancer, clinical trial

Pancreatic cancer (PC) is one of the most common cancers and has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MicroRNAs (miRNAs, miRs) are a group of non-coding, small RNAs with active biological activities. In our investigation, human pancreatic cancer cell line Capan-2 were transfected with miR-222 mimics, inhibitors or their negative controls. Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), EdU incorporation assay and cell cycle determination by flow cytometry. MiR-222 and putative target gene expression levels including p27, p57 and PTEN were determined using quantitative reverse transcription polymerase chain reactions and Western blotting. Our results showed that miR-222 could lead to increased vitality and proliferative rate of Capan-2 cells, and also higher S-phase and lower G1-phase of cell cycle. Further, we found p57 at protein level, but not p27 nor PTEN, was regulated by miR-222 in Capan-2 cells. Finally, we co-transfected miR-222 inhibitor and p57 si-RNA into Capan-2 cells, and found that proliferation-suppressing effects of miR-222 inhibitor on Capan-2 cells could be partially reversed by silencing p57. Our results indicate that miR-222 controls Capan-2 cell proliferation by targeting p57. This study provides a novel idea for developing effective therapeutic strategy for PC patients through inhibiting miR-222.

Tuesday, September 13, 2016 8:19 PM|Xiao-Bo Cheng, Norihiro Sato, Shiro Kohi, Atsuhiro Koga, Keiji Hirata|Journal of Cancer (RSS 2.0)|Labels: pancreatic cancer

Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) is a nonintegral cell surface receptor involved in the aggressive phenotype in a wide spectrum of human malignancies, but the significance of RHAMM in pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we investigated the expression of RHAMM and its clinical relevance in PDAC. RHAMM mRNA expression was examined in 8 PDAC cell lines and in primary pancreatic cancer and adjacent non-tumor tissues from 14 patients using real-time RT-PCR. Western blotting was carried out to analyze the expression of RHAMM protein in PDAC cell lines. We also investigated the expression patterns of RHAMM protein in tissue samples from 70 PDAC patients using immunohistochemistry. The RHAMM mRNA expression was increased in some PDAC cell lines as compared to a non-tumorous pancreatic epithelial cell line HPDE. The RHAMM mRNA expression was significantly higher in PDAC tissues as compared to corresponding non-tumorous pancreatic tissues (P < 0.0001). The RHAMM protein expression was higher in the vast majority of PDAC cell lines relative to the expression in HPDE. The immunohistochemical analysis revealed strong expression of RHAMM in 52 (74%) PDAC tissues. Strong expression of RHAMM was significantly associated with a shorter survival time (P = 0.038). In multivariate analysis, tumor stage (P = 0.039), residual tumor (P = 0.015), and strong RHAMM expression (P = 0.034) were independent factors predicting poor survival. Strong expression of RHAMM may predict poor survival in PDAC patients and may provide prognostic and, possibly, therapeutic value.

Tuesday, September 13, 2016 8:19 PM|Elizabeth Donohue, Anitha Thomas, Norbert Maurer, Irina Manisali, Magali Zeisser-Labouebe, Natalia Zisman, Hilary J. Anderson, Sylvia S. W. Ng, Murray Webb, Marcel Bally, Michel Roberge|Journal of Cancer|Labels: pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. It has been described as requiring elevated autophagy for growth and inhibiting autophagy has been proposed as a treatment strategy. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which interfere with lysosomal function and block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here we report that PDAC cell lines show variable sensitivity to verteporfin in vitro, suggesting cell-line specific autophagy dependence. Using image-based and molecular analyses, we show that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrated that verteporfin accumulated in tumors at autophagy-inhibiting levels and inhibited autophagy in vivo, but did not reduce tumor volume or increase survival as a single agent. In combination with gemcitabine verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. While our results do not uphold the premise that autophagy inhibition might be widely effective against PDAC as a single-modality treatment, they do support autophagy inhibition as an approach to sensitize PDAC to gemcitabine.

Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: pancreatic cancer
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Franklin, O.; Ola, B.; Pär, J.;...
Background : Pancreatic cancer (PDACacrnm1) patients have alterations in blood levels of certain micro-RNA:s (miRNA) at the time of diagnosis. At the time of diagnosis, however, the majority of pancreatic cancer patients have a non-curable disease...
Friday, September 2, 2016 1:15 AM|Eiji Miyoshi, Yoshihiro Kamada|Cancer Science|Labels: pancreatic cancer
The prognosis of pancreatic cancer is extremely poor compared to other cancers. One of the reasons for this is the difficulty of early diagnosis. Surveillance using cancer biomarkers and image diagnosis can enable early detection and has improved the prognosis of hepatocellular carcinoma in Japan. However, it is very difficult to detect pancreatic cancer at an early stage using cancer biomarkers and image diagnosis alone. Fucosylation is one of the most important types of glycosylation involved in cancer and inflammation. We have developed a novel glycocancer biomarker, fucosylated haptoglobin (Fuc-Hpt), and have investigated its usefulness for the diagnosis of pancreatic cancer over approximately 10 years. Recently, we also found that most pancreatic tissues surrounding pancreatic cancer exhibit chronic pancreatitis with fibrosis and/or fatty degeneration. Certain forms of chronic pancreatitis might indicate high risk for the development of pancreatic cancer. In this review, we provide a historical summary of our research on Fuc-Hpt as a cancer biomarker, and discuss a potential early detection system for pancreatic cancer. This manuscript is a summary of our researches about a novel glyco-cancer biomarker, fucosylated haptoglobin (Fuc-Hpt), in pancreatic cancer over approximately 10 years
Friday, September 2, 2016 1:00 AM|Keisuke Taniuchi, Mutsuo Furihata, Seiji Naganuma, Ken Dabanaka, Kazuhiro Hanazaki, Toshiji Saibara|Cancer Science|Labels: pancreatic cancer
The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. Thus, PODXL enhances motility and invasiveness through an increase in gelsolin–actin interactions in cell protrusions. The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. High PODXL expression is an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promotes pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin.
Thursday, September 1, 2016 10:05 PM|Li, L., Chen, H., Gao, Y., Wang, Y.-W., Zhang, G.-Q., Pan, S.-H., Ji, L., Kong, R., Wang, G., Jia, Y.-H., Bai, X.-W., Sun, B.|Molecular Cancer Therapeutics current issue|Labels: pancreatic cancer

Recently, pancreatic ductal adenocarcinoma (PDAC) has emerged as one of the most aggressive malignant tumors with the worst prognosis. Previous studies have demonstrated that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is increased in pancreatic cancer and is identified as a diagnostic biomarker. Nonetheless, the molecular mechanism of elevated MALAT1 levels and tumor aggressiveness remains unknown. In this study, MALAT1 was found to be highly expressed in PDAC tissues, and elevated expression was associated with poorer prognoses. In addition, MALAT1 was positively linearly correlated with the expression of LC3B mRNA. Furthermore, several molecules involved in cellular autophagic flux were modulated following the downregulation of MALAT1, including LC3, P62, and LAMP-2. Mechanistically, we found that MALAT1 interacted with RNA binding protein HuR, and silencing of MALAT1 greatly enhanced the posttranscriptional regulation of TIA-1 and had further effects on inhibiting autophagy. MALAT1 was speculated to regulate tumorigenesis via HuR-TIA-1–mediated autophagic activation. Hence, we investigated the biological properties of MALAT1 in terms of tumor proliferation and metastasis by promoting autophagy in vitro. In brief, these data demonstrate that MALAT1 could facilitate the advanced progression of tumors in vivo. Our study highlights the new roles of MALAT1 on protumorigenic functioning and anticancer therapy via activating autophagy in pancreatic cancer. Mol Cancer Ther; 15(9); 2232–43. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Zhu, S., He, C., Deng, S., li, X., Cui, S., Zeng, Z., Liu, M., Zhao, S., Chen, J., Jin, Y., Chen, H., Deng, S., Liu, Y., Wang, C., Zhao, G.|Molecular Cancer Therapeutics current issue|Labels: HIF, pancreatic cancer

Hypoxic microenvironments contribute to the tumorigenesis of numerous cancers by regulating the expression of a subset of miRNAs called "hypoxiamiRs." However, the function and mechanism of these deregulated miRNAs in hypoxic microenvironments within pancreatic cancers remain undefined. This study demonstrates that miR-548an is significantly downregulated in pancreatic cancer tissues and correlates with increased tumor size, advanced TNM stage, distant metastasis, and poor prognosis. Moreover, the overexpression of miR-548an significantly inhibited the proliferation and invasion of pancreatic cancer cells in vitro and in vivo. We further revealed that hypoxia-induced factor-1α (HIF-1α) induces the downregulation of miR-548an in pancreatic cancer cells during hypoxia. Our co-IP and ChIP assays revealed that HIF-1α and histone deacetylase 1 (HDAC1) form a complex and bind to the hypoxia response elements (HRE) on the miR-548an promoter. In addition, inhibition of HDAC1 with trichostatin A antagonizes the suppression of miR-548 by hypoxia. Our dual luciferase assay validated that miR-548an directly binds to the 3' untranslated region of vimentin mRNA. The downregulation of vimentin suppresses the proliferation and invasion of pancreatic cancer cells in vitro and in vivo. In addition, vimentin was inversely correlated with miR-548an expression in pancreatic cancer samples. In conclusion, our findings suggest that the HIF-1α–HDAC1 complex transcriptionally inhibits miR-548an expression during hypoxia, resulting in the upregulation of vimentin that facilitates the pancreatic tumorigenesis. Mol Cancer Ther; 15(9); 2209–19. ©2016 AACR.

Wednesday, August 31, 2016 11:00 PM|Kobes, Joseph E.; Daryaei, Iman; Howison, Christine M.; Bontrager, Jordan G.; Sirianni, Rachael W.; Meuillet, Emmanuelle J.; Pagel, Mark D.|Pancreas - Current Issue|Labels: AKT, pancreatic cancer
imageObjectives: This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. Methods: PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles (SE-PLGA-427 and DE-PLGA-427). The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole-body biodistribution in an orthotopic model of MIA PaCa-2 pancreatic cancer. Anatomical magnetic resonance imaging (MRI) was used to noninvasively assess the effects of 4 weeks of nanoparticle drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity. Results: DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity during drug treatment with both types of drug-loaded nanoparticles. Both SE- and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors and an elimination of primary pancreatic tumor in 68% of the mice. Conclusions: These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of MIA PaCa-2 pancreatic cancer.
Wednesday, August 31, 2016 11:00 PM|Dotan, Efrat; Alpaugh, R. Katherine; Ruth, Karen; Negin, Benjamin P.; Denlinger, Crystal S.; Hall, Michael J.; Astsaturov, Igor; McAleer, Cecilia; Fittipaldi, Patricia; Thrash-Bingham, Catherine; Meropol, Neal J.; Cohen, Steven J.|Pancreas - Current Issue|Labels: pancreatic cancer
imageObjectives: Development of targeted therapies for pancreatic cancer could be enhanced by a reliable method for noninvasive tumor cell assessment. In this pilot study, we isolated and phenotypically characterized circulating tumor cells (CTCs) from patients with metastatic pancreatic cancer and explored their relationship to clinical outcome. Methods: Peripheral blood from 50 patients was collected at treatment initiation and first disease evaluation for CTC enumeration and phenotyping by CellSearch® system. Expression of human mucin 1 (MUC-1) was performed. Results: Forty-eight and 37 patients had evaluable samples at baseline and first disease evaluation, respectively. The cohort was 62% male, with a median age of 63 years. At least 1 CTC per 7.5 mL was detected in 23 patients (48%) pretreatment and 11 patients (30%) at first disease evaluation. No difference was seen in overall survival between patients with 1 or more CTCs versus no CTC at baseline (P = 0.14). Patients with MUC-1 expressing CTC (n = 10) had shorter median overall survival compared with those with MUC-1 negative CTC (n = 13; 2.7 vs 9.6 m; P = 0.044). Conclusions: Circulating tumor cell enumeration and phenotypic characterization from metastatic pancreatic cancer patients are feasible. No correlation was found between CTC isolation and survival. However, the presence of MUC-1 expressing CTC demonstrated a trend toward inferior survival.
Wednesday, August 31, 2016 11:00 PM|Hashimoto, Daisuke; Arima, Kota; Yokoyama, Naomi; Chikamoto, Akira; Taki, Katsunobu; Inoue, Risa; Kaida, Takayoshi; Higashi, Takaaki; Nitta, Hidetoshi; Ohmuraya, Masaki; Hirota, Masahiko; Beppu, Toru; Baba, Hideo|Pancreas - Current Issue|Labels: RAS, pancreatic cancer
imageObjectives: Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma. Methods: Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing. Results: Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes. Conclusions: Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.
Thursday, August 25, 2016 2:45 AM|Satoshi Matsukuma, Kiyoshi Yoshimura, Tomio Ueno, Atsunori Oga, Moeko Inoue, Yusaku Watanabe, Atsuo Kuramasu, Masanori Fuse, Ryoichi Tsunedomi, Satoshi Nagaoka, Hidetoshi Eguchi, Hiroto Matsui, Yoshitaro Shindo, Noriko Maeda, Yoshihiro Tokuhisa, Reo Kawano, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigefumi Yoshino, Shoichi Hazama, Masaaki Oka, Hiroaki Nagano|Cancer Science|Labels: pancreatic cancer
Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by two-dimensional electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis demonstrated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in CRThigh/CD44v9low population is much higher than that in CRTlow/CD44v9high population. CRT expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients’ clinicopathological features and disease outcomes in the Cox's proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and post-operative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy. This article is protected by copyright. All rights reserved.
Wednesday, August 24, 2016 6:00 PM|Donnele Daley, Constantinos Pantelis Zambirinis, Lena Seifert, Neha Akkad, Navyatha Mohan, Gregor Werba, Rocky Barilla, Alejandro Torres-Hernandez, Mautin Hundeyin, Vishnu Raj Kumar Mani, Antonina Avanzi, Daniel Tippens, Rajkishen Narayanan, Jung-Eun Jang, Elliot Newman, Venu Gopal Pillarisetty, Michael Loran Dustin, Dafna Bar-Sagi, Cristina Hajdu, George Miller|Cell|Labels: pancreatic cancer
γδT cells are key regulators of effector T cell activation in pancreatic cancer and a new target for cancer immunotherapy.
Sunday, August 14, 2016 10:05 PM|Huang, Y., Nahar, S., Nakagawa, A., Fernandez-Barrena, M. G., Mertz, J. A., Bryant, B. M., Adams, C. E., Mino-Kenudson, M., Von Alt, K. N., Chang, K., Conery, A. R., Hatton, C., Sims, R. J., Fernandez-Zapico, M. E., Wang, X., Lillemoe, K. D., Fernandez-del Castillo, C., Warshaw, A. L., Thayer, S. P., Liss, A. S.|Clinical Cancer Research recent issues|Labels: pancreatic cancer

Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC.

Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC.

Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models.

Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259–70. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Dawkins, J. B. N., Wang, J., Maniati, E., Heward, J. A., Koniali, L., Kocher, H. M., Martin, S. A., Chelala, C., Balkwill, F. R., Fitzgibbon, J., Grose, R. P.|Cancer Research recent issues|Labels: pancreatic cancer
Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0–G1. RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. Cancer Res; 76(16); 4861–71. ©2016 AACR.
Sunday, August 14, 2016 10:05 PM|Muthuswamy, S. K.|Clinical Cancer Research recent issues|Labels: pancreatic cancer

There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

This abstract is also being presented as Poster B10.

Citation Format: Senthil K. Muthuswamy. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR01.

Sunday, August 14, 2016 10:05 PM|Hidalgo, M.|Clinical Cancer Research recent issues|Labels: pancreatic cancer

Pancreatic cancer remains one of the most deadly cancers. Very few therapeutics advanced have been achieved in this disease. Over the last few years, several studies have started to elucidate the molecular biology of PDAC including the genomic landscape of the disease, the importance of the stroma and the immunesuppressive environment characteristic of PDAC. One important development in translational research in PDAC is the availability of preclinical models of the disease. This includes genetically engineered mouse models of cancer, patient derived xenografts (aka Avatar models) and organoids. These models are becoming useful for drug screening, biomarker development and personalize medicine. Using Avatar models we identified Nab-paclitaxel as an effective agent in pancreas cancer in contrast to paclitaxel that does not result antitumor effects. We also showed that Nab-paclitaxel disrupts PDAC stroma, an observation, however, has not been confirmed by others. In addition, studies in mouse models revealed the lack of predictability of SPARC expression for clinical outcome. More recently, we have identified demcizumab and palbociclib as potentially effective agents in PDX models as the basis for their clinical development. PDX models have also de potential to be used as a platform for personalizes cancer treatment. In this regard, we are now conducting the AVATAR clinical trial in which patients with advanced cancer are randomized to receive either a conventional treatment or a treatment based on integrating genomic data with AVATAR mouse mode development.

Citation Format: Manuel Hidalgo. Application of PDX models to pancreas cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA17.

Sunday, August 14, 2016 10:05 PM|Khazak, V., Skobeleva, N., Beglyarova, N., Bobrov, E., Zhou, Y., Jablonski, S. A., Weiner, L. M., Paz, K., Astsaturov, I.|Clinical Cancer Research recent issues|Labels: pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. With almost 90% lethality even when diagnosed prior to metastasis, there is an urgent unmet medical need for new therapies or better matching of existing therapies to patients. To address this emergency, we first had developed a panel of new physiological models for study of PDAC, rapidly expanding surgical PDAC tumor samples in culture with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). Using this panel, we evaluated sensitivity to a large panel of existing drugs. Only a small minority of agents were cytotoxic in vitro in a significant number of independent PDAC models. Among these, transcriptional repressors were predominated. From a short list of drugs not previously used in PDAC, triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Triptolide is a natural product compound from Chinese medicinal plant Tripterygium wilfordii, and it was found to be the most active agent in the screen. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers.

Citation Format: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Egor Bobrov, Yan Zhou, Sandra A. Jablonski, Louis M. Weiner, Keren Paz, Igor Astsaturov. Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B07.

Sunday, August 14, 2016 10:05 PM|Radulovich, N., Ibrahimov, E., Holt, C., Raghavan, V., Zhao, T., Denroch, R., Pham, N.-A., Gallinger, S., Pintilie, M., Stein, L., McPherson, J., Muthuswamy, L., Tsao, M. S.|Clinical Cancer Research recent issues|Labels: pancreatic cancer

Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer deaths in North America, for both men and women with a 5-year survival rate of less than 5%. The poor prognosis rate is attributed to late presentation of the disease and the lack of effective treatment options. Large-scale genome sequencing efforts on PDAC tumors show evidence of high mutational burden and revealed a number of mutated genes affecting multiple oncogenic pathways. While there are significant endeavors in developing specific targeted agents against "driver" mutations, tumor diversity within and across patient population remains a key factor affecting therapeutic efficacy. In this context, the availability of large cohorts of genomically characterized patient-derived xenograft (PDX) tumor models may help to accelerate the development of novel therapies against this lethal cancer.

PDX models provide a renewable resource to maintain a patient's tumor ex vivo for pre-clinical or co-clinical studies. As part of The International Cancer Genome Consortium (ICGC), our laboratory has established 93 PDX models in non-obese diabetic and severe combined immune-deficient (NOD-SCID) mice from Whipple resection specimens. These tumors represent a heterogeneous group of neoplasms arising from the head, body and tail of pancreas, bile duct and Ampulla of Vater. All implantations including in the subcutaneous pocket at the flank or at the orthotopic pancreas site, were performed using 4-8 weeks old NOD-SCID mice. Successful growth and serial transplant to multiple mouse generations were observed in in 74 PDX models of the 93 implanted PDAC specimens, achieving an 80% engraftment rate, one of the highest reported in any type of cancer. Histology fidelity was preserved in the PDX models compared to corresponding patient tumors. Failed implants were due to specimens characterized by borderline malignancy and absence of tumor cells.

Whole exome sequencing and copy number aberration profiling was completed for 61 PDXs and blood from the matched patients. Cancer-specific single nucleotide variation (SNV) load varied widely from 38 to 305 in PDXs. The most recurrent activating mutation was observed in KRAS with 77% of PDX models showing alterations at codon G12 (65%), G13 (8%) and Q61 (4%); in addition, 26% PDXs had a copy number gain in KRAS. Molecular comparisons of the 21 PDX models and their matched patient tumors showed that alternate allele frequency of KRAS mutation from exome sequencing of primary tumor is a strong indicator of the tumor cellularity; a higher tumor cellularity results in a larger overlap of cancer specific alterations between xenografts and corresponding patient tumors.

We have demonstrated a successful establishment of PDX models that represent genomic architecture of major subclonal populations of patient PDAC primary tumors.

Citation Format: Nikolina Radulovich, Emin Ibrahimov, Carson Holt, Vibha Raghavan, Tracy Zhao, Rob Denroch, Nhu-An Pham, Steve Gallinger, Melania Pintilie, Lincoln Stein, John McPherson, Lakshmi Muthuswamy, Ming Sound Tsao. Establishment and molecular characterization of patient-derived tumor xenografts from resected tumors or ascites fluids of patients with pancreatic/ampullary/bile duct carcinomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B31.

Wednesday, August 3, 2016 3:58 AM|Takahiro Domoto, Ilya V. Pyko, Takuya Furuta, Katsuyoshi Miyashita, Masahiro Uehara, Takeo Shimasaki, Mitsutoshi Nakada, Toshinari Minamoto|Cancer Science|Labels: pancreatic cancer, glioma
Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and therefore the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemo-, radio- and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. This article is protected by copyright. All rights reserved.
Monday, August 1, 2016 10:05 PM|Waghray, M., Yalamanchili, M., Dziubinski, M., Zeinali, M., Erkkinen, M., Yang, H., Schradle, K. A., Urs, S., Pasca Di Magliano, M., Welling, T. H., Palmbos, P. L., Abel, E. V., Sahai, V., Nagrath, S., Wang, L., Simeone, D. M.|Cancer Discovery recent issues|Labels: pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer–associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis.

Significance: The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal–epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886–99. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 803

Sunday, July 31, 2016 11:00 PM|Burtness, Barbara; Powell, Mark; Catalano, Paul; Berlin, Jordan; Liles, Darla K.; Chapman, Andrew E.; Mitchell, Edith; Benson, Al B.|American Journal of Clinical Oncology - Most Popular Articles|Labels: pancreatic cancer, clinical trial
imageObjectives: The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. Patients and Methods: Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m2) and irinotecan (50 mg/m2) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. Results: A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. Conclusions: Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer.
Sunday, July 31, 2016 10:05 PM|Zagorac, S., Alcala, S., Fernandez Bayon, G., Bou Kheir, T., Schoenhals, M., Gonzalez–Neira, A., Fernandez Fraga, M., Aicher, A., Heeschen, C., Sainz, B.|Cancer Research recent issues|Labels: pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients. Cancer Res; 76(15); 4546–58. ©2016 AACR.
Thursday, July 28, 2016 7:56 AM|Saur, D.|Cancer Research recent issues|Labels: pancreatic cancer
Maintenance and drug resistance of pancreatic ductal adenocarcioma (PDAC) depends on cancer cell intrinsic mechanisms and a stroma that supports tumor growth. Mouse models of human PDAC have provided important insights into the evolution of this highly lethal tumor, but there are no models that allow secondary genetic manipulation of autochthonous tumors, the tumor microenvironment or the metastatic host niche once the tumor has formed.We generated an inducible dual-recombinase system by combining Flp/frt and Cre/loxP. This novel PDAC model permits spatial and temporal control of gene expression enabling unbiased genetic approaches to study the role of tumor cell-autonomous and non-autonomous functions in endogenous cancers. This tool provides unparalleled access to the native biology of cancer cells and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets. We performed tumor cell-autonomous and non-autonomous targeting, uncovered hallmarks of human multistep carcinogenesis, validated genetic tumor therapy, and showed that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are in fact dispensable for tumor formation.Citation Format: Dieter Saur. Modeling and targeting the tumor microenvironment of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA22.
Thursday, July 28, 2016 7:56 AM|Rath, N., Kadir, S., Morton, J. P., Pinho, A. V., Helbig, L., Julian, L., McGhee, E. J., Kalna, G., Vazquez, A., Anderson, K. I., Rooman, I., Samuel, M. S., Olson, M. F.|Cancer Research recent issues|Labels: pancreatic cancer
Pancreatic cancer is one of the leading causes of cancer death and despite advances in chemotherapeutic regimens the overall 5-year survival rate remains less than 5%. The actomyosin-regulating ROCK1 and ROCK2 kinases are downstream-targets of the Rho GTPase pathway. They contribute to various processes, such as cell adhesion, motility, proliferation, differentiation and survival, which then influence numerous stages of cancer growth and progression. Interestingly, exome sequencing of pancreatic cancer genomes revealed that 15% of pancreatic cancer patients carry an amplification of the ROCK1 gene (1). Moreover, we found significant increases in ROCK1 and ROCK2 RNA expression in pancreatic cancer datasets obtained using Oncomine. When we further determined the protein expression of ROCK2 in pancreatic ductal adenocarcinoma (PDAC) we found an up-regulation of ROCK2 during disease progression. Higher ROCK2 levels also correlated with less differentiated tumors. A characteristic of advanced stages of pancreatic cancer is a collagen and fibroblast enriched stroma. To analyze the effect of ROCK kinases on cancer cell invasion, we performed 3-dimensional organotypic assays. Our results demonstrate that increased ROCK signaling was sufficient to convert non-invasive PDAC cells into ones capable of invasion into organotypic collagen matrix. Using an RNA sequencing approach, we investigated the effect of ROCK activation on pancreatic cancer cell gene transcription. Differential expression analysis revealed an enrichment of gene sets that are involved in cell-matrix interaction, and we found a higher release of matrix metalloproteinases MMP10 and MMP13 upon ROCK activation. In addition, our organotypic studies revealed extensive tissue remodeling and an accumulation of cleaved collagen bundles at the sites of PDAC cell invasion. Furthermore, collagen degradation and cell invasion into organotypic matrices were significantly reduced by application of a broad-spectrum MMP inhibitor, confirming that ROCK-induced invasion is dependent on MMP activity. Interestingly, our studies also indicated that ROCK-driven invasion of PDAC cells into collagen matrix enabled cell growth. To study the function of ROCK kinase signaling in pancreatic cancer in vivo, we expressed conditionally active ROCK2 in a mouse model of PDAC. We found that an increase of ROCK activity in pancreatic cancer cells accelerated PDAC progression, which resulted in reduced survival. Contrary, the administration of a ROCK inhibitor during tumor progression had a beneficial effect on survival. In summary, our results suggest that targeting ROCK kinases should be considered for chemotherapy of invasive pancreatic cancer.(1) Biankin et al. Nature. 2012 Nov 15;491(7424):399-405Citation Format: Nicola Rath, Shereen Kadir, Jennifer P. Morton, Andreia V. Pinho, Lena Helbig, Linda Julian, Ewan J. McGhee, Gabriela Kalna, Alexei Vazquez, Kurt I. Anderson, Ilse Rooman, Michael S. Samuel, Michael F. Olson. ROCK kinases drive invasive pancreatic tumor growth. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C22.
Thursday, July 28, 2016 7:56 AM|Babicky, M. L., Harper, M. M., Mose, E. S., Jaquish, D. J., French, R. P., Waltz, S. E.|Cancer Research recent issues|Labels: pancreatic cancer
Introduction: The RON (receptor d'origine nantais) tyrosine kinase is overexpressed in >80% of human pancreatic cancers, but its effect on pancreatic carcinogenesis is largely unknown.Methods: We developed a transgenic mouse that overexpresses RON specifically in the pancreas (Pdx-1-RON). Additionally, we utilized an existing transgenic mouse with a functionally inactive RON tyrosine kinase domain (Pdx-1-RTK-/-). These strains were crossed with the established CK murine model of pancreatic cancer yielding compound strains, RCK and CK/TK-/-. We performed immunofluorescent staining, flow cytometry, and western blot analysis on the tissues from these animals to study the effects of RON overexpression and the loss of RON signaling in the setting of oncogenic Kras.Results: RON overexpression results in increased acinar-ductal metaplasia, accelerates PanIN progression to invasive cancer, and results in an accumulation of alternatively-activated (MRC1+) macrophages in the tumor microenvironment. We found that RON overexpression results in upregulation of its own ligand, macrophage-stimulating protein (MSP), activating a positive autocrine/paracrine signaling loop that effects tumor growth and the differentiation of tumor-associated macrophages. Knockdown of RON expression and/or MSP expression results in decreased tumor growth in vivo. Additionally, loss of RON signaling in CK/TK-/- mice leads to a profound decrease in alternatively-activated (MRC1+) macrophages in the tumor microenvironment. In contrast, these animals demonstrate an accumulation of classically activated (CD11c+) macrophages. RON signaling is also associated with downregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), a known driver of CD11c+ macrophage activation. The correlation of RON and MSP and the inverse correlation with MCP-1 expression were validated in a database analysis of human pancreatic tumor specimens.Conclusion: Our studies demonstrate that murine RON overexpression accelerates the development of invasive pancreatic cancer in the setting of oncogenic Kras. Active RON signaling results in upregulation of its own ligand, MSP, initiating a positive autocrine/paracrine feedback loop that promotes tumor growth and alters the differentiation of macrophages in the tumor microenvironment.Citation Format: Michele L. Babicky, Megan M. Harper, Evangeline S. Mose, Dawn J. Jaquish, Randall P. French, Susan E. Waltz. The RON tyrosine kinase accelerates pancreatic duct neoplasia and activates a positive autocrine/paracrine signaling loop that promotes alternative macrophage activation. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A26.
Thursday, July 28, 2016 7:56 AM|Sherman, M. H., Evans, R. M.|Cancer Research recent issues|Labels: pancreatic cancer
Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.Citation Format: Mara H. Sherman, Ronald M. Evans. Control of pancreatic cancer metabolism and histone acetylation by the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B03.
Wednesday, July 27, 2016 11:11 AM|YAMASAKI, A., ONISHI, H., IMAIZUMI, A., KAWAMOTO, M., FUJIMURA, A., OYAMA, Y., KATANO, M.|Anticancer Research recent issues|Labels: Hh/SMO, pancreatic cancer

Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor.

Friday, July 22, 2016 8:19 AM|Guo, K., Cui, J., Quan, M., Xie, D., Jia, Z., wei, D., Wang, L., Gao, Y., Ma, Q., Xie, K.|Clinical Cancer Research Online First Articles|Labels: pancreatic cancer

Purpose: Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the present study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design: MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biologic functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results: MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions: Lost expression of KLF4, a transcriptional repressor of MSI2, results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis.

Thursday, July 21, 2016 6:00 PM|Christine A. Iacobuzio-Donahue|Nature Reviews Cancer - Issue - nature.com science feeds|Labels: pancreatic cancer

Nature Reviews Cancer 16, 553 (2016). doi:10.1038/nrc.2016.66

Authors: Alvin Makohon-Moore & Christine A. Iacobuzio-Donahue

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for

Sunday, July 17, 2016 10:05 PM|Romeo, C., Weber, M. C., Zarei, M., DeCicco, D., Chand, S. N., Lobo, A. D., Winter, J. M., Sawicki, J. A., Sachs, J. N., Meisner-Kober, N., Yeo, C. J., Vadigepalli, R., Tykocinski, M. L., Brody, J. R.|Molecular Cancer Research recent issues|Labels: TNF, pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3'-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR's role in affecting TRAIL apoptotic resistance. NanoString analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in antiapoptotic processes. Taken together, these data extend HuR's role as a key regulator of TRAIL-induced apoptosis.

Implications: Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients. Mol Cancer Res; 14(7); 599–611. ©2016 AACR.

Friday, July 8, 2016 8:57 AM|Wang, J., Yang, S., He, P., Schetter, A., Gaedcke, J., Ghadimi, B. M., Ried, T., Yfantis, H. G., Lee, D. H., Gaida, M. M., Hanna, N., Alexander, H. R., Hussain, S. P.|Clinical Cancer Research Online First Articles|Labels: pancreatic cancer

Purpose Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early stage PDAC cases with extremely poor survival (< 7 months) and those surviving 2 years or more following surgical resection. Experimental Design Gene-expression profiling was performed in tumors in a test cohort of PDAC (N=50), which included short (<7 months, N=11) and long surviving (>2 years, N=14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan Meier and pathway analyses with validations in independent cohorts for mechanistic and functional analyses. Results Gene-expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking 1st. Lower expression of Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. Conclusion Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC.

Monday, June 13, 2016 8:46 AM|Guo, X., Zheng, L., Jiang, J., Zhao, Y., Wang, X., Shen, M., Zhu, F., Tian, R., Shi, h., Xu, M., Li, X., Peng, F., Zhang, H., Feng, Y., Xie, Y., Xu, X., Jia, W., He, R., Xie, C., Hu, J., Ye, D., Wang, M., Qin, R.|Clinical Cancer Research Online First Articles|Labels: NFKb, pancreatic cancer, IL

Purpose:We sought to find new immune-based treatments for pancreatic cancer (PC). Experimental Design: We detected interleukin (IL)-18 expression in plasma and specimens from patients with PC. We then investigated whether IL-18 had a therapeutic effect for PC in vitro and in vivo, and any underlying mechanisms. Results: Higher plasma IL-18 was associated with longer overall survival, but higher IL-18 in PC tissues was associated with shorter overall survival and increased invasion and metastasis. Recombinant IL-18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral bloods and lymph nodes. However, IL-18 promoted the proliferation and invasion of PC cells, in vitro and in vivo, through the NF-B pathway. Nevertheless, by co-administrating IL-18 with BAY11-7082, a NF-B inhibitor, we were able to prevent the pro-cancerous effects of IL-18 and prolong the survive time of the mice. Conclusions: IL-18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on PC, when combined with the NF-B pathway inhibitor, IL-18 improved survival in a murine PC model. Our study implies the possibility of a combinational immunotherapy that uses IL-18 and targets NF-B pathway.

Thursday, June 9, 2016 1:41 PM|Stracquadanio, G., Vrugt, B., Flury, R., Schraml, P., Würl, P., Müller, T. H., Knippschild, U., Henne-Bruns, D., Breitenstein, S., Clavien, P.-A., Graf, R., Bond, G. L., Grochola, L. F.|Clinical Cancer Research Online First Articles|Labels: pancreatic cancer, biomarker diagnostic

Purpose: Although pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, like other common cancers, it displays a wide range of biology. However, at present, there are no reliable tests to predict patients' cancer-specific outcomes and guide personalized treatment decisions. In this study, we aim to identify such biomarkers in resectable PDAC by studying single nucleotide polymorphisms (SNPs) in the CD44 gene, which drives the progression of pancreatic cancer. Experimental Design: 348 PDAC patients from three independent cohorts (Switzerland, Germany, The Cancer Genome Atlas (TCGA)) who underwent pancreatic resection are included in the study. Information on the haplotype structure of the CD44 gene is obtained using 1000 Genomes Project data and the genotypes of the respective tagging SNPs are determined. Cox proportional hazards models are utilized to analyze the impact of SNP genotype on patients' survival. Results: We identify a SNP in the CD44 gene (SNPrs187115) that independently associates with allelic differences in prognosis in all study cohorts. Specifically, in 121 Swiss patients, we observe an up-to 2.38-fold (p=0.020) difference in tumor-related death between the genotypes of SNPrs187115. We validate those results in both the German (hazard ratio (HR)=2.32, p=0.044, 101 patients) and the TCGA cohort (HR=2.36, p=0.044, 126 patients). Conclusions: CD44 SNPrs187115 can serve as a novel biomarker readily available at the time of PDAC diagnosis that identifies patients at risk for faster tumor progression and guide personalized treatment decisions. It has the potential to significantly expand the pool of patients that would benefit from tumor resection.

Tuesday, June 7, 2016 10:41 AM|Zhao, S., Chen, C., Chang, K. W., Karnad, A., Jagirdar, J., Kumar, A. P., Freeman, J. W.|Clinical Cancer Research Online First Articles|Labels: pancreatic cancer

Purpose: A subpopulation of pancreatic adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabine resistant tumors. Experimental Design: RT-PCR, Western blotting and DNA sequencing was used to determine CD44 isoform and expression levels. Flow cytometry was used to sort cells on the basis of their CD44 expression level. CD44 expression was knocked down using shRNA. Tumorigenic properties were determined by clonogenic and Matrigel assays, immunohistochemistry, tumor growth in vivo using luciferase imaging and by tumor weight. Results: We identified an invasive cell population that gives rise to gemcitabine resistant tumors. These cancer cells express a high level of CD44 standard isoform and have an EMT phenotype (CD44s/EMT). In vivo, CD44s/EMT engraft and expand rapidly and give rise to tumors that express high levels of CD44 isoforms that contain multiple exon variants. CD44 low expressing cells show continued sensitivity to gemcitabine in vivo and knockdown of CD44 in CD44s/EMT cells increases sensitivity to gemcitabine and decreases invasiveness. Conclusion: PDAC cells expressing high levels of CD44s with a mesenchymal-like phenotype were highly invasive and developed gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response.

Wednesday, June 1, 2016 6:34 AM|German Cancer Research Center|Labels: pancreatic cancer

A microRNA suppresses the ability of cancer cells in the pancreas to invade surrounding tissue and spread metastases, researchers at the German Cancer Research Center and colleagues revealed in their latest study. In patients with pancreatic cancer, the researchers discovered that the lower the detected levels of this microRNA in the tumor are, the more unfavorably the disease progresses. Levels of this microRNA are often already reduced in chronic pancreatitis, which often precedes cancer.

Copyright: Dr. Nathalie Giese, Chirurgische Universitätsklinik Heidelberg

Copyright: Dr. Nathalie Giese, Chirurgische Universitätsklinik Heidelberg

Tuesday, May 31, 2016 6:00 PM|Oberg, A. L.|Journal of Clinical Oncology Subject Collection: Statistics in Oncology|Labels: pancreatic cancer
PurposeThe inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and MethodsOf newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. ResultsMedian survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naive to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. ConclusionOur findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.
Thursday, May 5, 2016 3:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: pancreatic cancer
CONCLUSIONSThe SIRI can be used to predict the survival of patients with pancreatic adenocarcinomas who receive chemotherapy, potentially allowing clinicians to improve treatment outcomes by identifying candidates for aggressive therapy. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, April 28, 2016 9:59 AM|YAMAGUCHI, Y., KATATA, Y., OKAWAKI, M., SAWAKI, A., YAMAMURA, M.|Anticancer Research recent issues|Labels: pancreatic cancer

Background/Aim: Adoptive immunotherapy (AIT) using autologous zoledronate-activated killer (ZAK) cells has been performed for developing a novel modality of cancer treatment. In this study, data series from incurable pancreatic cancer were analyzed. Patients and Methods: Patients were treated with AIT using intravenous administration of ZAK cells every 3 to 4 weeks in combination with standard chemotherapy and possible clinical benefits were examined. Results: Seventy-five patients were treated. A median overall survival (OS) time of 6.7 months was achieved for all patients and 13.1 months for those treated 5 times or more, that increased to 14.6 and 18.3 months, respectively, when the previous treatment period of chemotherapy alone was included in the analysis. The disease control rate was 58.5 %. Multivariate regression analysis showed a significant positive correlation between the survival and baseline value of lymphocyte percentage in white blood cell counts (p=0.031). Conclusion: The data suggest that AIT using ZAK cells in combination with chemotherapy is safe and feasible and may be effective in prolonging survival for patients with incurable pancreatic cancer. The lymphocyte percentage at baseline may be a good biomarker for predicting the survival benefit of ZAK cell AIT.

Friday, April 15, 2016 3:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via MedWorm.com|Comments|Labels: pancreatic cancer
Authors: Okada T, Minehira D, Takada M, Urata H, Kato A, Adachi I, Kurashima Y, Kaji S, Ogura T, Chiba S, Esumi H, Toyooka N Abstract We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4'-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68μM) although the moderate preferential cytotoxicity (PC50 1.68μM in NDM vs PC50 20μM in DMEM). The 3'-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96μM in NDM vs less than 50% inhi...
Friday, February 19, 2016 5:16 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: STAT, pancreatic cancer
Authors: Wu X, Tang W, Marquez RT, Li K, Highfill CA, He F, Lian J, Lin J, Fuchs JR, Ji M, Li L, Xu L Abstract Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer c...

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Wednesday, February 17, 2016 7:28 AM|Cancer Investigation|MedWorm: Cancer Therapy|Comments|Labels: pancreatic cancer
Authors: Zhan Q, Fang Y, Deng X, Chen H, Jin J, Lu X, Peng C, Li H, Shen B Abstract We discovered the expression level of miR-148a significantly decreased in pancreatic cancer tissues whereas that of DNMT1 increased. In ASPC-1 cancer cells, the overexpression of miR-148a led to a decreased level of DNMT1 and reduced the proliferation and metastasis of ASPC-1 cells. Moreover, the increased expression of miR-148a arrested the UTR methylation of p27, giving rise to an increased level of p27. Interestingly, it was shown that the DNMT1 inhibition enhanced the expression of miR-148a. In vivo studies demonstrated that the tumorigenesis of ASPC-1 was significantly arrested by either the overexpression of miR-148a or the inhibition of DNMT1. PMID: 25950085 [PubMed - indexed for MEDLINE...
Wednesday, January 13, 2016 4:00 PM|World Journal of Gastroenterology : WJG|MedWorm: Cancer Therapy|Comments|Labels: pancreatic cancer
Authors: Matsuoka T, Yashiro M Abstract Pancreatic cancer is the fourth most common cause of cancer deaths worldwide. Although recent therapeutic developments for patients with pancreatic cancer have provided survival benefits, the outcomes for patients with pancreatic cancer remain unsatisfactory. Molecularly targeted cancer therapy has advanced in the past decade with the use of a number of pathways as candidates of therapeutic targets. This review summarizes the molecular features of this refractory disease while focusing on the recent clinical and experimental findings on pancreatic cancer. It also discusses the data supporting current standard clinical outcomes, and offers conclusions that may improve the management of pancreatic cancer in the future. PMID: 26811624 [PubM...
Sunday, January 10, 2016 4:00 PM|Acta Biochimica et Biophysica Sinica|MedWorm: Cancer Therapy|Comments|Labels: pancreatic cancer
In conclusion, our results suggest that miR-125a promotes chemo-resistance to gemcitabine in pancreatic cells through targeting A20, which may provide novel therapeutic targets or molecular biomarkers for cancer therapy and improve tumor diagnosis or predictions of therapeutic responses. PMID: 26758190 [PubMed - as supplied by publisher] (Source: Acta Biochimica et Biophysica Sinica)
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5 year survival rate of less than 5%. Deaths caused by pancreatic cancer are projected to exceed the number from colorectal carcinoma by 2020, making PDAC the second leading cause of cancer-related death in the United States, behind only NSCLC. At the molecular level, PDAC is enriched for a number of genetic events central to CDK4/6:CyclinD1 control of cell cycle progression - 90% of tumors harbor oncogenic KRAS mutations, which are synthetic lethal with CDK4/6 inhibition, while the majority of PDAC cases also feature loss of p16INK4A, the endogenous inhibitor of CDK4/6. Rb loss is uncommon in PDAC and phosphorylation of Rb, the canonical CDK4/6 substrate, is detectable at high frequencies, suggesting th...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: pancreatic cancer, IL
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:15 PM ET Friday, November 6.Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. Repositioning Bazedoxifene as a novel inhibitor of IL-6/GP130 signaling for pancreatic cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A177. (Source: Molecular Cancer Therapeutics)