We hypothesize the optimal targeting of the DNA damage repair and related pathways will yield improved clinical outcome in BRCA1/2 mutation-associated, BRCA-like, and homologous recombination deficient (HRD)-women's cancers, which are rare subsets of women's cancers with critical unmet need. We have initiated a new clinical trials direction, targeted to treat this population. The first PARP inhibitor (PARPi;olaparib)/carboplatin study (08-C-0092) is completing accrual of nonmutation carriers and analysis of prospectively planned exploratory translational endpoints in the mutation carrier cohort. A manuscript describing our experience and results of translational endpoints in blood and tissue samples is being completed for submission. Accrual is nearly complete on my PK/PD study of olaparib/ carboplatin (11-C-0022) for which I received ASCO Jane C. Wright Young Investigator Award. Preclinical work to investigate biochemical mechanisms underlying the sequences of the agents is being readied for manuscript submission. Further, I hypothesized that I could build a predictive biomarker using a flow cytometry method for response to PARPi therapy and validate the finding with the PK/PD study of olaparib/carboplatin;I received a Caring Together, NY Ovarian Cancer Research Award for this project now ongoing. Prior work in our group demonstrated an interactive benefit of the addition of a PARPi with an angiogenesis inhibitor (Kohn, Kim, Lee, Hays, unpublished). We are an accruing member of a multi-institutional phase 2 study (12-C-0091) examining a olaparib with the angiogenesis inhibitor, cediranib. These studies will allow evaluation of HRD regulation by the drug combinations in tissue and surrogate PBMCs, and cross analysis in putative HRD populations. We also investigated and published our experience with serial biopsies from our clinical trials. This information is important to show the value, utility, and safety of this translational approach. Identification and development of new therapeutic target combinations while minimizing significant toxicities is critical in early drug development. I hypothesized combination of a PARPi, veliparib, with antiapoptotic protein Bcl-2/Bcl-XL inhibitor, navitoclax, will yield clinical synergy at doses lower than used for single agents, thus with the potential to minimize the thrombocytopenia issue. My group has initiated experiments with preliminary data demonstrating additive cytotoxicity in breast and ovarian cancer cell lines with lower doses of each agents. We are also investigating potential biomarkers including quantities of Bcl-2, Bcl-XL, and Mcl-1, another prosurvival BH3 protein, and BAG3 a prosurvival chaperone known to protect Bcl2 and Bcl-XL. This work will be presented at 2013 AACR-NCI-EORTC meeting.
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