I hypothesize the optimal targeting of the DNA damage repair and related pathways will yield improved clinical outcome in BRCA1 and BRCA2 mutation (gBRCAm)-associated, BRCA-like, and homologous recombination deficient (HRD)-women's cancers, which are rare subsets of women's cancers with critical unmet need. I have initiated a new clinical trials direction, targeted to treat this population. The first PARP inhibitor (PARPi;olaparib)/carboplatin study (08-C-0092) showed clinical activity in heavily pretreated gBRCAm - associated ovarian cancer, and high grade serous ovarian cancer (HGSOC) at low genetic risk, with clinical benefit rates of 82% and 72%, respectively. Our exploratory proteomic analysis demonstrated that high pretreatment tissue FOXO3a expression correlates with duration of response to olaparib/carboplatin treatment in women with gBRCAm -associated ovarian and breast cancers. The phase I olaparib/carboplatin study completed accrual of nonmutation carriers and analysis of prospectively planned exploratory translational endpoints is ongoing. My medical oncology fellow, Dr. Chiou, won the 2014 AACR/GlaxoSmithKline Outstanding Clinical Scholar Award based on clinical data from nonmutation carriers of 08-C-0092 study. Accrual of patients of my PK/PD study of olaparib/ carboplatin (11-C-0022) is nearly complete, and analysis of correlative studies is now ongoing. Preclinical work, for which I received ASCO Jane C. Wright Young Investigator Award, to investigate biochemical mechanisms underlying the sequences of the agents is being readied for manuscript submission. Further, we reported at 2014 SGO that a ratio of gH2AX/MRE11 measured in PBMC by flow cytometry may be a surrogate marker of DNA DSB damage/repair, and these findings may be a predictive biomarker for response to olaparib/carboplatin treatment. We recently reported the combination of olaparib and cediranib (12-C-0091) demonstrated improved clinical activity against olaparib alone in women with platinum-sensitive recurrent ovarian cancer. Predictive and selective biomarkers to guide treatment are needed, and exploratory biomarker endpoints were planned prospectively into the study. I reported at 2014 ASCO that women who were treated with olaparib/cediranib had a median 3.5 fold increase of circulating endothelial cells (CECs) compared to those on olaparib alone and the increase of CECs correlated with survival longer than 6 months in all patients. Biomarker correlates from this phase II study is being readied for manuscript submission. Further, these promising data led us to develop a phase II/III study of the combination of cediranib and olaparib in platinum-resistant ovarian cancer patients through NRG (NSABP-RTOG-GOG) Oncology (PI: Jung-min Lee). A phase III study will examine biomarkers including CECs and other translational studies. The concept was approved by NCI/CTEP and anticipated opening is 1st quarter of 2015. I have expanded my HRD-women's cancers clinical program, and now developing two new phase II studies. First, I will evaluate the mechanisms of PARPi clinical resistance. There are limited data on the prevalence of secondary mutations/changes in the DNA damage pathways that leads to PARPi resistance. I received a NCI/CTEP CRDL, a career development LOI award, to write and activate a protocol to examine this molecular and clinical question using the new potentially more potent PARPi, BMN673. BMN673 has a greater PARP-trapping activity, and anti-tumor activity in vitro and in vivo at lower concentrations than first generation PARPi. My single arm phase II trial will examine activity of BMN673 in women with recurrent gBRCAm-associated ovarian cancer, with progression on a PARPi monotherapy. Blood and tissue acquisition is a key element of this trial;by requiring pretreatment biopsies, I will be able to sample gBRCAm women who have recently progressed on PARPi yielding a strong prospective collection for secondary mutation analysis. This study will provide initial findings with which to lead to randomized trials in the role of repeat PARPi therapy. Protocol was approved by CTEP, with anticipated submission to IRB in September and anticipated opening in November 2014. Secondly, I hypothesize targeting other elements of DNA damage repair and cell cycle checkpoint pathways will yield improved clinical outcome in HRD-women's cancers. CHK1/2 are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. CHK1 functions as the primary mediator of cell-cycle arrest in tumors with dysfunctional p53. When CHK1 protein is depleted, more replication origins are activated in early S phase than the replication apparatus can tolerate, resulting in slowed and arrested DNA replication forks and DNA DSB. Thus, I hypothesized inhibition of CHK1/2 (CHKi) will yield clinical activity in HRD-women's cancers. I championed negotiation with Lilly, where they have an active first and second generation CHKi under development. My protocol for use of LY2606368, the second generation CHKi with single agent activity, in HRD-women's cancers, will be Lilly's first investigator-initiated trial of an early phase development agent. Several translational endpoints have been built into this study for potential therapeutic targets and predictive biomarkers. Completion of the Cooperative Research and Development Agreement (CRADA) between NCI and Lilly is near completion. FDA approval of the IND and final IRB protocol approval are completed with anticipated study opening in September 2014. Understanding more about the molecular abnormalities involved in HRD-women's cancers and their responses to targeted agents, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are important to create more efficient targeted therapies and therapeutic directions in rare subsets of women's malignancies. I will continue to focus on development of investigator-initiated clinical trials and translational analyses of molecular events to improve clinical outcome for these subsets of women's cancers.
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