cabozantinib and Pancreatic-Neoplasms

Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

Topics: Adenocarcinoma; Adult; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Deoxycytidine; Female; Follow-Up Studies; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Prognosis; Pyridines; Survival Rate

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. Cancer stem cells (CSCs), which are not targeted by current therapies, may be the reason for pronounced therapy resistance. A new treatment option in phase II trials is cabozantinib that inhibits the pancreatic CSC surface marker and tyrosine kinase receptor c-Met. The purpose of this study was to evaluate the effect of cabozantinib to stem-like features and therapy resistance. Established PDA cell lines, a gemcitabine-resistant subclone, non-malignant pancreatic ductal cells and primary spheroidal cultures from patient tumors were analyzed by MTT-assay, flow cytometry, colony and spheroid formation assays, western blotting, qRT-PCR, antibody protein array, immunohistochemistry and morphological features. Cabozantinib inhibited viability and spheroid formation and induced apoptosis in malignant cells with minor effects in non-malignant cells. After long-term cabozantinib treatment, PDA cells had altered anti- and pro-apoptotic signaling, but still responded to cabozantinib, as apoptosis only slightly decreased and viability only slightly increased suggesting a low resistance-inducing potential of cabozantinib. In parallel, c-Met expression and the pluripotency transcription factor SOX2 were downregulated, which might counteract development of full therapy resistance in long-term treated subclones. In single-treatment studies, cabozantinib increased efficacy of gemcitabine. Most importantly, cabozantinib strongly induced apoptosis and reduced viability in PDA cell lines, which are completely resistant toward gemcitabine. In primary, CSC-enriched spheroidal cultures cabozantinib downregulated CSC markers SOX2, c-Met and CD133 and induced apoptosis. These findings suggest that the clinical use of cabozantinib may be more effective than current chemotherapeutics.

Topics: Anilides; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Down-Regulation; Drug Resistance, Neoplasm; Gemcitabine; Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; SOXB1 Transcription Factors; Stem Cells

A new study by Sennino and colleagues demonstrates that selective VEGF inhibition via the use of an anti-VEGF antibody is sufficient to increase invasion and metastasis in a c-Met-dependent manner. Anti-VEGF therapy induced tumor hypoxia, hypoxia-inducible factor 1α, and c-Met activation in the RIP-Tag2 model of neuroendocrine pancreatic cancer. Selective c-Met inhibition was sufficient to block these effects, providing a potential mechanism for and solution to overcome increased invasion in the face of anti-VEGF therapy.

Topics: Anilides; Animals; Antibodies, Neutralizing; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Vascular Endothelial Growth Factor A

Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met.. This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis.

Topics: Anilides; Animals; Antibodies, Neutralizing; Cell Line, Tumor; Humans; Mice; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Vascular Endothelial Growth Factor A

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.

Topics: Adenoma, Islet Cell; Anilides; Animals; Apoptosis; Basement Membrane; Cell Hypoxia; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Quinolines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3

Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target.. We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice.. c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases.. c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.

Topics: Adenocarcinoma; Anilides; Animals; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Deoxycytidine; Drug Therapy, Combination; Flow Cytometry; Gemcitabine; Humans; Immunoblotting; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplastic Stem Cells; Pancreatic Neoplasms; Proto-Oncogene Proteins c-met; Pyridines