Novel Preclinical Testing Strategies for Treatment of Metastatic Pheochromocytoma.

摘要

Pheochromocytomas (PCC) are catecholamine-producing neuroendocrine tumors. Up to 30% give rise to metastases, for which there is no effective treatment. There are also no human PCC cell lines for pre-clinical drug testing. In this research period we used cultures of mouse pheochromocytoma (MPC) cell lines developed in our laboratory as the principal model for pre- clinical testing of strategies to improve the efficacy of existing chemotherapeutic drugs and for testing potential new drugs that might be used to treat patients with metastatic PCC. Findings with the mouse model were validated against primary cultures of human PCC. Cytotoxicity assays showing cooperative effects of topoisomerase 1 inhibitors with 5-azacytidine, an inhibitor of DNA methylation, were completed and results were submitted for publication. Cytotoxicity testing of a new type of drug, Gamitrinib, was also published as part of a collaborative study relating the mechanism of action of the drug to the SDHB gene, which when mutated is a major cause of metastatic PCC. Gamitrinib is highly toxic to both MPC cells and primary human PCC cells, and might prove to be both the most effective drug and the one most specifically targeting the defect in the majority of malignant PCC. Despite these positive results there are differences between MPC and human PCC cells in responsiveness to some drugs including 5-azacytidine, and a pressing need for human cell lines remains. However, human PCC cells immediately and completely cease proliferating when placed into conventional cell cultures. We extensively tested potential ways to propagate human PCC cells from primary tumors in mouse xenografts but these efforts were unsuccessful, even with cells that grew rapidly in a patient with widely metastatic tumor. A major focus in the next funding period will therefore be on testing novel approaches to developing human cell lines from primary cultures.