BRCA gene homozygous deficiency has been identified as a predictor of response to poly ADP- ribose polymerase (PARP) inhibitors. ABT-888 is one of such compounds. A closer look at BRCA function shows that BRCA is involved in homologous recombination (HR), an example of double strand break repair. This would suggest that inhibiting a repair mechanism in patients already deficient for another leads to tumor death. Although the numbers of cancer patients with germ line BRCA deficiency are low, BRCA is just one of close to 20 genes that collaborate in the same repair pathway. This pathway has been named the Fanconi Anemia (FA) pathway, given the presence of a hereditary syndrome characterized by developmental abnormalities, progressive bone marrow failure and cancer predisposition, driven by a defect in one of several genes of this pathway. We have hypothesized that a substantial number of patients across different organs and histologies have somatic deficiency in at least one gene in this pathway and that these patients are more likely to derive benefit from PARP inhibition. This benefit would be more significant following induced DNA damage. A test that could examine the functionality of this pathway as a whole and that could be practically applied for large-scale screening would be necessary to identify these patients. We believe we have developed such a test, and have generated preliminary data for somatic deficiency of this pathway in patients'tumors across several histologies. In this proposal we will: 1- screen cancer patients across different histological sites to identify those with functional defects in the FA pathway in their tumors;2- establish the safety and practicality of treating patients with FA deficient tumors with the PARP inhibitor ABT- 888 as protracted monotherapy;3- establish the safety and practicality of treating patients with FA deficient tumors with the combination of mitomycin C and ABT-888;and 4- generate and in vitro and in vivo system capable of evaluating and optimizing combinations of DNA breaking agents and PARP inhibitors.
Experience with novel agents that have been designed to interfere with the repair process suggests that patients who have additional defects in repair enzymes are more likely to benefit from these treatments. We have developed a test that can effectively screen patients for the functionality of the Fanconi anemia repair pathway, which is represented by more than 20 genes, all of which need to work together for repair to occur. In this proposal, we will select patients with functional defects in this pathway for treatment with the repair inhibitor ABT-888 as monotherapy and in combination with chemotherapy. We hypothesize that these patients will derive substantial clinical benefit from such treatment.
|Duan, Wenrui; Gao, Li; Zhao, Weiqiang et al. (2013) Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient-enrichment strategy for treatment with DNA interstrand crosslinking agents. Transl Res 161:156-64|