My clinical and translational program is focused on targeting of the DNA repair and related pathways for therapeutic potential in recurrent ovarian cancer through investigator-initiated clinical trials and biomarker analysis. Currently, my effort is 70% clinical/translational and 30% laboratory investigation. My laboratory work is aimed at investigating novel therapeutic combinations in HGSOC, focused on targeting key proteins in the DNA repair and cell cycle pathways. These preclinical projects will provide the ability to move rapidly into the hypothesis-driven clinical trials of the combination of the different pathway regulators in recurrent ovarian cancer. 1) Project #1: Therapeutic modulation of cell cycle checkpoint pathways in women's cancer Checkpoint signaling is critical for coordination between DNA damage response and cell cycle control. In response to DNA damage or replication stress (RS), ATR activates cell cycle checkpoint kinase1 (CHK1) which subsequently deactivates cyclin-dependent kinases to arrest the cell cycles for DNA repair. Due to universal p53 dysfunction and the consequent G1 checkpoint defect, HGSOC cells heavily depend on ATR/CHK1-mediated G2/M cell cycle arrest for DNA repair. Thus, targeting of cell cycle checkpoints is a promising therapeutic strategy in HGSOC to augment RS while attenuating DNA repair responses. I hypothesized that a CHK1 inhibitor (CHK1i) would induce lethal DNA damage and resultant clinical activity in recurrent HGSOC patients. I have developed and opened a phase II investigator-initiated study of the second generation CHK1 inhibitor (CHK1i), prexasertib (14-C-0156) in HGSOC patients with and without germline BRCA mutation. We completed accrual of HGSOC patients without germline BRCA mutation (Cohort 2), and observed early activity of CHK1i monotherapy in heavily pre-treated recurrent platinum-resistant BRCA wild type (BRCAwt) HGSOC patients (The Lancet Oncol, 2018). This is the first demonstration of clinical activity of the CHK1i monotherapy in recurrent BRCAwt HGSOC patients. I opened the two cohorts (biopsy Cohort 5 and non-biopsy Cohort 6) of recurrent platinum-resistant BRCAwt HGSOC within the 14-C-0156 study to further confirm clinical activity of prexasertib in this population and also to investigate de novo and acquired clinical resistance mechanisms. These cohorts incorporate mandatory pre-treatment and at progression tumor biopsies (for biopsy Cohort 5) and blood collections (for both Cohorts). We continue to enroll patients for these two BRCAwt Cohorts as well as Cohort 1 BRCA mutated HGSOC patients. In the laboratory I am investigating biomarkers that predict the response or no response to CHK1i and mechanisms of resistance of cell cycle inhibitors. We developed CHK1i-resistant BRCAwt HGSOC cell lines to recapitulate the patient population of Cohort 2 who progressed on CHK1i therapy. Our preliminary findings suggest the development of acquired resistance to CHK1i is associated with reduced cyclinB1 levels and increased RAD51-induced DNA repair (manuscript in preparation). To further improve the efficacy of CHK1i, I conducted a high throughput drug combination screen in collaboration with the National Center for Advancing Translational Sciences, NIH. In the screen, several inhibitors of PI3K family, AKT and mTOR pathways induced supra-additive cytotoxic activity with a CHK1i. I am extending this work to other molecular targets within this DNA damage checkpoint pathway (e.g. ATM, ATR, and Wee1) to develop the next generation of clinical trials (e.g., combinations that might increase the activity of cell cycle inhibitors). 2) Project #2: Therapeutic strategies to complement immune checkpoint inhibition in HGSOC Immunotherapy has emerged as a major therapeutic modality in oncology, yet most patients with ovarian cancer do not derive benefit from immune checkpoint blockade monotherapy, suggesting the need to develop and test rational combination strategies. Inhibition of DNA repair and angiogenesis pathways can modulate immune response by increasing DNA damage and tumor mutational burden and by attenuating immunosuppressive microenvironment. The PARP inhibitor (PARPi) olaparib and a VEGFR inhibitor (cediranib) together were shown to be clinically superior to olaparib alone in recurrent platinum-sensitive ovarian cancer patients, suggesting an important new direction for immune checkpoint blockade combination therapy. I hypothesize that PARPi olaparib and cediranib will enhance the anti-tumor activity of immune checkpoint blockade, by creating higher mutational loads and a more immunogenic environment. I have developed and opened a phase I/II investigator-initiated study (15-C-0145), which tests this hypothesis by combining the PD-L1 inhibitor, durvalumab (MEDI4736) with olaparib and/or cediranib. The phase I studies for durvalumab and olaparib or durvalumab and cediranib have been published in Journal of Clinical Oncology in 2017 and this work has been highly cited. Also, phase I findings of triplet therapy (durvalumab plus olaparib and cediranib) are now in press in Journal of Immunotherapy for Cancer. Phase II studies with biomarker analysis in HGSOC and triple negative breast cancer are currently ongoing. In addition, the concept of triplet therapy (durvalumab + olaparib and cediranib) vs. doublet therapy (olaparib and cediranib) in platinum-resistant ovarian cancer is currently being reviewed by NCI Gynecologic Cancer Steering Committee for the randomized phase 2 multi-center study. This clinical trial has been expanded to bring these therapeutic opportunities and translational research approaches to other tumor types such as metastatic castrate resistant prostate cancer. Early clinical findings from a prostate cancer cohort demonstrated promising activity in heavily pretreated patients. 3) Project #3: Therapeutic targeting the key proteins of DNA repair and angiogenesis pathways in recurrent HGSOC patients Angiogenesis and DNA damage repair pathways are active and interactive therapeutic targets in recurrent HGSOC. I hypothesized optimal targeting of PARP and VEGF/VEGFR pathways will improve clinical outcome in recurrent HGSOC patients. This newly uncovered anti-tumor activity of the combination led to the development of two NRG Oncology multi-center trials (opened in April 2016) of olaparib and cediranib in platinum-resistant (PI: J-M Lee, a late phase II/III study, NRG GY005 [16-C-0088]) and platinum-sensitive recurrent ovarian cancer (PI: J Liu; a phase III study, NRG GY004). I have developed this clinical trial, through CTEP, NRG (NSABP-RTOG-GOG) Oncology and have worked with intramural and extramural experts in successful clinical and translational collaborations. NRG GY005 study has enrolled a target accrual of 208 patients for a phase II part and phase III part (additional 440 patients) is now enrolling the patients in the United States and Canada. GY005 amendment to open the sites in Japan and South Korea is now being reviewed by the central IRB. The correlative endpoints built into this trial will further our understanding of the DNA repair and angiogenesis pathways modulation by targeted agents and lead to the next generation of pathway combinations for recurrent HGSOC patients. Collectively, this focused clinical and translational approach will make our branch/CCR a recognized center focusing on the treatment of women with genetically high-risk breast and/or ovarian cancer, or those with tumor DNA repair deficient phenotypes with a strong translational research program.