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. Because there are no human PCC cell lines, this project uses cultures of mouse pheochromocytoma (MPC) cell lines developed in our laboratory as the principal model for pre-clinical testing of chemotherapeutic drugs and validates the findings with primary cultures of human PCC. In this funding period we: 1. Completed and published the major experiments proposed in our original SOW showing cooperative cytotoxic effects of topoisomerase 1 (TOP1) inhibitors, which block enzymes that protect against DNA damage during transcription, with 5-azacytidine, an inhibitor of DNA methylation that increases transcriptional activity. 2. Showed that several drugs (5-azacytidine, lithium and caffeine) that augment TOP1 inhibitors in targeting MPC cells are ineffective against nondividing human PCC cells 3. Completed testing of Gamitrinib, a new drug that we previously found to be highly effective in cultures of both human and mouse PCC cells, against MPC xenografts in nude mice and showed initial suppression of tumor growth followed by loss of anti-tumor effect. 4. Tested a new strain of immunodeficient mice called NSG for grafting human PCC cells and concluded that these mice, like previously tested strains, are unlikely to be effective in establishing human PCC xenografts or cell lines. 5. Tested novel approaches for directly deriving human PCC cell lines from primary cultures using protocols designed to maintain or induce stem cell properties and concluded that these are also unlikely to be effective in establishing cell lines. Despite positive results pointing to new possible therapies, 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.