Novel Preclinical Testing Strategies for Treatment of Metastatic Pheochromocytoma
Abstract
Pheochromocytomas (PCC) are catecholamine-producing neuroendocrine tumors. Up to 30% give rise to metastases, for which there is no effective treatment. A deficiency in current treatment strategies is that they do not account for the fact that, in contrast to many other malignant tumors, metastatic PCCs usually grow very slowly and most of the cells are quiescent at any given time. Treatments that target replicating tumor cells have therefore been mostly unsuccessful. The need to improve treatment requires new strategies and valid models for pre-clinical testing. In this research period we: 1. Completed development and characterization of a bioluminescent mouse PCC cell line as a model, 2. Used the model in cytotoxicity assays to test two promising treatment strategies represented by different types of prototype drugs, 3.Validated the findings with human PCC cells in primary cultures. The first strategy tested was inhibition of topoisomerase 1 (TOP1) in conjunction with inhibition of DNA methylation. TOP1 inhibitors interfere with mechanisms that maintain DNA integrity during transcription in both quiescent and dividing cells, while DNA methylation inhibitors increase transcription of genes silenced by methylation, and are therefore mechanistically complementary. The second strategy tested a new type of drug, Gamitrinib, that accumulates in the mitochondria of tumor cells but not of normal cells, and attacks the chaperone protein TRAP-1. The rationale for testing Gamitrinib was that malignant PCC are often caused by mutations of the SDHB gene, which encodes a subunit of the mitochondrial enzyme succinate dehydrogenase. We found that Gamitrinib is highly toxic to both MPC cells and primary human PCC cells. It might therefore be both the most effective drug and the one most specifically targeting the defect in the majority of malignant PCC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2012
- Accession Number
- ADA584309
Entities
People
- Arthur S. Tischler
Organizations
- Tufts Medical Center