My clinical and translational program is focused on targeting the DNA repair and related pathways in high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) through investigator-initiated clinical trials and biomarker analysis. My lab efforts are aimed at investigating novel therapeutic combinations in HGSOC and TNBC, 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 (1) Cell cycle checkpoint kinase 1 and 2 (CHK1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. CHK1/2 functions as the primary mediator of cell-cycle arrest in tumors with dysfunctional p53, such as HGSOC. I hypothesized inhibition of CHK1/2 will yield clinical activity in recurrent HGSOC. (2) I have developed and opened a phase II investigator-initiated study of the second generation CHK1/2 inhibitor, prexasertib (LY2606368, 14-C-0156) in HGSOC patients with and without germline BRCA mutation where I negotiated drug supply and CRADA-based study support from Eli Lilly. (3) We completed accrual of HGSOC patients without germline BRCA mutation, and observed the promising activity of prexasertib monotherapy in heavily pre-treated recurrent platinum-resistant BRCA wild type HGSOC patients (a response rate of 35%). I reported this phase II study data at the European Society of Medical Oncology meeting in October 2016. My work was also recognized in the ASCO Post. Based on my work, the company (Eli Lilly) is exploring breakthrough status with the FDA. (4) This study incorporates tumor biopsies and blood collections, genomic analyses and other molecular investigations to identify mechanisms of sensitivity, and to better define the subsets that respond to therapy, which have not clinically been examined in HGSOC. Correlative study endpoints evaluation is currently ongoing. (5) I recently opened the cohort of recurrent platinum-resistant HGSOC within the 14-C-0156 study to confirm clinical activity of prexasertib in this patient population and also to investigate de novo and acquired clinical resistance mechanisms. This cohort incorporates mandatory pre-treatment and at progression tumor biopsies and blood collections. (6) To capitalize and expand on the benefits of prexasertib, I am combining targeted agents with prexasertib to enhance response rates in recurrent HGSOC. My group is examining the cytotoxic effect of a PARP inhibitor, olaparib and prexasertib preclinically in HGSOC cells. We presented the preliminary in vitro data of the combination at the AACR meeting in April 2016 and a manuscript is currently under review. (7) To develop the next generation of clinical trials (e.g. combinations that might increase the activity of prexasertib), I am collaborating with Dr. C Thomas using a quantitative high throughput screening approach developed by the National Center for Advancing Translational Sciences (NCATS) that enables the discovery of synergistic drug combinations. This work is currently ongoing. (8) Although prexasertib showed promising single agent activity in recurrent HGSOC, the patients eventually progress on the treatment. Potential resistance mechanisms of the cell cycle checkpoint inhibition are not well studied. My group is in collaboration with Dr. Steeg's Lab and Dr. Pommier's Lab to understand de novo and acquired resistance mechanisms of prexasertib and/or other cell cycle inhibitors in HGSOC and TNBC. 2) Project #2: Therapeutic strategies to complement immune checkpoint inhibition in HGSOC and TNBC (1) Emerging data suggest that the DNA repair and angiogenesis pathways modulate immune response by increasing DNA damage and tumor mutational loads. Mutational load, potential neoantigen expression, is associated with clinical response to immune checkpoint inhibition in solid tumors. I hypothesize that increased DNA damage and reduced angiogenesis, creating higher mutational loads and a more antigenic environment, will complement the anti-tumor activity of immune checkpoint inhibition in recurrent ovarian cancer and TNBC. (2) 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 a PARP inhibitor, olaparib and/or a VEGFR inhibitor, cediranib. I negotiated drug supply and CRADA-based study support from AZ/MedImmune. (3) I presented the phase I study of durvalumab in olaparib or cediranib combinations at the American Society of Clinical Oncology (ASCO) meeting in June 2016 and published our findings in Journal of Clinical Oncology in 2017. This is the first reported anti-PD-L1+olaparib or cediranib combination therapy. We found the recommended phase 2 doses of durvalumab+olaparib and durvalumab+intermittent cediranib are tolerable and clinically active. Phase II studies with biomarker analysis in HGSOC and TNBC are currently ongoing. Based on the safety and activity findings from this study, we also examined the 3 pathway regulators in women's cancer and found the recommended phase 2 doses of durvalumab+olaparib+intermittent cediranib are tolerable and clinically active in women's cancer. Phase II study of this three-drug combination in HGSOC will open in 3Q 2017. 3) Project #3: Therapeutic targeting the key proteins of DNA repair and angiogenesis pathways in recurrent HGSOC patients (1) 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 yield improved clinical outcome in recurrent HGSOC patients. I am approaching this through my continued studies of a PARP inhibitor. We reported a multi-institutional randomized phase II study of the combination of olaparib and cediranib in platinum-sensitive recurrent ovarian cancer, which showed a remarkable prolongation of progression free survival with the combination compared to olaparib alone (12-C-0081/J-M Lee: the translational PI). (2) This newly uncovered anti-tumor activity of the combination led to development of the two NRG Oncology international 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 completed a target accrual of 208 patients for a phase II part in June 2017, is temporarily closed for an interim analysis, and will reopen in 2Q 2018 for a phase III part of the trial. (3) 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 HRD phenotypes with a strong translational research program.
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