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Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

ABSTRACT: This phase III trial studies cabozantinib to see how well it works compared with placebo in treating patients with neuroendocrine or carcinoid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Cabozantinib is a chemotherapy drug known as a tyrosine kinase inhibitor, and it targets specific tyrosine kinase receptors, that when blocked, may slow tumor growth.

DISEASE(S): Neuroendocrine Tumors,Locally Advanced Pancreatic Neuroendocrine Tumor,Metastatic Pancreatic Neuroendocrine Neoplasm,Atypical Carcinoid Tumor,Gastrointestinal Neoplasms,Neuroendocrine Neoplasm,Non-functioning Pancreatic Neuroendocrine Tumor,Metastatic Lung Carcinoid Tumor,Locally Advanced Unresectable Digestive System Neuroendocrine Neoplasm,Neoplasms,Pancreatic Serotonin-producing Neuroendocrine Tumor,Thymic Carcinoid Tumor,Unresectable Thymic Neuroendocrine Neoplasm,Malignant Carcinoid Syndrome,Lung Carcinoid Tumor,Metastatic Digestive System Neuroendocrine Tumor G1,Metastatic Pancreatic Neuroendocrine Tumor,Unresectable Pancreatic Neuroendocrine Neoplasm,Pancreatic Neoplasms,Stomach Neoplasms,Functioning Pancreatic Neuroendocrine Tumor,Carcinoid Tumor,Adenoma, Islet Cell,Unresectable Digestive System Neuroendocrine Tumor G1,Locally Advanced Digestive System Neuroendocrine Tumor G1,Low Grade Lung Neuroendocrine Neoplasm,Metastatic Lung Neuroendocrine Neoplasm,Unresectable Digestive System Neuroendocrine Neoplasm,Locally Advanced Digestive System Neuroendocrine Neoplasm,Metastatic Thymic Neuroendocrine Neoplasm,Metastatic Digestive System Neuroendocrine Neoplasm,Lung Atypical Carcinoid Tumor,Unresectable Lung Neuroendocrine Neoplasm,Intestinal Neoplasms,Intermediate Grade Lung Neuroendocrine Neoplasm,Locally Advanced Lung Neuroendocrine Neoplasm

PROVIDER: 2261433 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Additionally, we have detected upregulated expression of MET and RET transcripts in SCNPC metastases relative to adenocarcinoma. Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits MET, RET and VEGFR2, on SCNPC patient-derived xenografts (PDX) in vivo. Surveillance of SU2C and University of Washington rapid autopsy mCRPC cohorts through RNA-Seq revealed that increased MET expression significantly correlated with loss of AR expression and activity. In vitro treatment of SCNPC PDX cells with AMG 337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability in LuCaP 93, but not in LuCaP 173.1. Notably, tumor volume was significantly decreased (p<0.001) with cabozantinib treatment in SCID mice bearing LuCaP 93 and LuCaP 173.1 tumors. Tissue analysis indicated that tumor cell proliferation was not inhibited by cabozantinib, but that cabozantinib decreased microvessel density (CD31) in LuCaP 93 (p<0.001) and LuCaP 173.1 (p<0.01) tumors. RNA-Seq and gene set enrichment analysis determined that hypoxia and glycolysis pathways were increased in cabozantinib treated tumors relative to control tumors. Thus, cabozantinib inhibited tumor growth in MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumors in vivo and this activity was independent of MET or RET expression in LuCaP 173.1. Our data suggest that the most likely mechanism of tumor growth suppression is through disruption of the stromal architecture and cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.

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Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

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