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demonstrated an interactive benefit of the addition of a PARPi with an angiogenesis inhibitor (Kohn, Kim, Lee, Hays, unpublished).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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011525-01
Application #
8763587
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$141,489
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Lee, Jung-min; Ivy, S Percy; Kohn, Elise C (2016) Challenges and Opportunities for Immunotherapies in Gynecologic Cancers. Oncology (Williston Park) 30:67-9
Botesteanu, Dana-Adriana; Lee, Jung-Min; Levy, Doron (2016) Modeling the Dynamics of High-Grade Serous Ovarian Cancer Progression for Transvaginal Ultrasound-Based Screening and Early Detection. PLoS One 11:e0156661
Botesteanu, Dana-Adriana; Lipkowitz, Stanley; Lee, Jung-Min et al. (2016) Mathematical models of breast and ovarian cancers. Wiley Interdiscip Rev Syst Biol Med 8:337-62
Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min et al. (2016) Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer. Expert Opin Investig Drugs 25:597-611
Noonan, Anne M; Bunch, Kristen P; Chen, Jin-Qiu et al. (2016) Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer. Cancer 122:588-97
Lee, Jung-Min; Gordon, Nicolas; Trepel, Jane B et al. (2015) Development of a multiparameter flow cytometric assay as a potential biomarker for homologous recombination deficiency in women with high-grade serous ovarian cancer. J Transl Med 13:239
Baird, John H; Minniti, Caterina P; Lee, Jung-Min et al. (2015) Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide. Br J Haematol 168:737-46
Lee, Jung-Min; Trepel, Jane B; Choyke, Peter et al. (2015) CECs and IL-8 Have Prognostic and Predictive Utility in Patients with Recurrent Platinum-Sensitive Ovarian Cancer: Biomarker Correlates from the Randomized Phase-2 Trial of Olaparib and Cediranib Compared with Olaparib in Recurrent Platinum-Sensitive Ovar Front Oncol 5:123
O'Sullivan, Ciara C; Moon, Dominic H; Kohn, Elise C et al. (2014) Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors. Front Oncol 4:42
Lee, Jung-Min; Hays, John L; Annunziata, Christina M et al. (2014) Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 106:dju089

Showing the most recent 10 out of 15 publications