Oncology Intelligence


VEGF is a sub-family of the PDGF family of growth factors. VEGF is a glycoprotein that stimulates vasculogenesis and angiogenesis. VEGF's normal function is to create new blood vessels. VEGF includes proteins from two families that result from alternate splicing of mRNA from a single, 8-exon, VEGF gene. The two different families are referred to according to their terminal exon (exon 8) splice site - the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb). In addition, alternate splicing of exon 6 and 7 alters their heparin-binding affinity, and amino acid number.(1) All members of the VEGF family stimulate cellular responses by binding to TYK receptors, VEGFRs on the cell surface, causing them to dimerize and become activated through transphosphorylation. The VEGF receptors belong to the Ig superfamily. VEGF receptors possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. The VEGF receptors have an extracellular portion consisting of 7 Ig-like domains, a single transmembrane spanning region, and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).(2) VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 may modulate VEGFR-2 signaling, may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.(3) VEGF-C and VEGF-D, but not VEGF-A, are ligands for VEGFR-3, which mediates lymphangiogenesis. VEGFR3 is the site of binding of main ligands (VEGFC and VEGFD), which mediates perpetual action and function of ligands on target cells. VEGF-C can stimulate lymphangiogenesis (via VEGFR3) and angiogenesis via VEGFR2. FGF2 and HGF are potent angiogenic factors. VEGF-A has effects vascular endothelium, monocyte/macrophage migration, neurons, cancer cells, and kidney epithelial cells. In vitro, VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.(1)
VEGFxxx production can be induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces HIF, HIF, a transcription factor. HIF stimulates the release of VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a TYK Pathway leading to angiogenesis. The expression of Ang-2 in the absence of VEGF leads to endothelial cell death and vascular regression. HIF1 α and HIF1 β are constantly being produced but HIF1 α is highly O2 labile, so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 α persists and the HIF1α/β complex stimulates VEGF release.(1) Once released, VEGFxxx may elicit several responses. It may cause a cell to survive, move, or further differentiate.(1)
VEGF is induced in growing tumors and stimulates EC proliferation and migration primarily through VEGFR2, Flk1/KDR.(4) VEGFxxx has been implicated with poor prognosis in BC. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch.(1) VEGF-D serum levels are significantly elevated in patients with angiosarcoma.(1, 5) VEGF is secreted by tumor cells, in a hypoxia-inducible manner, and it binds to VEGFR-2 to increase proliferation and survival of vascular endothelial cells.(6)
VEGF inhibitors can reduce the growth of primary tumors, but can also concomitantly promote invasiveness and metastasis of tumors.(1, 7) Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.(8) NRP1 is a membrane-bound co-receptor to a tyrosine kinase receptor for both VEGF and semaphorin family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion.(9)

Marketed Drugs
Generic Code Old Code Brand Company Indication trials
aflibercept, ziv-aflibercept AVE0005 VEGF-Trap, Zaltrap Sanofi Mkt: CRC; P3: ovarian, NSCLC, PC, pancreatic (Terminated); P2: rectal, bladder, RCC, MM, leukemia, HNN, melanoma, BC, solid, endometrial, MDS; P2: brain, lymphoma, myelodysplasia, RCC, urothelial; P1: NHL trials
axitinib AG-013736 Inlyta Pfizer Mkt: RCC; P3: pancreatic; P2: solid, GBM, CRC, adrenal, HNN, HCC, thyroid, melanoma, PC, NET, BC, MDS, AML, NSCLC; P1/2: mesothelioma; P1: gastric trials
bevacizumab RG00000435 RO4876646 Avastin Roche Mkt: GBM, NSCLC, CRC, RCC, ovarian, cervical; P3: BC, pancreatic, GIST, NET, mesothelioma, HNN, lymphoma, osteosarcoma, PC; P2: MM, HCC, bladder, leukemia, sarcoma, melanoma, esophageal, endometrial, solid trials
cabozantinib BMS-907351 XL184 Cometriq BMS Mkt: thyroid; P2: NSCLC, brain, BC, melanoma, gastric, pancreatic, HCC, ovary, PC, GBM, solid; P1: lymphoma, RCC trials
dasatinib, desatinib BMS-354825 Sprycel BMS Mkt: CML, Ph+ ALL; P3: PC; P2: BC, CLL, MDS, NSCLC; P1/2: GBM, leukemia, melanoma, NHL, scleroderma; P1: CRC, mesothelioma, MM trials
nintedanib BIBF1120 Vargatef, Ofev Boehringer Ingelheim Mkt: NSCLC; P3: ovarian, CRC; P2: HCC, PC, ovarian, SCLC, glioma, GBM, endormetrial, fallopian, methothelioma, esophaphageal, thyroid; P1/2: AML, P1: solid, MM trials
pasireotide SOM230 Signifor Novartis Mkt: Cushing's; P3: pancreatic, HCC; P2: PC, thyroid, BC, RCC, SCLC, pituitary, melanoma, MM; P1: gastric trials
pazopanib GW786034 SB-786034 Votrient, Armala, Patorma GSK Mkt: sarcoma, RCC; P3: ovarian; P2: brain, BC, cervical, endometrial, HCC, NSCLC, mesothelioma, MM, nasopharyngeal, neuroendocrine, PC, thyroid, urothelial, CNS, gastric, HNN, melanoma, bladder, NET; P1: CRC, solid, lymphoma, SCLC trials
ramucirumab IMC1121B LY3009806 Cyramza Eli Lilly Mkt: gastric, NSCLC; P3: BC, HCC, NSCLC, CRC; P2: RCC, melanoma, PC, ovary, GBM; P1: solid, stomach trials
regorafenib BAY 73-4506 Stivarga Bayer Mkt: GIST, CRC; P3: HCC; P2: esophageal, pancreatic, biliary, liposarcoma, ovarian, fallopian, Ewing's, cholangiocarcinoma; P1: solid trials
sorafenib BAY 43-9006 Nexavar Bayer Mkt: HCC, thyroid, RCC, angiosarcoma; P3: BC, NSCLC, pancreatic, melanoma; P2: ovarian, GIST, bladder, sarcoma, GBM, CRC, PC, MM, cervical, esophageal, HNN, lymphoma, leukemia; P1: glioma trials
sunitinib SU011248 PNU 290940 Sutent Pfizer Mkt: RCC, GIST; P3: NSCLC, BC, pancreatic, CRC, HCC, PC; P2: bladder, biliary, astrocytoma, CNS, ovary, thyroid, sarcoma, melanoma, MM, NET, lymphoma, leukemia, HNN, esophageal, cervical, bladder, stomach, endometrial trials
vandetanib ZD6474 Caprelsa, Zictifa, Zactima AstraZeneca Mkt: thyroid; P3: lung (Discontinued for NSCLC); P2: CRC, BC, HCC, PC, HNN, CNS, ovarian, fallopian, GIST, bladder, esophageal, mesothelioma, RCC; P1: solid, pancreatic trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
brivanib BMS-582664 BMS-540215 BMS Filed: HCC; P3: CRC, HCC; P2: NSCLC, sarcoma, cervical, endometrial, RCC, bladder, pancreatic, gastric; P1: solid trials
plitidepsin Aplidin PharmaMar Filed/not approved: MM (orphan EU), lymphoma; P2: PC, leukemia, lymphoma; P1: solid trials
telatinib BAY 57-9352 Bayer Filed/orphan status approved: P2: gastric cancer (one trial) trials
lenvatinib E7080 Eisai P3: thyroid, HCC; P2: endometrial, melanoma, NSCLC; P1/2: RCC, ovarian; P1: solid, lymphoma trials
dovitinib TKI258 CHI258 Novartis P3: RCC; P2/3: solid; P2: HCC, CRC, pancreatic, bladder, GBM, GIST, mesothelioma, melanoma, PC, thyroid, BC, urothelial, NSCLC; P1: AML trials
apatinib YN968D1 Advenchen P3: NSCLC, HCC, CRC (China), BC (China); P2/3: gastric, P2: BC; P1: solid trials
endostatin BAY 86-5274 MS-275, M2ES, NDX-275, MORAb-004 Endostat, Endostar, rhEndostatin Bayer P3: NSCLC, BC; P2/3: nasopharyngeal; P2: AML, MDS, HL, melanoma, SCLC, CRC, HNN, gastric, leukemia, solid, pancreatic trials
tesevatinib XL647 KD019 Kadmon, Exelixis P3: NSCLC (terminated); P2: BC, brain mets; P1: solid, esophageal (2014), stomach (2014), BC (2015) trials
motesanib AMG 706 Takeda, Amgen P3: NSCLC (failed); P2: thyroid, BC (failed), GIST (failed), ovarian (failed), fallopian (failed), neuroendocrine, solid; P1: lymphoma, CRC, pancreatic trials
cediranib AZD2171 Recentin AstraZeneca P3: NSCLC (discontinued). CRC (discontinued), GBM, CRC, ovarian (in combination), biliary; P2: sarcoma, gastric, solid, BC, cervical, neurofibroma, mesothelioma, PC, cholangiocellular, HCC, NSCLC, endometrial, AML, HNN, CLL, RCC, fallopian, melanoma, MDS, CNS, leukemia, neurofibromatosis; P1/2: thyroid; P1: rhabdoid trials
tivantinib ARQ 197 AV-951 ArQule P3: NSCL, HCC, RCC; P2: CRC, gastric, BC, ovarian, fallopian, peritoneal, germ, MM, GBM, pancreatic, PC; P12: mesothelioma, solid trials
linifanib ABT-869 RG3635 Abbvie P3: HCC; P2: NSCLC,CRC, BC, RCC; P1: solid trials
orantinib TSU-68 SU6668 Taiho P3: HCC (terminated; primary endpoint of overall survival was not met); P1: BC, CRC, gastric, RCC, solid, NCSCL (Japan) trials
vatalanib PTK787 ZK222584 Bayer P3: CRC; P2: MM, leukemia, brain, CNS, BC, NSCLC, NET, lymphoma, melanoma, mesothelioma, MDS, pancreatic, PC, cervical, solid trials
famitinib SHR1020 Jiangsu P3: CRC; P2: GIST, NSCLC, pancreatic, neuroendocrine, BC, nasopharyngeal; P1: solid trials
fruquintinib HMPL-013 Hutchison P3: CRC; P1: gastric, solid trials
anlotinib AL3818 Advenchen P2/3: NSCLC, CRC; P2: RCC; P1: HCC, solid trials
foretinib GSK1363089 XL880, GSK089 GSK P2:BC, RCC, HNN; P1/2: lung; P1: solid, HCC trials
icrucumab LY3012212 IMC18F1 Eli Lilly P2: urethral, RCC, CRC, BC; P1: solid trials
lucitanib E3810 AL3810 Eisai P2: NSCLC, BC; P1/2: solid trials
simtuzumab GS-6624 AB 0024 Gilead P2: MF, pancreatic, CRC trials
RO5520985 Roche P2: CRC; P1: solid trials
ENMD-2076 ENMD-981693 Entremed P2: BC, ovarian, HCC, fallopian; P1: hem, solid trials
BMS-690514 BMS P2: BC, NSCLC; P1: solid trials
golvatinib E7050 Eisai P1/2: solid, gastric (terminated), HNN, HCC trials
CM082 X-82 Challenge; Tyrogenex P1/2: pancreatic; P1: solid trials
MGCD265 Mirati (MethylGene) P1/2: NSCLC; P1: solid trials
rebastinib DCC-2036 Deciphera P1/2: CML; P1: solid trials
tanibirumab TTAC-0001 PharmAbcine P1: various trials
VGX-100 Circadian P1: various trials
TAK-593 Takeda P1: solid trials
anticalin, PEGylated PRS-050 AngioCal Pieris P1: solid trials
chiauranib CS 2164 Chipscreen P1: solid trials
henatinib Jiangsu P1: solid trials
sevacizumab Jiangsu P1: solid trials
IMC3C5 IMC31C1 Eli Lilly P1: solid trials
MNRP1685A Genentech P1: solid trials
VXM01 Vaximm P1: pancreatic trials
sulfatinib HMPL-012 Hutchison P1: NET, various trials
ALN-VSP02 Alnylam P1: HCC trials
4SC-203 SC 71710 4SC P1: AML (one trial, 2010) trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
oglufanide IM862 Cytran Last new trial started in 2001; P3: Kaposi; P2: ovarian, peritoneal, CRC (terminated) trials
elpamotide OTS102 Oncotherapy terminated; P2/3: pancreatic; P2 (Japan): biliary trials
azaspirane SK&F106615 Atiprimod Callisto, Gilead Last new trial 2007; P2: Neuroendocrine; P1/2: MM; P1: solid trials
pegdinetanib BMS-844203 CT-322 Angiocept BMS terminated; P2: NSCLC, CRC; P1: various trials
terameprocol EM-1421 Erimos Last new trial 2007; P2: brain; P1: leukemia, lymphoma, solid, glioma, cervical, HNN trials
AG-6013736 Pfizer Last new trial started in 2005; P2: thyroid trials
CP-547,632 Pfizer Last new trial started in 2004; P2: ovarian, fallopian, peritoneal; P1: lung trials
SU014813 Pfizer Last new trial started in 2006; P2: BC; P1: solid trials
XL820 Exelixis; GSK Last new trial started in 2007; P2: GIST; P1: solid trials
AEE788 Novartis Last new trial started in 2004; P1/2: GBM, brain, CNS; P1: various, solid trials
BMS-817378 BMS withdrawn; P1: solid trials
CEP-11981 SSR106462 Cephalon Last new trial started in 2007; P1: various trials
CYC116 Cyclacel terminated; P1: solid trials
JI-101 CGI-1842 Roche terminated: P1/2: neuroendocrine, ovarian, CRC, solid trials
JNJ-26483327 JNJ Last new trial started in 2006; P1: solid trials
LY6K Eli Lilly Last new trial started in 2007; P1: esophageal trials
OSI-930 Astellas (OSI) Last new trial started in 2007; P1: solid trials
PF-05057459 CVX-241 Pfizer terminated; P1: solid trials
PTC299 PTC terminated; P1/2: Kaposi; P1: brain, CNS, BC, various trials
RG1530 Roche Last trial started in 2007; P1: solid trials
TAS-115 Taiho P1 (Japan): solid trials
VEGFR1-1084 Noncorporate Last new trial 2007; P1/2: pancreatic trials

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Wednesday, September 21, 2016 4:25 AM|Reuters: Health News|Labels: VEGF, ovarian cancer
LONDON (Reuters) - AstraZeneca has pulled an application seeking European approval to sell its experimental cancer drug cediranib in combination with chemotherapy to treat ovarian cancer because of late-stage questions raised by regulators reviewing the product.
Purpose: Hepatic malignancies can easily develop resistance to antiangiogenic therapy, but the underlying mechanism remains poorly understood. This study explores whether antiangiogenic therapy influences the tumor vascular network and/or the vessels feeding the hepatic tumor. Methods: Mice implanted with Lewis lung carcinoma (LLC) cells were subcutaneously injected 3 times (once every other day starting 1 week after LLC implantation) with either an antiangiogenic agent [vascular endothelial growth factor (VEGF)-Trap] or control agent (bovine serum albumin) at a dose of 25 mg/kg before performing angiography. Hepatic arteriography and portography were performed using a vascular cast method with vascular latex. Results: Arteriography of the control-treated LLC-implanted mice showed marked staining of the mass with a prominent feeding artery, suggesting that the tumor is supplied by arterial perfusion. No significant staining was observed on portography. By contrast, 33% (n = 3/9) of the LLC-implanted mice treated with the antiangiogenic agent VEGF-Trap showed intratumoral staining during portography, indicating that these tumors received perfusion via the portal vein. Conclusion: Antiangiogenic treatment can induce rearrangement of the hepatic tumor vascular network to establish communication with the portal vein. This implies that hepatic tumors can develop resistance to antiangiogenic therapy by maintaining perfusion through portal venous perfusion.
J Vasc Res 2016;53:72-82
Friday, September 16, 2016 4:27 PM|Peng Guo, Jiang Yang, Di Jia, Marsha A. Moses, Debra T. Auguste|Theranostics|Labels: VEGF, breast cancer

Lipocalin 2 (Lcn2) is a promising therapeutic target as well as a potential diagnostic biomarker for breast cancer. It has been previously shown to promote breast cancer progression by inducing the epithelial to mesenchymal transition in breast cancer cells as well as by enhancing angiogenesis. Lcn2 levels in urine and tissue samples of breast cancer patients has also been correlated with breast cancer status and poor patient prognosis. In this study, we have engineered a novel liposomal small interfering RNA (siRNA) delivery system to target triple negative breast cancer (TNBC) via a recently identified molecular target, intercellular adhesion molecule-1 (ICAM-1). This ICAM-1-targeted, Lcn2 siRNA- encapsulating liposome (ICAM-Lcn2-LP) binds human TNBC MDA-MB-231cells significantly stronger than non-neoplastic MCF-10A cells. Efficient Lcn2 knockdown by ICAM-Lcn2-LPs led to a significant reduction in the production of vascular endothelial growth factor (VEGF) from MDA-MB-231 cells, which, in turn, led to reduced angiogenesis both in vitro and in vivo. Angiogenesis (neovascularization) is a requirement for solid tumor growth and progression, and its inhibition is an important therapeutic strategy for human cancers. Our results indicate that a tumor-specific strategy such as the TNBC-targeted, anti-angiogenic therapeutic approach developed here, may be clinically useful in inhibiting TNBC progression.

Friday, September 16, 2016 10:17 AM|Onclive Articles|Labels: mTOR, VEGF, kidney cancer
The European Commission has approved lenvatinib (Kisplyx) in combination with everolimus for patients with advanced renal cell carcinoma following 1 prior VEGF-targeted therapy.
Background and Aim: Lipopolysaccharide(LPS) could promote the progression of colorectal cancer, but the specific regulatory mechanisms are largely unknown. So, this study aim to clarify the mechanisms that LPS upregulated VEGFR-3, which promotes colorectal cancer cells migration and invasion with a mechanism of increased NF-#x03BA;B bind to the promoter of VEGFR-3. Methods: The present study examined the VEGFR-3 expression in colorectal cancer tissues and analyzed the relationship between the VEGFR-3 expression with clinical parameters. PCR, Western blot, CCK-8, colone formation assay, and Transwell assay detected that LPS promoted the migration and invasion and the role of VEGFR-3 in the process of colorectal carcinoma in vitro. Used the methods of promoter analysis, EMSA assay and ChIP assay to explore the mechanisms LPS increased the expression of VEGFR-3. Results: VEGFR-3 was significantly high expression in the colorectal cancer tissues. And the high expression was associated with the TNM stage and lymph node metastasis of colorectal cancer. LPS could promote the migration and invasion, which could be blocked by the neutralizing antibody IgG of VEGFR-3. And found that -159 nt to +65 nt was the crucial region of VEGFR-3 promoter. And detected that the NF-#x03BA;B was important transcription factor for the VEGFR-3 promoter. And LPS could increase NF-#x03BA;B binding to VEGFR-3 promoter and upregulated the expression of VEGFR-3 to exert biological functions. Conclusion: We have elucidated the relationship between LPS and the VEGFR-3 expression and revealed that VEGFR-3 play very important role in the process of LPS promoting the migration and invasion of colorectal cancer cells. Further illuminated the mechanism that LPS upregulated VEGFR-3 expression via increased NF-#x03BA;B bind to the promoter of VEGFR-3.
Cell Physiol Biochem 2016;39:1665-1678
Thursday, September 15, 2016 6:45 AM|Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., Grina, J. A., Halfmann, M. M., Maddie, M. A., Olive, S. R., Schlachter, S. T., Tan, H., Wang, B., Wang, K., Xie, S., Xu, R., Yang, H., Josey, J. A.|Cancer Research recent issues|Labels: HIF, VEGF, kidney cancer
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
Thursday, September 15, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: mTOR, VEGF, kidney cancer
The European Commission approved Kisplyx lenvatinib from Eisai Co. Ltd. (Tokyo:4523) in combination with Afinitor everolimus to treat advanced renal cell carcinoma (RCC) in patients previously treated with a VEGF inhibitor.In May, FDA approved the inhibitor of multiple VEGF receptor tyrosine kinases for the same indication. The drug is marketed for thyroid cancer in the U.S. and EU, and is known as Lenvima in some countries.Novartis AG (NYSE:NVS; SIX:NOVN) markets Afinitor, an oral mammalian target of rapamycin (mTOR; FRAP; RAFT1) protein inhibitor.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, prostate cancer
This pilot clinical trial studies cabozantinib in treating men with hormone-resistant prostate cancer. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, ovarian cancer, clinical trial
This randomized phase III trial studies olaparib or cediranib maleate and olaparib to see how well they work compared with standard platinum-based chemotherapy in treating patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer that has come back. Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate may stop the growth of ovarian, fallopian tube, or primary peritoneal cancer by blocking the growth of new blood vessels necessary for tumor growth. Drugs used in chemotherapy, such as carboplatin, paclitaxel, gemcitabine hydrochloride, and pegylated liposomal doxorubicin hydrochloride 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 olaparib or cediranib maleate and olaparib is more effective than standard platinum-based chemotherapy in treating patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, clinical trial
This trial will be the first study of axitinib in children and adolescents. The primary objective of this Phase 1 trial is to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of axitinib in pediatric patients with refractory solid tumors. Additional objectives include measurement of pharmacokinetic and pharmacodynamic parameters, description of the toxicity profile of this agent in children and adolescents, and assessment of response within the confines of a Phase 1 trial. A standard rolling 6 design will be used for dose escalation. Further development of axitinib will focus on development of a joint cooperative group (COG/ECOG) Phase 2 study of axitinib in pediatric, adolescent and young adult translocation renal cell carcinoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: MET, VEGF, liver cancer, clinical trial
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, kidney cancer, clinical trial
This protocol will generate safety data on nivolumab monotherapy for advanced Renal Cell Carcinoma (RCC) patients and will have as its primary objective, the assessment of high grade immune-mediated adverse events (IMAE) in this patient population treated with nivolumab. In addition to continuing the investigation of safety for RCC patients with clear cell histology and prior treatment with anti- vascular endothelial growth factor (VEGF) therapy, this study will explore the safety and efficacy data for RCC patients with non-clear cell histology and RCC patients with either histology and brain metastases.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, kidney cancer, clinical trial
The purpose of this study is to evaluate the progression free survival (PFS), based on investigator radiologic review, of AGS-16C3F compared to axitinib in subjects with metastatic renal cell carcinoma.
Wednesday, September 14, 2016 11:10 AM|Yi Lu, Xiongwen Zhang, Jun Zhang|Journal of Cancer|Labels: VEGF, breast cancer

p16-mediated inhibition of cancer cell proliferation and tumor suppression have been studied before,; the common consensus is that p16's cell-cycle arrest function plays a primary role in these actions, with some additional apoptotic induction by p16. However, other effects of p16 that may potentially contribute to p16-mediated anti-tumor ability have not been well studied. The emerging data including ours indicated that p16 contributes its anti-cancer ability by inducing tumor cells to senescence. Moreover, we showed that p16 inhibits breast cancer cell growth by inhibiting the VEGF signaling pathway and angiogenesis. In this study, we used adenoviral-mediated p16 expression (AdRSVp16) and breast cancer cell line MDA-MB-231 as the model to simultaneously analyze all these p16's anti-tumor functions. We demonstrated that adenoviral-mediated p16 expression exhibited multiple anti-tumor functions by simultaneously suppressing in vitro growth and in vivo angiogenesis of breast cancer cells, blocking cell division, as well as inducing senescence and apoptosis. The in vivo study implies that p16's effect on anti-angiogenesis may play a more significant role than its anti-cell proliferation in the overall suppression of tumor growth. These results suggest, for the first time, that AdRSVp16-mediated tumor suppression results from a combination of p16's multiple anti-tumor functions including p16's well-known anti-proliferation/cell division function, apoptotic and senescence induction function, and its lesser-known/under-investigated anti-angiogenesis function. These combined results strongly indicate that p16 gene therapy has a multi-module platform with different anti-tumor functions; therefore, this study justifies and promotes the viral-mediated p16 gene therapy as a promising and powerful treatment approach for cancer patients due to p16's multiple anti-tumor functions.

Wednesday, September 14, 2016 7:55 AM|BERTELLI, G., DREWS, F., LUTCHMAN-SINGH, K.|Anticancer Research current issue|Labels: VEGF, ovarian cancer

Bevacizumab has become a ‘community standard’ at many UK centres as part of first-line treatment of patients with ovarian cancer at high risk of progression [International Federation of Gynecology and Obstetrics (FIGO) stage IV, or suboptimally debulked stage III] based on the results of phase III trials such as ICON-7. Its impact in patients treated outside clinical trials is, however, still unknown. In this study, we investigated patient characteristics, treatment patterns, adverse events and progression-free survival in ‘real-world’ patients in South West Wales. A total of 60 patients, treated between 2012 and 2015, were included in the study. Patient characteristics were less favourable compared to the bevacizumab-treated high-risk group in the ICON-7 trial (median age: 66 vs. 60 years; stage IV: 58% vs. 42%; performance status 0: 18% vs. 41%); 75% had received neoadjuvant chemotherapy before starting bevacizumab. After a median treatment duration of 8 months (range=0-34 months), 45 patients (75%) had experienced disease progression and 34 (56.7%) had died. Median progression-free survival was 16 months (95% confidence interval=14.4-17.6 months). The most common toxicities consisted of proteinuria (66.7%, all grade 1) and grade 1-2 hypertension (15%). Cardiovascular incidents, two of which were fatal, occurred in 6.7% of patients. In conclusion, our study provides encouraging evidence that the routine use of bevacizumab as part of first-line treatment of patients with ovarian cancer at high risk of progression may be associated with outcomes comparable with those obtained in clinical trials.

Wednesday, September 14, 2016 3:30 AM|Takuji Okusaka, Taiga Otsuka, Hideki Ueno, Shuichi Mitsunaga, Rie Sugimoto, Kei Muro, Isao Saito, Yusuke Tadayasu, Kohei Inoue, Arsene-Bienvenu Loembé, Masafumi Ikeda|Cancer Science|Labels: FGFR, PDGF, VEGF, liver cancer, clinical trial
This phase I, dose-escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (Group I: AST and ALT ≤2x ULN and Child–Pugh score 5 [n=14] or 6 [n=2]) or moderate (Group II: Child–Pugh score 5–6 and AST or ALT >2x to ≤5x ULN [n=7] or Child–Pugh score 7 [n=7]); 22 patients had prior sorafenib treatment. Nintedanib was administered twice daily in 28-day cycles until disease progression or unacceptable adverse events, starting at 150 mg (Group I) or 100 mg (Group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose-limiting toxicities during Cycle 1 (Grade ≥3 non-hematological and Grade 4 hematological adverse events). No dose-limiting toxicities were reported during Cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of Group I and 21% of Group II had dose reductions. Median time to progression was 2.8 months (95% CI 1.05–5.52) for Group I and 3.2 months (95% CI 0.95–6.70) for Group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. ClinicalTrials. gov NCT01594125; 1199.120 This article is protected by copyright. All rights reserved.
Wednesday, September 14, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: MET, mTOR, VEGF, kidney cancer, regulatory
The European Commission approved Cabometyx cabozantinib from Exelixis Inc. (NASDAQ:EXEL) as monotherapy to treat advanced renal cell carcinoma (RCC) in patients previously treated with a VEGF inhibitor. The approval triggers a $60 million milestone payment to Exelixis from Ipsen Group (Euronext:IPN), which holds Cabometyx's rights outside the U.S., Canada and Japan (see BioCentury Extra, Feb. 29).Cabometyx is a tablet formulation of cabozantinib, a spectrum-selective kinase inhibitor of VEGF receptor 2 (VEGFR-2;KDR/Flk-1) and c-Met receptor tyrosine kinase (c-MET; MET; HGRF; c-Met proto-oncogene). It is approved in the U.S. for second-line treatment of RCC. Exelixis and Ipsen market a capsule form of cabozantinib as Cometriq for thyroid cancer.Exelixis gained $0.70 to $13.01 on Wednesday.
Tuesday, September 13, 2016 11:38 PM|Tiejun Li, Yuwen Xue, Guilan Wang, Tingting Gu, Yunlong Li, York Yuanyuan Zhu, Li Chen|Journal of Cancer|Labels: VEGF, liver cancer

Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments.

Tuesday, September 13, 2016 11:38 PM|Lichao Sun, Yipeng Wang, Hebao Yuan, Joseph Burnett, Jian Pan, Zhihua Yang, Yuliang Ran, Ila Myers, Duxin Sun|Journal of Cancer|Labels: VEGF, lung cancer

Background. Carboxypeptidase A4 (CPA4) belongs to a member of the metallocarboxypeptidase family, and its expression in lung cancer samples and clinical significance are still not investigated until now. In this study, we aimed to evaluate the level of CPA4 in non-small-cell lung cancer (NSCLC) samples and correlate its level with clinical outcome.

Methods. CPA4 gene expression in lung cancer tissues were analyzed by using the Oncomine database ( The expression of CPA4, Survivin and VEGF in lung cancer and adjacent normal tissues were evaluated by IHC using the corresponding primary antibodies on two different commercial tissue arrays (Shanghai Biochip Co., Ltd., Shanghai, China). Their levels in serum were determined by using commercial human enzyme-linked immunosorbent assay kits. We also examined their relations to clinicopathologic parameters, and explored the diagnostic and prognostic value in NSCLC.

Results. We identified an elevation of CPA4 in mRNA level and gene amplification in lung cancer tissues in comparison to normal lung tissues. High CPA4 expression was observed in 120/165 (72.7%) NSCLC samples, and significantly correlated with Tumor size, Depth of invasion, Lymph Node Metastasis, Stage, VEGF level and Survivin level. High CPA4 expression is associated with poor prognosis of NSCLC patients. Multivariable Cox regression analysis demonstrated that CPA4 expression was an independent prognostic factor. Furthermore, serum CPA4 level was also significantly higher in NSCLC patients than in healthy controls. Logistic regression analysis revealed that serum CPA4 and CYFRA21-1 level were the significant parameters for detecting NSCLC. Receiver operating characteristic curves (ROC) in NSCLC patients versus normal people yielded the optimal cut-off value was 2.70 ng/ml for CPA4 and 19 ng/ml for CYFRA21-1, respectively. The area under ROC curve (AUC) was 0.830 for the combination of the two tumor markers.

Conclusion. Our results demonstrated that overexpression of CPA4 in NSCLC is associated with an unfavorable prognosis, and serum CPA4 level combining with serum CYFRA21-1 level could be used to aid early detection of NSCLC.

Cabometyx™ (cabozantinib) is the first and only targeted therapy to improve Overall Survival (OS), Objective Response Rate (ORR), and Progression Free Survival (PFS) in RCC in METEOR randomized Ph...
Tuesday, September 13, 2016 8:19 PM|Shu-Dong Zhang, Ka Lai Leung, Cian M. McCrudden, Hang Fai Kwok|Journal of Cancer (RSS 2.0)|Labels: FLT, VEGF, brain cancer

Tumor cells require angiogenesis to deliver nutrients and oxygen to support their fast growth and metabolism. The vascular endothelial growth factor (VEGF) pathway plays an important role in promoting angiogenesis, including tumor-induced angiogenesis. Recent clinical trials have demonstrated the benefit of targeting VEGF in the treatment of glioblastoma. However, the prognostic significance of the expression of VEGFA and its receptors VEGFR1 (FLT1) and VEGFR2 (KDR) are still largely elusive. In the present study, we aimed to investigate the prognostic significance of these three factors, alone or in combination, in glioma patients. Gene mRNA expression was extracted from three independent brain tumor cohorts totaling 242 patients and the association between gene expression and survival was tested. We found that when VEGFA, FLT1 and KDR expressions were considered alone, only VEGFA demonstrated a significant association with patient survival. Patients with high expression of both VEGFA and either receptor had significantly worse survival than patients expressing both factors at a low level. Importantly, we found that those patients whose tumors overexpressed all three genes had a significantly shorter survival compared to those patients with a low level expression of these genes. Our results suggest that a high level expression of VEGFA and its receptors, both FLT1 and KDR, may be required for brain tumor progression, and that these three factors should be considered together as a prognostic indicator for brain tumor patients.

Tuesday, September 13, 2016 8:19 PM|Eun Jung Sohn, Gunho Won, Jihyun Lee, Sangyoon Lee, Sung-hoon Kim|Journal of Cancer (RSS 2.0)|Labels: HIF, VEGF, prostate cancer

Recently microRNAs (miRNAs) have been attractive targets with their key roles in biological regulation through post-transcription to control mRNA stability and protein translation. Though melatonin was known as an anti-angiogenic agent, the underlying mechanism of melatonin in PC-3 prostate cancer cells under hypoxia still remains unclear. Thus, in the current study, we elucidated the important roles of miRNAs in melatonin-induced anti-angiogenic activity in hypoxic PC-3 cells. miRNA array revealed that 33 miRNAs (>2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control. Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells. Consistently, melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells by qRT-PCR analysis. Of note, overexpression of miRNA3195 and miRNA374b mimics attenuated the mRNA levels of angiogenesis related genes such as HIF-1alpha, HIF-2 alpha and VEGF in PC-3 cells under hypoxia. Furthermore, overexpression of miRNA3195 and miRNA374b suppressed typical angiogenic protein VEGF at the protein level and VEGF production induced by melatonin, while antisense oligonucleotides against miRNA 3195 or miRNA 374b did not affect VEGF production induced by melatonin. Also, overexpression of miR3195 or miR374b reduced HIF-1 alpha immunofluorescent expression in hypoxic PC-3 compared to untreated control. Overall, our findings suggest that upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property induced by melatonin in hypoxic PC-3 cells.

Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: VEGF, CRC
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Petrov, A.; Minkov, G.; Nikolov, S.;...
Background : A series of factors of angiogenesis determine local progression and metastatic potential of several carcinoma. However, their prognostic role in clinical practice remains unclear. The aim of our study was to evaluate the prognostic si...
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Leongito, M.
Background : Preoperative treatment of resectable liver metastases from colorectal cancer (CRCacrnm1) is a matter of debate. The aims of this study were to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting and to expl...
Tuesday, September 13, 2016 2:05 PM|Artur Jurczyszyn, Jacek Czepiel, Grażyna Biesiada, Joanna Gdula-Argasińska, Dorota Cibor, Danuta Owczarek, William Perucki, Aleksander B. Skotnicki|Journal of Cancer|Labels: TGF, VEGF, MM

Background. In the last few years, it has been widely reported that proinflammatory and angiogenic cytokines are important for the development and progression of multiple myeloma (MM).

Objectives. To further validate and acquire more insight into this view we decided to check whether plasma levels of certain cytokines and their soluble receptors differ between MM patients and healthy subjects.

Patients and Methods. The study was conducted in 76 MM patients aged 22 to 77 years (60±10 years) and 35 healthy controls aged 20 to 63 years (33±10 years). Plasma levels of interleukin-6 (IL-6), b-fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), as well as soluble receptors for IL-6 (sIL-6R) and VEGF (sVEGF-R2) were measured using enzyme-linked immunosorbent assay (ELISA).

Results. Significantly higher plasma levels of IL-6 (13.65±42.61 vs. 1.04±1.12 pg/ml, p=0.006), HGF (2174±2714 vs. 648±130 pg/ml, p<0.001), b-FGF (7.92±10.78 vs. 2.54±5.38 pg/ml, p<0.001) and sIL-6R (37.1±14.2 vs. 25.3±6.4 ng/ml, p=0.003) were observed in MM patients vs. healthy controls, respectively. Plasma sVEGF-R2 was significantly lower in MM patients than in controls (7518±2119 vs. 8725±1281 pg/ml, respectively; p<0.001). We observed an inverse correlation between length of treatment and the level of sIL-6R, and TGF-β1 in plasma.

Conclusions. Plasma levels of HGF, b-FGF, IL-6 and sIL-6R in MM patients were higher ​​when compared to the control group. Antineoplastic therapy leads to a time-dependent decrease in plasma levels of sIL-6R, and TGF-β1 in MM patients. Blood plasma level of HGF is an optimal measure to differentiate patients in whom disease is progressing versus patients who respond to therapy.

Tuesday, September 13, 2016 2:05 PM|Yi Lu, Chikezie Madu, Jordan Masters, Andrew Lu, Liyuan Li|Journal of Cancer|Labels: HIF, VEGF

Breast cancer (BCa) is the most diagnosed cancer and the second leading cause of cancer death in the American women. Adaptation to the hypoxic environment seen in solid tumors is critical for tumor cell survival and growth. The activation of hypoxia inducible factor-1 alpha (HIF-1α), an important master transcriptional factor that is induced and stabilized by intratumoral hypoxia, stimulates a group of HIF-1α-regulated genes including vascular endothelial growth factor (VEGF), leading tumor cells towards malignant progression. Therefore, a promising therapeutic approach to cancer treatment is to target HIF-1α. The goal of this project was to develop and validate a screening system coupled with secondary screen/validation process that has the capability to screen large numbers of potential anti-cancer small-molecule compounds based on their anti-HIF-1α activities. Breast cancer MDA-231 cells were used as the model to select potent anti-HIF-1α compounds by their abilities to inhibit transactivation of a VEGF promoter fused to a luciferase reporter gene under hypoxia. Positive compounds were then validated by a series of assays that confirm compounds' anti-HIF-1α activities including measurement of HIF-1α downstream VEGF gene expression and angiogenic ability of BCa cells. Results of our pilot screening demonstrate that this prototype screening coupled with validation system can effectively select highly potent anti-HIF-1α agents from the compound library, suggesting that this prototype screen system has the potential to be developed into a high-throughput screen (HTS) coupled with automated validation process for the screening and identification of novel and effective anti-cancer drugs based on anti-HIF-1α mechanism.

Monday, September 12, 2016 6:00 PM|José Leone|International Journal of Molecular Sciences|Labels: CDK, EGFR, VEGF, breast cancer
The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.
Monday, September 12, 2016 1:07 PM|Benson, A. B., Kiss, I., Bridgewater, J., Eskens, F. A. L. M., Sasse, C., Vossen, S., Chen, J., Van Sant, C., Ball, H. A., Keating, A., Krivoshik, A.|Clinical Cancer Research Online First Articles|Labels: VEGF, CRC, clinical trial

Purpose: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab.

Experimental Design: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses.

Results: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693–1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies.

Conclusions: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 1–10. ©2016 AACR.

Sunday, September 11, 2016 11:00 PM|Aspeslagh, Sandrine; Awada, Ahmad; S. Matos-Pita, Arturo; Aftimos, Philippe; Bahleda, Ratislav; Varga, Andréa; Soria, Jean-Charles|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: VEGF, clinical trial
This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m2, n=3; 3.8 mg/m2, n=4; and 4.8 mg/m2, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m2 and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m2 for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Friday, September 2, 2016 4:50 AM|Shin Kumagai, Kei Ishibashi, Masao Kataoka, Toshiki Oguro, Yuichirou Kiko, Tomohiko Yanagida, Ken Aikawa, Yoshiyuki Kojima|Cancer Science|Labels: VEGF, kidney cancer
Heparan sulfate-specific endosulfatase-2, SULF-2, can modulate the signaling of HSPG-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCCs) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCCs with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCCs and low SULF-2 RCCs were 100% and 71.4%, respectively (log-rank p = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCCs with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling. This article is protected by copyright. All rights reserved.
Thursday, September 1, 2016 10:05 PM|Park, S. Y., Piao, Y., Jeong, K. J., Dong, J., de Groot, J. F.|Molecular Cancer Therapeutics current issue|Labels: VEGF, brain cancer

Periostin (POSTN) interacts with multiple integrins to coordinate a variety of cellular processes, including epithelial-to-mesenchymal transition (EMT) and cell migration. In our previous study, anti-VEGF-A therapy was associated with resistance and EMT. This study sought to determine the role of POSTN in the resistance of glioma stem cells (GSC) to antiangiogenic therapy. In mouse xenograft models of human glioma, POSTN expression was associated with acquired resistance to anti-VEGF-A therapy and had a synergistic effect with bevacizumab in prolonging survival and decreasing tumor volume. Resistance to anti-VEGF-A therapy regulated by POSTN was associated with increased expression of TGFβ1 and hypoxia-inducible factor-1α (HIF1α) in GSCs. At the molecular level, POSTN regulated invasion and expression of EMT (caveolin-1) and angiogenesis-related genes (HIF1α and VEGF-A) through activation of STAT3. Moreover, recombinant POSTN increased GSC invasion. Collectively, our findings suggest that POSTN plays an important role in glioma invasion and resistance to antiangiogenic therapy. Mol Cancer Ther; 15(9); 2187–97. ©2016 AACR.

Wednesday, August 31, 2016 10:05 PM|Fournier, P., Dussault, S., Fusco, A., Rivard, A., Royal, I.|Cancer Research recent issues|Labels: Src, VEGF
The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability, and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated postnatal angiogenesis and vascular permeability in a DEP-1–deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell–specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1–deficient mice. Furthermore, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1–deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment. Cancer Res; 76(17); 5080–91. ©2016 AACR.
Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: FLT, VEGF, melanoma

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Ji Yoon Lee, Seok-Ho Hong, Minsang Shin, Hye-Ryeon Heo, In Ho Jang The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis.

Sunday, August 14, 2016 10:05 PM|Tiper, I. V., Temkin, S. M., Spiegel, S., Goldblum, S. E., Giuntoli, R. L., Oelke, M., Schneck, J. P., Webb, T. J.|Clinical Cancer Research recent issues|Labels: VEGF, ovarian cancer

Purpose: Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell–mediated antitumor responses.

Experimental Design: To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer–associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA.

Results: Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses.

Conclusions: We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249–58. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Sarkaria, J. N., Calligaris, D., Ma, D., Parrish, K., Mladek, A. C., Laramy, J., Kim, M., Zhang, S., Schroeder, M., Carlson, B. L., Bakken, K., Johnson, A., Agar, N., Elmquist, W.|Clinical Cancer Research recent issues|Labels: VEGF, brain cancer

Clinical data indicate that certain regions within glioblastoma (GBM) have a relatively intact blood-brain barrier (BBB), but controversy surrounds whether associated heterogeneous delivery may limit efficacy for otherwise highly active drugs with poor brain distribution. In this study, the efficacy of molecularly targeted therapies was compared in relevant GBM patient-derived xenograft (PDX) models grown either as heterotopic or orthotopic tumors. The impact of further disrupting BBB integrity in non-responsive orthotopic tumors was evaluated by over-expressing vascular endothelial growth factor (VEGF) and measuring drug distribution by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The brain:plasma ratio for five targeted agents was determined by LC-MSMS and treatment efficacy was evaluated in target-relevant GBM PDX lines: erlotinib (brain:plasma = 0.02 ± 0.02; efficacy tested in GBM6), palbociclib (brain:plasma = 0.06; efficacy tested in GBM22), AZD1775 (brain:plasma = 0.05; efficacy tested in GBM22), SAR405838 (brain:plasma = 0.01 ± 0.003; efficacy tested in GBM108), and AZD4547 (brain:plasma = 0.045 ± 0.02; efficacy tested in GBM150). Each of these drugs was effective in relevant GBM PDX flank tumor models with a 27% to 218% prolongation in the median time to exceed their pre-specified endpoint compared to placebo treatment (p≤0.02 for each drug). In contrast, none of these drugs were effective in prolonging survival in the same target-relevant orthotopic tumor models (-6% to 8% extension in median survival; p>0.05 for each drug). Consistent with partial and heterogeneous disruption of the BBB, MALDI-MSI of erlotinib, AZD1775 or SAR405838 distribution within orthotopic tumors demonstrated highly heterogeneous drug levels with large regions within each tumor approaching the low drug levels observed within surrounding normal brain. To further evaluate whether heterogenous drug distribution in orthotopic tumors could account for poor treatment efficacy, GBM108 was transduced with lentiviral constructs encoding for VEGF or empty vector (EV). While both GBM108-sublines were readily detectable with gadolinium-enhanced magnetic resonance imaging (MRI), the GBM108-VEGF tumors had a significantly more disrupted BBB, as evidenced by a more uniform and intense distribution of a brain-impenetrant TexasRed-dextran vascular marker. Similarly, the distribution of SAR405838, measured by MALDI-MSI, was markedly higher and more uniform in the GBM108-VEGF tumors when compared to the GBM108-EV tumors. Enhanced delivery of SAR405838 into orthotopic GBM108-VEGF models translated into a marked enhancement in treatment efficacy in comparison to GBM108-EV with a median survival prolongation of 37 vs. 4 days, respectively (p=0.0055). Collectively, these data highlight the importance of testing novel therapeutic agents in orthotopic tumor models and suggest that limited brain penetration for many molecules may significantly limit their efficacy in brain tumors that have a partially intact BBB. In the face of continued failure to develop effective targeted agents for GBM, these in vivo results highlight the importance of re-evaluating the dogma in neuro-oncology that the BBB is fully disrupted in GBM and, therefore, drug delivery across the BBB is not a major factor limiting treatment efficacy.

Citation Format: Jann N. Sarkaria, David Calligaris, Daniel Ma, Karen Parrish, Ann C. Mladek, Janice Laramy, Minjee Kim, Shuangling Zhang, Mark Schroeder, Brett L. Carlson, Katrina Bakken, Aaron Johnson, Nathalie Agar, William Elmquist. The critical importance of the blood-brain barrier in modulating the response to otherwise highly effective targeted therapies in patient-derived orthotopic glioblastoma xenografts. [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 B25.

Sunday, July 31, 2016 10:05 PM|Morfoisse, F., Tatin, F., Hantelys, F., Adoue, A., Helfer, A.-C., Cassant-Sourdy, S., Pujol, F., Gomez-Brouchet, A., Ligat, L., Lopez, F., Pyronnet, S., Courty, J., Guillermet-Guibert, J., Marzi, S., Schneider, R. J., Prats, A.-C., Garmy-Susini, B. H.|Cancer Research recent issues|Labels: HSP, VEGF, lymphoma
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5′UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394–405. ©2016 AACR.
Thursday, July 28, 2016 1:46 PM|Onclive Colorectal Cancer Articles|Labels: FGFR, PDGF, VEGF, CRC, clinical trial
Axel Grothey, MD, discusses both the LUME-1 and LUME-2 trials, the differences between left and right tumors in colorectal cancer, and how that information could potentially be used in diagnosis and treatment.
Thursday, July 28, 2016 7:56 AM|Kang, Y. H., Jin, H. A., Heo, J. H., Kim, K. H., Han, K. S., Hong, S. J.|Cancer Research recent issues|Labels: VEGF, prostate cancer
Background: Tumor requires excessive oxygen and nutrients due to their rapid growth. Tumor is generally vascular but the vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of normalizing tumor vasculature on tumor progression and treatment efficacy of conventional chemotherapy in prostate cancer.Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunofluorescent confocal imaging with immunocytochemistry was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week.Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness and improved hypoxia were found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts.Conclusions: SAC-1004 improves hypoxic tumor microenvironment and restores abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization induced tumor regression and docetaxel combination following vascular normalization sensitized prostate cancer to docetaxel treatment.Citation Format: You Hyun Kang, Hyun A Jin, Jun Hyeok Heo, Ki Hong Kim, Kyung Seok Han, Sung Joon Hong. Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate 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 B19.
Thursday, July 28, 2016 7:56 AM|Yan, L., Sundaram, S.|Cancer Research recent issues|Labels: TNF, VEGF, lung cancer
Obesity is a risk factor for cancer. Adipose tissue is considered an endocrine organ that produces pro-inflammatory adipokines, e.g. monocyte chemotactic protein-1 (MCP-1), that may contribute to obesity-related malignant progression. This study investigated effects of MCP-1 deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice using a spontaneous metastasis model. The high-fat diet (45% of energy from fat) significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet (16% of energy from fat). Deficiency of MCP-1 reduced the number of lung metastases by 37% (p < 0.05) in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% (p < 0.05) and volume by 69% (p < 0.05) compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts, but they were not detectable in MCP-1 deficient mice regardless of diets. Plasma concentrations of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly higher in MCP-1 deficient mice than in wild-type mice. We conclude that adipose-produced MCP-1, at least partly, contributes to high-fat diet-enhanced metastasis and suggest that the overproduction of inflammatory cytokines (PAI-1, TNF-α) and angiogenic factors (VEGF, TIMP-1) in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.Citation Format: Lin Yan, Sneha Sundaram. Effects of monocyte chemotactic protein-1 deficiency on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. [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 C33.
Wednesday, July 27, 2016 11:11 AM|KARLIKOVA, M., TOPOLCAN, O., NARSANSKA, A., KUCERA, R., TRESKOVA, I., TRESKA, V.|Anticancer Research recent issues|Labels: VEGF, breast cancer

Aim: To evaluate the possibility of selected biomarkers for breast cancer diagnostics and/or treatment monitoring, lymph node (LN) status determination and clinical decision regarding axillary node dissection. Patients and Methods: Two hundred and eleven patients with malignant breast cancer and 42 age-matched healthy controls were enrolled. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and plasma epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG) and osteopontin (OPN) were measured. We compared patients versus controls, patients with negative versus positive lymph node and patients with and without axillary lymph node dissection (ALND). Results: We found elevated IGF1 and VEGF levels in patients with lymph node metastases compared to controls (p=0.0179 and p=0.0091, respectively) and in patients with ALND (p=0.0337 and p=0.0438, respectively). Conclusion: Circulating IGF1 and VEGF levels may predict the presence of lymph node metastases and help in the decision to avoid ALND in patients with early-stage breast cancer.

Wednesday, July 27, 2016 11:11 AM|ILHAN, N., GUNGOR, H., GUL, H. F., EROKSUZ, H.|Anticancer Research recent issues|Labels: TGF, VEGF, CRC

Background/Aim: Endoglin (CD105) is a receptor for the transforming growth factor-beta 1 (TGFβ1) with crucial role in vascular development and angiogenesis. Additionally, vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival for several cancer types. These molecules have been shown to be useful markers for identifying proliferating endothelium involved in tumor angiogenesis, especially in patients with cancer at risk of developing metastases. The aim of this study was to evaluate the relationship between VEGF and endoglin expression in an experimental model of colorectal cancer, as well as to investigate the effect of cyclooxygenase-2 (COX2) inhibitors on tumor development incidence. Materials and Methods: Colon cancer was induced with 1,2-dimethylhydrazine dihydrochloride (DMH). Celecoxib and diclofenac treatment was started simultaneously with DMH induction. Endoglin protein expression was performed using western blot analysis. VEGF plasma concentrations were measured by enzyme-linked immunosorbent assay. Results: In histopathological evaluations, no pathological change was observed in control rats, while adenocarcinoma (62.5%), dysplasia (31.25%) and inflammation (6.25%) were detected in the group given DMH. In treatment groups, a marked decrease was observed in adenocarcinoma rate. Expression of endoglin protein was significantly elevated in the DMH group compared to controls (p<0.001). No statistically significant difference was noted between treatment groups and DMH group regarding endoglin expression but a decrease was detected in the celecoxib-treated groups. Conclusion: It was confirmed by histopathology and western blotting that COX2 inhibitors, particularly celecoxib, decrease the rate of disease and slow-down progression of existing CRC. These data show that endoglin expression may have an important role in tumor angiogenesis and predict of tumor invasion.

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on anticancer agent lenvatinib mesylate (generic name, “lenvatinib”) in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF) targeted therapy. If approved, lenvatinib will be launched under the brand name Kisplyx(R) for this indication.
Wednesday, July 20, 2016 9:31 AM|Duran, R., Mirpour, S., Pekurovsky, V., Ganapathy-Kanniappan, S., Brayton, C. F., Cornish, T. C., Gorodetski, B., Reyes, J., Chapiro, J., Schernthaner, R. E., Frangakis, C., Lin, M., Sun, J. D., Hart, C. P., Geschwind, J.-F.|Clinical Cancer Research Online First Articles|Labels: VEGF, liver cancer

Purpose: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intraarterial therapy (HAIAT) with evofosfamide in a rabbit model. Experimental Design: VX2-tumor-bearing rabbits were assigned to 4 intraarterial therapy (IAT) groups (n=7/group): 1) saline (control); 2) evofosfamide (Evo); 3) doxorubicin-Lipiodol emulsion followed by embolization with 100-300μm beads (conventional, cTACE); or 4) cTACE and evofosfamide (cTACE+Evo). Blood samples were collected pre-IAT and 1/2/7/14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia and metabolism were quantified (-H2AX/annexin V/caspase-3/Ki-67/HIF1α/VEGF/GAPDH/MCT4 and LDH). Results: cTACE+Evo showed a similar profile of liver enzymes elevation and pathologic scores compared to cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE+Evo demonstrated smaller tumor volumes, lower tumor growth rates and higher necrotic fractions compared to cTACE. cTACE+Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE+Evo promoted antitumor effects as evidenced by increased expression of -H2A.X, apoptotic biomarkers and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT. Conclusions: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer.

Friday, July 15, 2016 9:26 AM|De Robertis, M., Loiacono, L., Fusilli, C., Poeta, M. L., Mazza, T., Sanchez, M., Marchionni, L., Signori, E., Lamorte, G., vescovi, A. L., Garcia-Foncillas, J., Fazio, V. M.|Clinical Cancer Research Online First Articles|Labels: EGFR, FAK, VEGF, CRC

Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks including EGFR, FAK and VEGF pathways, with which it collaborates to stimulate cell migration, invasion and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular crosstalk and microRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in CRC patients. Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results: We identified a gene expression pattern (EphA2, Efna1, EGFR, Ptpn12, Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/EGFR gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/EGFR genes, linked to a possible control by mir-200a and mir-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

Monday, July 11, 2016 1:55 PM|Horikawa, N., Abiko, K., Matsumura, N., Hamanishi, J., Baba, T., Yamaguchi, K., Yoshioka, Y., Koshiyama, M., Konishi, I.|Clinical Cancer Research Online First Articles|Labels: VEGF, ovarian cancer

Purpose:High vascular endothelial growth factor (VEGF) expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSCs), in ovarian cancer. Experimental Design:High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and immunohistochemistry for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. Additionally, the therapeutic effects of anti-Gr-1 antibodies were examined. Results:Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocytes-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment. Conclusions:VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis.

Thursday, June 30, 2016 11:00 PM|Rose, Peter G.; Mahdi, Haider; Jernigan, Amelia; Yang, Bin|International Journal of Gynecological Cancer - Current Issue|Labels: VEGF, ovarian cancer
imageObjectives: The aim of this study was to evaluate the antitumor activity of bevacizumab in low-grade serous ovarian carcinoma (LGSOC). Methods: We retrospectively identified patients with LGSOC treated with bevacizumab. Results: Twelve patients with LGSOC who received bevacizumab were identified. Eleven patients received bevacizumab alone. Only 1 (8.3%) of 12 patients had evidence of a partial response. Ten (90.9%) of the 11 patients were progression free at 6 months. All but 1 patient who received only 2 courses before treatment interruption had a progression-free survival (PFS) of greater than 6 months. The median PFS was 48 months (range, 5–123+ months). Three of the patients reported in this series had extended disease stabilization that lasted for 123+, 48, and 15+ months after progression-free intervals on prior chemotherapy regimens of 2.5, 4, and 7 months, respectively. The median overall survival was not reached at a median follow-up of 32 months, with only 1 of the 12 patients dying of disease. Conclusions: In our series, in patients with LGSOC treated primarily with bevacizumab, primarily as a single agent, a low response rate but very long PFS is observed. In addition, patients have had secondary PFS durations that exceeded their prior PFS, which is a sign of anticancer activity.
Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: mTOR, VEGF, kidney cancer, regulatory

The FDA has approved the combination of lenvatinib and everolimus to treat advanced or metastatic renal cell carcinoma. The approval marks the first time that tyrosine kinase and mTOR inhibitors have been combined successfully as second-line treatment for renal cell carcinoma following prior VEGF-targeted therapy.

Sunday, June 19, 2016 1:00 AM|Anette Kargo, Parvin Adimi, Karina Dahl Steffensen|International Journal of Cancer Therapy and Oncology|Labels: VEGF, ovarian cancer

Treatment of multiresistant ovarian cancer is palliative and patients have needs for less toxic treatment. Anti-angiogenic treatments have a less toxic profile, and bevacizumab has shown improvement of progression free survival (PFS) in front-line trials. Bevacizumab is generally introduced in combination with chemotherapy; however this case report will describe the use of single-agent bevacizumab for more than five years (102 cycles) in a patient with relapse of advanced ovarian cancer.

Saturday, June 18, 2016 12:05 PM|Elsevier|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: MET, mTOR, VEGF, kidney cancer, clinical trial

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial

The Lancet Oncology, Vol. , No. (2016) pp. -
Publication date: Available online 5 June 2016 Source:The Lancet Oncology Author(s): Toni K Choueiri, Bernard Escudier, Thomas Powles, Nizar M Tannir, Paul N Mainwaring, Brian I Rini, Hans J Hammers, Frede Donskov, Bruce J Roth, Katriina Peltola, Jae Lyun Lee, Daniel Y C Heng, Manuela Schmidinger, Neeraj Agarwal, Cora N Sternberg, David F McDermott, Dana T Aftab, Colin Hessel, Christian Scheffold, Gisela Schwab, Thomas E Hutson, Sumanta Pal, Robert J Motzer Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p&lt;0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p&lt;0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.

Friday, June 17, 2016 11:15 PM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF
Patients with advanced or metastatic renal cell carcinoma derive a significant overall survival benefit from second-line treatment with the multi-tyrosine kinase inhibitor cabozantinib relative to everolimus.
CONCLUSIONSBoth HAT and HA‐HAT have promising activity in patients with HER2‐positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Tuesday, June 7, 2016 5:38 PM|Onclive Brain Cancer Articles|Labels: PD-1/PD-L1, VEGF, brain cancer
An immunotherapy/antiangiogenesis combination proved to be safe and tolerable for patients with recurrent glioblastoma, preliminary data from an ongoing trial showed.
Tuesday, June 7, 2016 6:23 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF, kidney cancer
Data presented today at the American Society of Clinical Oncology congress showed that cabozantinib, a next generation tyrosine kinase inhibitor (TKI) can extend the lives of patients by nearly two years following failure of one or more anti-angiogenic therapies almost five months longer than everolimus, a current standard of care therapy.
Monday, June 6, 2016 4:58 AM|TAMIYA, M., TAMIYA, A., YASUE, T., NAKAO, K., OMACHI, N., SHIROYAMA, T., TANI, E., HAMAGUCHI, M., MORISHITA, N., SUZUKI, H., OKAMOTO, N., OKISHIO, K., KAWAGUCHI, T., ATAGI, S., HIRASHIMA, T.|Anticancer Research recent issues|Labels: VEGF, lung cancer

Aim: Malignant effusion is associated with high serum and plasma levels of vascular endothelial growth factor (VEGF). There are no biomarkers of outcome for bevacizumab treatment in patients with malignant pleural effusion (MPE). We previously reported that carboplatin–paclitaxel plus bevacizumab was effective for patients with advanced non-squamous non-small cell lung cancer (NSCLC) and MPE, although we did not evaluate the relationship between treatment outcomes and plasma or pleural effusion levels of VEGF. Therefore, this study evaluated whether plasma or pleural effusion VEGF might predict bevacizumab treatment outcome. Patients and Methods: We enrolled 23 patients with NSCLC and MPE between September 2010 and June 2012. Plasma VEGF levels were measured in 19 patients and pleural VEGF levels were measured in 22 patients. Results: Compared to patients with a low plasma VEGF level, patients with a high level exhibited significantly shorter overall survival (OS: 13.8 vs. 6.5 months, p=0.04), progression-free survival (PFS: 8.7 vs. 4.8 months, p<0.01), and period to re-accumulation of MPE (pPFS: 9.7 vs. 6.2 months, p=0.02). Compared to patients with a low VEGF level in pleural effusion, patients with a high VEGF level exhibited significantly shorter OS (19.6 vs. 6.9 months, p<0.01) and pPFS (9.6 vs. 6.7 months, p=0.04), although there was no significant difference in their PFS (6.6 vs. 5.9 months, p=0.18). Conclusion: VEGF levels in the plasma and pleural effusion may predict the outcome of bevacizumab treatment in patients with NSCLC and MPE.

Monday, June 6, 2016 4:58 AM|NASIR, A., REISING, L. O., NEDDERMAN, D. M., FULFORD, A. D., UHLIK, M. T., BENJAMIN, L. E., SCHADE, A. E., HOLZER, T. R.|Anticancer Research recent issues|Labels: VEGF, CRC

Background: The vascular endothelial growth factor (VEGF) pathway plays an important role in growth and progression of human cancer, including colorectal carcinomas (CRC). The key mediators of VEGF signaling are VEGFR1, VEGFR2, and VEGFR3, part of a family of related receptor tyrosine kinases. The relative expression, activity, or interplay among these receptors may determine the response of CRC patients to anti-angiogenic therapies. Materials and Methods: We developed technically sound immunohistochemical (IHC) assays to quantify VEGFR1, 2 and 3, and using a well-annotated CRC tissue microarray (TMA), we carried out comprehensive comparative evaluation of the three VEGFRs in archival primary CRC tissues (n=84). For each TMA core, tumor cell VEGFR1 expression was reported as H-score (range=0-300); vascular VEGFR2/VEGFR3 expression was manually scored as the number of receptor-positive tumor stromal vessels. Each case was defined as VEGFR1/ VEGFR2/VEGFR3-negative, low, medium or high. Results: Based on the differential expression of the three VEGFRs, eight VEGFR staining profiles were observed: Triple VEGFR positive (n=12, 14%), VEGFR1 predominant (n=17, 20%), VEGFR2 predominant (n=7, 8%), VEGFR3 predominant (n=1, 1%), VEGFR1/2 predominant (n=39, 46%), VEGFR1/3 predominant (n=2, 2%), VEGFR2/3 predominant (n=3, 4%), and triple-VEGFR-negative (n=3, 4%). Conclusion: Herein we demonstrated heterogeneity of expression of VEGFRs in human CRC stromal vessels and tumor cells. The observed VEGFR expression-based subsets of human CRCs may reflect differences in biology of pathologic angiogenesis in primary CRC tissues. Furthermore, the heterogeneity of expression of VEGFRs unraveled in this analysis merits independent validation in larger cohorts of primary and metastatic human CRC tissues and in pertinent experimental models treated with various anti-angiogenic therapies.

Wednesday, June 1, 2016 8:50 PM|Peter Stopfer|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: FGFR, PDGF, VEGF

Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer
Claudia Dallinger Dirk Trommeshauser, Kristell Marzin, Andre Liesener, Rolf Kaiser, Peter Stopfer
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef®) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma NSCLC after first‐line chemotherapy, and as monotherapy (Ofev®) in the USA and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single‐ and multiple‐doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4‐hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first‐pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice‐daily dosing. Nintedanib's PK was time‐independent; accumulation after repeated administration was negligible. This article is protected by copyright. All rights reserved

Thursday, April 28, 2016 9:59 AM|CUMPĂNAS, A. A., CIMPEAN, A. M., FERICIAN, O., CEAUSU, R. A., SARB, S., BARBOS, V., DEMA, A., RAICA, M.|Anticancer Research recent issues|Labels: PDGF, VEGF, kidney cancer

Background/Aim: Studies developed in the field of platelet-derived growth factors/platelet-derived growth factor receptors (PDGFs/PDGFRs) inhibition have focused on the therapeutic effects on tumor cells, neglecting their potential effects on tumor blood vessels. We herein propose a differential and critic assessment of platelet-derived growth factor B (PDGF-B) and platelet-derived growth factor receptor β (PDGFRβ) in renal cell carcinoma, correlated with the four main vascular patterns previously reported by our team. Materials and Methods: PDGF-B and PDGFRβ were evaluated on 50 archival paraffin embedded specimens related to vascular endothelial growth factor (VEGF), its inhibitory isoform VEGF165b and vascular patterns. Results and Conclusion: Our results support the involvement of VEGF165b in the phosphorylation of PDGFRβ with an inhibitory effect on endothelial proliferation and migration. The simultaneous action of PDGF-B/PDGFRβ and VEGF165b on the same type of receptor may explain the resistance to antiangiogenic therapy, which depends on the degree of modulation of PDGFRβ phosphorylation.

Thursday, February 25, 2016 4:00 PM|Targeted Oncology|MedWorm: Cancer Therapy|Comments|Labels: VEGF
Abstract Recent studies suggest that neuropilin-1 (NRP-1) promotes angiogenesis mainly via VEGF and its receptors. It promotes tumorigenesis via formation of the NRP-1/ VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) complex. In addition to VEGF and its receptors, NRP-1 also binds with other growth factors such as platelet-derived growth factor (PDGF) and platelet-derived growth factor receptor (PDGFR). PDGF plays important roles in cellular proliferation and, in particular, blood vessel formation. Moreover, recent studies show that NRP-1 promotes angiogenesis via the NRP-1-ABL pathway, but independent of VEGF-VEGFR2. RAD51 is a protein involved in the signaling pathways of NRP1-ABL and PDGF(R), the expression of which is positively...
Sunday, February 21, 2016 4:00 PM|Angiogenesis|MedWorm: Carcinoma in Situ|Comments|Labels: INT, VDA, VEGF, breast cancer
In conclusion, total α v ß 3 integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial α v ß 3 for differentiating benign from cancerous lesions. (Source: Angiogenesis)
Thursday, February 18, 2016 5:58 PM|Current Cancer Drug Targets|MedWorm: Cancer Therapy|Comments|Labels: AKT, mTOR, PI3K, VEGF
In conclusion, our data demonstrated that the chimeric VEGF121-VEGF165 arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF121-VEGF165 targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1α- VEGF165/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy. PMID: 26882030 [PubMed - in process] (Source: Current Cancer Drug Targets)
Wednesday, February 17, 2016 7:36 AM|Expert Review of Anticancer Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: FGFR, PDGF, VEGF, lung cancer
Authors: Syrios J, Nintos G, Georgoulias V Abstract Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcin...
Thursday, January 21, 2016 10:49 AM|Oncology Letters|MedWorm: Carcinoma in Situ|Comments|Labels: EGFR, VEGF, esophageal cancer
Authors: Niyaz M, Anwer J, Liu H, Zhang L, Shayhedin I, Awut I Abstract The present study aimed to understand the expression characteristics of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) in individuals of Uygur, Han and Kazak ethnicity with esophageal carcinoma in Xinjiang (China) and their interrelation analysis, and to investigate the expression differences in these genes between esophageal carcinoma and pericarcinoma tissue samples, and between the three ethnic groups. The expression levels of EGFR and VEGFR-2 from 119 pairs of esophageal carcinoma tissue and corresponding pericarcinoma tissue from Uygur, Han and Kazak patients with esophageal carcinoma were detected by immunohistochemistry following surgical resection, an...
Conclusions: The combination of VAN and EV was reasonably well tolerated at the highest doses of each of the drugs. Evidence of response was noted in heavily pre-treated patients with refractory solid tumors and targetable genomic aberrations specifically RET. The combination has CNS penetration in RET fusion NSCLC.Citation Format: Tina Cascone, Kenneth R. Hess, Sarina Piha-Paul, David S. Hong, Michael Roxas, Ishwaria M. Subbiah, Siquing Fu, Aung Naing, Filip Janku, Daniel Karp, Steven I. Sherman, Funda Meric-Bernstam, John V. Heymach, Vivek Subbiah. A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations. [abstract]. In: Proceedings of the AACR-NCI-EORTC...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: MET, VEGF, prostate cancer
Several kinase inhibitors targeting aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in early phase clinical trials, particularly in cancer patients with bone metastases. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with increased neutrophil chemotactic factor expression, including CXCL12 and HMGB1 production by tumor cells, and robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutrali...