ZIA BC 011525 (ZIA) | |||
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Title | Leveraging DNA damage repair pathways as therapeutic targets in women's cancers | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Lee, Jung-Min | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $535,337 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Genetic Testing (10.0%) |
Breast (20.0%) Ovarian Cancer (80.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
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 |