Oncology Intelligence

JAK belongs to a family of PTKs, which includes JAK1, JAK2, JAK3 and TYK2.(1) The JAK/STAT pathway regulates cell proliferation, differentiation, survival, and apoptosis.(2) JAK activates STAT. The STAT family consists of seven proteins: STAT-1 (P91), STAT-2 (p113), STAT-3, STAT-4, STAT-5a, STAT-5b, and STAT-6. Two phosphorylated subunits of Stat 1 form an activation factor that binds to an activation sequence (GAS).(3) After activation by the receptor-JAK complex, STATs translocate to the nucleus and regulate the expression of target genes.(4) Functions of activated STATs can be altered through association with other transcription factors (c-Jun, IRF-9, c-Fos, NF-KB, SMAD, and SP1) and cofactors like p300, CBP, BRCA1, mini-chromosome maintenance-5.(1, 5, 6) STAT3 is a transcription factor encoded by the STAT3 gene.(7, 8) Similar to JAKs, STATs are post-translationally modified by tyrosine and/or serine phosphorylation, methylation, acetylation, attachment of small ubiquitin-related modifier proteins.(9) Stat3 is activated not only by cytokine receptors, such as the receptor for the IL6 family cytokines, but also growth RTKs, such as the EGFR and c-MET, non-RTKs, such as Src and Abl, and in response to stimulation of G-protein-coupled receptors.(7, 10-14) Stat3 upregulates Bcl-xL, survivin, Akt, VEGF, HGF, Myc, and HIF1, while the p53 tumor suppressor is downregulated by Stat3 activity.(10) Different JAKs and STATs are activated by different ligands.(4) RTK pathway activity promotes JAK/STAT signaling by: (i) the activation of some RTKs, including EGFR and PDGFR, results in the JAK-independent tyrosine phosphorylation of STATs, probably by the Src kinase, and (ii) RTK/Ras pathway stimulation causes the downstream activation of MAPK, which specifically phosphorylates a serine near the C-terminus of most STATs. JAK/STAT indirectly promotes Ras signaling through the transcriptional activation of SOCS3, which binds RasGAP.
Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.(7, 10) A single gain-of function point mutation in the JAK2 kinase is present in the majority of myeloproliferative neoplasms.(15) STATs are also involved in many diseases like BC, HNC, MM, AML, Burkitt's lymphoma, and herpes virus salmiri-dependent lymphoma.(1, 5, 6) There is a direct connection between the PTEN-Akt-FOXO axis and the leukemia inhibitory factor receptor-STAT3 signaling pathway.(7) A tumor suppressor role of STAT3 has also been reported.(16)

Marketed Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
ruxolitinib INCB18424 Jakafi, Jakavi Incyte Mkt: myelofibrosis; P3: pancreatic, leukemia; P2:HL, BC, MM, MDS, NSCLC, BC, CML, PC, CRC; P1/2: CLL, lung; P1: solid trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
fedratinib TG101348 SAR302503 Sanofi P3: hem, MDS; P2: myelofibrosis; P1: solid trials
YM BioSciences P3: myelofibrosis, myeloproliferative disorders; P2: pancreatic; P1: NSCLC trials
pacritinib ONX 0803 SB-1518, CT-1578 S*BIO P3: myelofibrosis; P2: CRC, leukemia; P1/2: AML, NSCLC; P1: lymphoma trials
Astex P2: MM; P1/2: AML; P1: NHL, solid trials
AZD9150 ISIS-STAT3 AstraZeneca P2: ovarian; P1/2: DLBCL, lymphoma; P1: HCC, hem trials
INCB18424 Incyte P2: PTCL, lymphoma trials
INCB39110 Incyte P2: NSCLC; P1: various, pancreatic, trials
LY2784544 Eli Lilly P2: various; P1: myeloproliferative disorders trials
BMS-911543 BMS P1/2: various trials
NS-018 Nippon Shinyaku P1/2: myelofibrosis trials
OPB-31121 Otsuka P1/2: HCC; P1: solid, MM, NHL, leukemia (terminated) trials
OPB-111077 Otsuka P1: solid, HCC trials
OPB-51602 Otsuka P1: solid, nasal esophageal, MM, NHL, AML, ALL trials
PRT062070 Portola P1: CLL, SLL, NHL trials
WP1066 EMD P1: BC, melanoma, brain, CNS, solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
AZD1480 AstraZeneca terminated; P1/2: myeloproliferative disorders; P1: solid, HCC, NSCLC, gastric trials
INCB47986 Incyte Terminated; P1/2: MDS; P1: solid, HL, NHL trials
bardoxolone RTA 402 Kyowa Hakko Kirin, Abbott No ongoing trials in oncology; PIII in kidney disease due to cardiac safety; P2: melanoma; P1/2: pancreatic; P1: solid, lymphoma trials

Pharmstatus Pro
Subscription portal Jaks/STAT therapeutics

1. Oltmanns U, Issa R, Sukkar MB, John M, Chung KF. Role of c?jun N?terminal kinase in the induced release of GM?CSF, RANTES and IL?8 from human airway smooth muscle cells. British journal of pharmacology. 2003;139(6):1228-34.

2. Wang YH, Huang ML. Organogenesis and tumorigenesis: insight from the JAK/STAT pathway in the Drosophila eye. Developmental Dynamics. 2010;239(10):2522-33.

3. Asmana Ningrum R. Human Interferon Alpha-2b: a therapeutic protein for cancer treatment. Scientifica. 2014;2014.

4. Morales J, Falanga Y, Depcrynski A, Fernando J, Ryan J. Mast cell homeostasis and the JAK-STAT pathway. Genes and immunity. 2010;11(8):599-608.

5. Poehlmann T, Busch S, Mussil B, Winzer H, Weinert J, Mebes I, et al. The possible role of the Jak/STAT pathway in lymphocytes at the fetomaternal interface. 2005.

6. Grote K, Luchtefeld M, Schieffer B. JANUS under stress-role of JAK/STAT signaling pathway in vascular diseases. Vascular pharmacology. 2005;43(5):357-63.

7. K F. P53, cyclin-dependent kinase and abnormal amplification of centrosomes. Biochim Biophys Acta. 2008;1786(1):15-23. PMCID: 18472015.

8. Akira S, Nishio Y, Inoue M, Wang X-J, We S, Matsusaka T, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994;77(1):63-71.

9. Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Molecular biosystems. 2006;2(11):536-50.

10. Raptis L, Arulanandam R, Geletu M, Turkson J. The R (h) oads to Stat3: Stat3 activation by the Rho GTPases. Experimental cell research. 2011;317(13):1787-95.

Thursday, September 15, 2016 6:45 AM|Quick, L., Young, R., Henrich, I. C., Wang, X., Asmann, Y. W., Oliveira, A. M., Chou, M. M.|Cancer Research current issue|Labels: STAT
Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a role for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC), and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP6′s relevant substrates has been obscure. Here we report that the Jak1–STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1–STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression. Cancer Res; 76(18); 5337–47. ©2016 AACR.
Tuesday, September 13, 2016 11:38 PM|Wei Huang, Quan Zhou, Xia Yuan, Ze-mei Ge, Fu-xiang Ran, Hua-yu Yang, Guang-liang Qiang, Run-tao Li, Jing-rong Cui|Journal of Cancer|Labels: Bcl-2, STAT, ovarian cancer

Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome.

Tuesday, September 13, 2016 8:19 PM|Sen Wang, Weifang An, Yunhong Yao, Renhuai Chen, Xiaoxuan Zheng, Wanyong Yang, Yi Zhao, Xinrong Hu, Enping Jiang, Yanhong Bie, Zhangquan Chen, Ping Ouyang, He Zhang, Hui Xiong|Journal of Cancer (RSS 2.0)|Labels: STAT, TNF, cervical cancer

Objectives: The most recently discovered cytokine interleukin 37 (IL-37) received growing attention. Its function on tumor is largely unknown. Here, we investigated the biological function of IL-37 on cervical cancer (CC).

Materials and methods: HPV+ Hela cells and HPV- C33A cells were used. RT-qPCR was performed to detect the transcription of IL-37, STAT3, TNF-αand IL-1β. Western blotting was used for protein detection. CCK-8 assay and transwell assay were employed for cell proliferation and invasion detection, respectively.

Results: Successful gene transfection of IL-37 suppressed the proliferation and invasion of CC. Interestingly, IL-37 showed higher anticancer ability in HPV+ Hela cells than that in HPV- C33A cells. Then, the molecular mechanism of IL-37 anticancer was explored. Firstly, we found that IL-37 inhibited STAT3 expression at both mRNA and protein levels. IL-37 also down regulated the phosphorylation of STAT3. Secondly, blockage of STAT3 using siRNAs reduced significantly the ability of IL-37 to suppress cell proliferation and invasion. Thirdly, STAT3 knockdown reduced markedly the inhibition of IL-37 on the transcription of tumor-derived TNF-α and IL-1β, indicating the contribution of STAT3 for the cancer associated antiinflammation of IL-37. Finally, STAT3 up regulation restored the ability of cell proliferation, cell invasion and the expression of inflammatory cytokines, TNF-α and IL-1β.

Conclusions: IL-37 suppressed cell proliferation and invasion of CC and STAT3 is involved in this process. Thus, IL-37 emerges as a new anticancer cytokine for CC. This study demonstrated a new biological function of IL-37 and offered a potential molecule for CC treatment.

Monday, September 12, 2016 10:00 PM|New GEO Series|Labels: STAT, lymphoma, HL
Contributors : Kathrin Wurster ; Stephan Mathas ; Martin Janz ; Karl Koechert
Series Type : Expression profiling by array
Organism :

Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed–Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbyl myristate acetate stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis

Monday, September 12, 2016 12:42 PM|Mancikova, V., Montero-Conde, C., Perales-Paton, J., Fernandez, A. F., Santacana, M., Jodkowska, K., Inglada-Perez, L., Castelblanco, E., Borrego, S., Encinas, M., Matias-Guiu, X., Fraga, M. F., Robledo, M.|Clinical Cancer Research Online First Articles|Labels: STAT, thymic

Purpose: Medullary thyroid carcinoma (MTC) is a rare disease with few genetic drivers, and the etiology specific to each known susceptibility mutation remains unknown. Exploiting multilayer genomic data, we focused our interest on the role of aberrant DNA methylation in MTC development. Experimental Design: We performed genome-wide DNA methylation profiling assessing >27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. mRNA and miRNA expression data was available for 33 and 31 tumors, respectively. Two human MTC cell lines and 101 paraffin-embedded MTCs were used for validation. Results: The most distinctive methylome was observed for RETM918T-related tumors. Integration of methylation data with mRNA and miRNA expression data identified genes negatively regulated by promoter methylation. These in silico findings were confirmed in vitro for PLCB2, DKK4, MMP20 and miR-10a, -30a and -200c. The mutation-specific aberrant methylation of PLCB2, DKK4 and MMP20 was validated in 25 independent MTCs by bisulfite pyrosequencing. The methylome and transcriptome data underscored JAK/Stat pathway involvement in RETM918T MTCs. Immunostaining (IHC) for the active form of signaling effector STAT3 was performed in a series of 101 MTCs. As expected, positive IHC was associated with RETM918T-bearing tumors (p-value<0.02). Pharmacological inhibition of STAT3 activity increased the sensitivity to Vandetanib of the RETM918T-positive MTC cell line, MZ-CRC-1. Conclusions: Multilayer OMIC data analysis uncovered methylation hallmarks in genetically defined MTCs and revealed JAK/Stat signaling effector STAT3 as a potential therapeutic target for the treatment of RETM918T MTCs.

Thursday, September 1, 2016 6:00 PM|Michael Chan|International Journal of Molecular Sciences|Labels: STAT, gastric
Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.
Friday, August 26, 2016 3:15 AM|Horlad Hasita, Chaoya Ma, Hiromu Yano, Cheng Pan, Koji Ohnishi, Yukio Fujiwara, Shinya Endo, Yoshitaka Kikukawa, Yutaka Okuno, Masao Matsuoka, Motohiro Takeya, Yoshihiro Komohara|Cancer Science|Labels: PD-1/PD-L1, STAT, IL
Immune escape and tolerance in the tumor microenvironment are closely involved in tumor progression, and are caused by T-cell exhaustion and mediated by the inhibitory signaling of immune checkpoint molecules including programmed death-1 (PD-1), cytotoxic T-lymphocyte associated protein 4, and T-cell immunoglobulin and mucin domain-containing molecule-3. In the present study, we investigated expression of the PD-1 ligand 1 (PD-L1) in a lymphoma microenvironment using paraffin embedded tissue samples, and subsequently studied the detailed mechanism of up-regulation of PD-L1 on macrophages using cultured human macrophages and lymphoma cell lines. We found that macrophages in lymphoma tissues of almost all cases of adult T-cell leukemia/lymphoma (ATLL), follicular lymphoma, and diffuse large B-cell lymphoma expressed PD-L1. Cell culture studies showed that the conditioned medium of ATL-T and SLVL cell lines induced increased expression of PD-L1/2 on macrophages, and that this PD-L1/2 overexpression was dependent on activation of signal transducer and activator of transcription 3 (Stat3). In vitro studies including cytokine array analysis showed that IL-27 (heterodimer of p28 and EBI3) induced overexpression of PD-L1/2 on macrophages via Stat3 activation. Since lymphoma cell lines produced IL-27B(EBI3) but not IL-27p28, it was proposed that the IL-27p28 derived from macrophages and the IL-27B(EBI3) derived from lymphoma cells formed an IL-27(heterodimer) that induced PD-L1/2 overexpression. Although the significance of PD-L1/2 expressions on macrophages in lymphoma progression has never been clarified, an IL-27-Stat3 axis might be a target for immunotherapy for lymphoma patients. This article is protected by copyright. All rights reserved.
Tuesday, August 16, 2016 1:45 PM|Xiang, M., Kim, H., Ho, V. T., Walker, S. R., Bar-Natan, M., Anahtar, M., Liu, S., Toniolo, P. A., Kroll, Y., Jones, N., Giaccone, Z. T., Heppler, L. N., Ye, D. Q., Marineau, J. J., Shaw, D., Bradner, J. E., Blonquist, T., Neuberg, D., Hetz, C., Stone, R. M., Soiffer, R. J., Frank, D. A.|BLOOD First Edition Papers|Labels: STAT

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically-available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron™), an FDA-approved anti-microbial, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor, but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130 (gp130), which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically-accessible STAT3 inhibitor with evidence of anti-cancer efficacy in both animal models and humans.

Sunday, August 14, 2016 10:05 PM|Han, T. J., Choi, E. J., Cho, B. J., Song, S. H., Paek, S. H., Kim, I. A.|Clinical Cancer Research recent issues|Labels: STAT, brain cancer

Background and purpose: Despite aggressive treatment with radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential of targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome of glioblastoma.

Material and methods: We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188 combined with temozolomide and radiation in vitro assays using two established glioblastoma cell lines (U251, U87) and two patients-derived glioblastoma cell lines (GBL12, GBL28) and in vivo studies using nude mice bearing intracranial U251 xenografts.

Results: Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cell which has high levels of p-STAT3 expression. Increased radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and the reversion of epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth both alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 of GBL28 cell which was originated from a patient with high level of STAT3 expression and unmethylated MGMT.

Conclusion: Targeting STAT3 using Cpd188 could be a viable therapeutic approach to improve the outcome of current standard therapy for glioblastoma patients having high p-STAT3 expression regardless of MGMT methylation status.

*Work supported by the grant (#2013R1A1A2074531) from the Ministry of Science, ICT & Future Planning to In Ah Kim

Citation Format: Tae Jin Han, Eun Jung Choi, Bong Jun Cho, Sang Hyuk Song, Sun Ha Paek, In Ah Kim{Authors}. Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model. [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 B46.

Sunday, July 31, 2016 10:05 PM|Solary, E.|Clinical Cancer Research recent issues|Labels: STAT, CML

The proliferative component of chronic myelomonocytic leukemia, related to an increased sensitivity of myeloid progenitors to granulocyte macrophage–colony stimulating factor, suggests dedicated therapeutic approaches. In this issue, ruxolitinib, a JAK1 and -2 inhibitory drug, is shown to induce objective responses in chronic myelomonocytic leukemia patients. Clin Cancer Res; 22(15); 3707–9. ©2016 AACR.

See related article by Padron et al., p. 3746

Thursday, July 28, 2016 7:56 AM|Metz, H. E., Kargl, J., Busch, S., Kim, K.-H., Houghton, M.|Cancer Research recent issues|Labels: RAS, STAT, lung cancer
Lung cancer is the leading cause of cancer deaths worldwide. In the United States alone, lung cancer accounts for ~160,000 deaths per year while the five-year survival rate remains stagnant at ~15%. Lung adenocarcinoma (ADCA) accounts for over 50% of non-small lung cancer cases. Within this subset, K-ras is the most common activating mutation accounting for ~35% of cases. Kras mutant tumors have remained a largely un-targetable subtype and a better understanding of the signaling pathway involved in the different ADCA subtypes will be necessary for the development of therapeutics. Insulin Receptor Substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many of the pathways that are activated in lung cancer. We have undertaken a controlled study of this protein within the context of lung ADCA. Analysis of a well-annotated human lung ADCA TMA (n=136) revealed that positive IRS-1 staining provided a 75-month median survival advantage among all ADCA cases (p=0.01) and an 81-month median advantage within the K-ras subtype (p=0.006). EGFR and non-K-ras/non-EGFR cases did not display differences. To focus in on the K-ras subtype, we generated LSL-K-ras/IRS-1fl/fl mice and studied them over a time course. LSL-K-ras/IRS-1-/- mice displayed highly significant early mortality (p<0.0001) and increased tumor burden when compared to LSL-K-ras/IRS-1+/+ controls (p<0.01). Interestingly, IRS-1 loss in tumor cells generated a robust immune response. The bronchial alveolar lavage fluid of LSL-K-ras/IRS-1-/- mice showed increased immune infiltration, most prominently neutrophilic (5 times higher). Significant increases in many immune cell-recruiting chemokines were observed in the LSL-K-ras/IRS-1-/- mice compared to controls including CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL5. Surprisingly, an array of IRS-1 silenced A549 cells versus controls displayed no change in CC/CXC chemokine production. We decided to investigate which factor could be missing in our in vitro system that is necessary for activation of this chemokine response. IL-17 and IL-22 producing cells, which are present at sites of tumor in human lung cancer cases and LSL-K-ras mice are known to induce CC/CXC chemokine responses. The JAK/STAT pathway is also implicated in this response. We found that loss of IRS-1 increases pSTAT3 production in vivo and in vitro in the presence of IL-22. Finally, we treated LSL-K-ras/IRS-1-/- and LSL-K-ras/IRS-1+/+ controls with a JAK inhibitor (AZD1480). A significant reduction in tumor burden and chemokine response was observed in both genotypes, with the most pronounced response in the LSL-K-ras/IRS-1-/- group. K-ras mutant, IRS-1-low patients represent ~40% of K-ras mutant lung ADCA patients. The phenotype of this group of patients is counter-intuitive in that IRS-1 typically functions in a pro-growth manner. In the setting of certain oncogenic drivers, however, IRS-1 plays an opposing role to this in which its presence actually maintains homeostasis. This work provides evidence that JAK inhibition may be a viable therapeutic option for these patients as well as describes a novel role for IRS-1 as a mediator of immune cell recruitment in lung adenocarcinoma.Citation Format: Heather E. Metz, Julia Kargl, Stephanie Busch, Kyoung-Hee Kim, McGarry Houghton. Novel pro-host role for insulin receptor substrate-1 in lung adenocarcinoma. [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 B26.
Tuesday, July 19, 2016 9:22 AM|Wang, W.-J., Li, C.-F., Chu, Y.-Y., Wang, Y.-H., Hour, T.-C., Yen, C.-J., Chang, W.-C., Wang, J.-M.|Clinical Cancer Research Online First Articles|Labels: EGFR, P-gp, STAT, bladder cancer

Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel (PTX) for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with PTX, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. Experimental Design: Loss-of-function assays were performed to elucidate the role of the epidermal growth factor receptor (EGFR) and transducer and activator of transcription 3 (STAT3) in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and PTX sensitivity. Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and PTX. Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and PTX by combination with either gefitinib or S3I-201.

Thursday, June 30, 2016 11:00 PM|Hosh, Mona; Antar, Sarah; Nazzal, Ahmed; Warda, Mahmoud; Gibreel, Ahmed; Refky, Basel|International Journal of Gynecological Cancer - Current Issue|Labels: STAT, leiomyosarcoma, uterine cancer
imageObjective: The aim was to study the incidence and survival of patients with uterine sarcoma diagnosed in the period from 2000 to 2012 based on Surveillance, Epidemiology, and End Results (SEER) database. Methods: All 18 registries of the SEER database were used to select cases. We included women aged 30 years or older diagnosed with uterine sarcoma. Histological subtypes were defined as leiomyosarcoma, carcinosarcoma, stromal sarcoma, adenosarcoma, and sarcoma not otherwise specified according to the 2003 World Health Organization classification. Using SEER*Stat software version 8.1.2. We calculated the age-adjusted incidence rates, extent of disease at time of diagnosis, and survival rates with different treatment modalities for white, black, and other races. Univariate and multivariate Cox proportional hazards analysis were done to examine factors affecting survival. Results: We identified 13,089 patients diagnosed with uterine sarcoma in the period from 2000 to 2012. The age-adjusted incidence rate for patients aged 50 years or older was more than that of younger patients (6.4/105 vs 1.5/105, P < 0.0001). Also, the age-adjusted incidence rate for black women was twice that of white women (7.3/105 vs 3.5/105, P < 0.0001). Carcinosarcoma was the most commonly diagnosed subtype followed by leiomyosarcoma. Women aged 50 years or older had worse survival than those younger than 50 years (hazard ratio, 1.78; 95% confidence interval, 1.64–1.92; P < 0.001). The overall survival of patients who had surgery with radiation was better than those who had surgery alone (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; P < 0.001). In women with localized disease, surgery was associated with better survival than surgery with radiation (66.4% vs 74.4%, P < 0.00001). Conclusions: Uterine sarcoma is an aggressive tumor that occurs more in old age and among women of black race. Poor survival was associated with old age, black race, and advanced disease stage. Radiotherapy in patients with localized stage does not improve the survival.
Monday, June 27, 2016 10:52 AM|SHAH, B. K., KANDEL, P., KHANAL, A.|Anticancer Research recent issues|Labels: STAT, liver cancer

Background/Aim: A second primary malignancy is a serious long-term complication in cancer survivors. The aim of this study was to evaluate the risk of second primary malignancies in patients with hepatocellular carcinoma (HCC). Materials and Methods: We selected adult patients (≥18 years) diagnosed with HCC from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) 13 database. We calculated the risk of second primary malignancies in these patients using multiple primary standardized incidence ratio (MP-SIR) session of SEER* stat software. Second primary malignancy was defined as a metachronous malignancy diagnosed 6 months or more after an index HCC. Results: A total of 15,296 patients with a diagnosis of primary HCC were reported in the SEER 13 registry during January 1992 to December 2011. A total of 446 (2.83%) developed 466 second primary malignancies with an observed/expected ratio of 10.07 (95% confidence interval=0.97-1.17, p=0.16) and absolute risk of 7.17 per 10,000 population. Risk of stomach and of thyroid cancer were significantly increased among older patients. Risk of lung cancer and of hepatobiliary cancer were significantly higher compared to that of the general population after two years of latency. Conclusion: Risk of specific second primary malignancies in adult patients with HCC depends on age of the patient and latency.

Wednesday, June 15, 2016 10:05 PM|Handle, F., Erb, H. H. H., Luef, B., Hoefer, J., Dietrich, D., Parson, W., Kristiansen, G., Santer, F. R., Culig, Z.|Molecular Cancer Research recent issues|Labels: AR, STAT, prostate cancer

The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor–positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor–mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.

Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574–85. ©2016 AACR.

Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: STAT, breast cancer

JAK2 focal amplifications are associated with reduced survival and resistance to chemotherapy.

Wednesday, March 16, 2016 4:34 PM|Cellular Physiology and Biochemistry|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: AKT, STAT, survivin, lung cancer
Conclusion: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.Cell Physiol Biochem 2016;38:1199-1208 (Source: Cellular Physiology and Biochemistry)
Thursday, March 10, 2016 4:00 PM|Gene|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: STAT, CRC
Authors: Zhongde Z, Aihua W, Hui L, Hui Z, Feng L Abstract Taxol (paclitaxel) is one of the taxane class of anticancer drugs as a first-line chemotherapeutic agent against many cancers including colorectal cancer, breast cancer, non-small cell lung cancer, ovarian cancer and so on. It is verified to induce cytotoxicity in a concentration and time-dependent manner. Numerous novel formulations of Taxol have been remanufactured for better therapeutic effect. Though Taxol works as a common anticancer drug for a long time in clinical practice, drug resistance is a major limitation of its long-term administration. In-depth research on drug resistance is still in progress and researchers have made some achievements, however, the mechanism or key molecule related to Taxol resistance in col...
Sunday, February 28, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Carcinoma in Situ|Comments|Labels: STAT, breast cancer
In conclusion, truncating mutations of Prlr drive tumor development in a model of human ERa+ breast cancer and should be considered as novel antitumor targets.Citation Format: Elaine Mardis, Obi L. Griffith, Ruby Chan Szeman, Malachi Griffith, Kilannin Krysiak, Zachary Skidmore, Jasreet Hundal, Julie A. Allen, Arthur Cora, Alexander P. Miceli, Heather Schmidt, Lee Trani, Krishna-Latha Kanchi, Christopher A. Miller, David E. Larson, Robert S. Fulton, Richard K. Wilson, Robert D. Schreiber. Genomics of a STAT1 knockout mouse model of human ER+ breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA20. (Source: Molecular Cancer Researc...
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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Friday, February 19, 2016 5:16 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: STAT, CRC, liver cancer
Authors: Chongqiang Z, Wenlong W, Wenying Y, David J, Yina W, Haiyan M, Hui X, Hua Q, Z, Jiagao L, Sheng L, Chenglong L, Jiayuh L, Li L Abstract Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated in human liver and colon cancer cells and is required for cancer cell viability, survival and migration. Therefore, inhibition of STAT3 signaling may be a viable therapeutic approach for these two cancers. We recently designed a non-peptide small molecule STAT3 inhibitor, LY5, using in silico site-directed Fragment-based drug design (FBDD). The inhibitory effect on STAT3 phosphorylation, cell viability, migration and colony forming ability by LY5 were examined in human liver and colon cancer cells. We demonstrated that LY5 inhibited constitutive Inter...
Friday, February 12, 2016 4:00 PM|Pharmacology and Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: STAT
Publication date: Available online 12 February 2016 Source:Pharmacology & Therapeutics Author(s): Edna Zhi Pei Chai, Muthu K. Shanmugam, Frank Arfuso, Arunasalam Dharmarajan, Chao Wang, Alan Prem Kumar, Ramar Perumal Samy, Lina H.K. Lim, Lingzhi Wang, Boon Cher Goh, Kwang Seok Ahn, Kam Man Hui, Gautam Sethi Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. The current...
Saturday, January 30, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: STAT, brain cancer, breast cancer, prostate cancer
STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid–based and benzoic acid–based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src–transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of ...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: STAT, prostate cancer
Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many cancer cell lines, leading to survival, proliferation, angiogenesis and metastasis. The inhibition of STAT3 by natural or synthetic compounds has been shown to sensitise cancer cell lines to the chemotherapy agent cisplatin, however the molecular mechanisms contributing to this chemosensitisation have not yet been fully elucidated. Therefore we investigated the effect of STAT3 inhibition on cisplatin-induced DNA damage and key DNA repair factors.STAT3 inhibitors stattic and curcumin were investigated in combination with cisplatin using the Suphorhodamine B cell growth inhibition assay in the DU145 prostate cancer and A549 non-small cell lung cancer cell lines. Combination treatments result in a s...