Abstract 7120: Investigating PARP1 selective inhibitor DSB1559 efficacy in BRCA1-associated triple negative breast cancer

Abstract

Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have improved outcomes of BRCA-associated breast cancer. However, toxicity can limit patient response as well as the ability to be combined with other therapeutics. Current PARPi broadly inhibit members of the PARP protein family, however only inhibition of PARP1 is needed for PARPi-mediated cell death. As inhibition of PARP2 is associated with hematological toxicity seen in PARPi patients, selectively inhibiting PARP1 may reduce PARPi toxicity and lead to better outcomes for patients. Here we characterize and test the efficacy of the PARP1 selective inhibitor (PARP1i) DSB1559 compared to Olaparib in BRCA1-associated triple negative breast cancer (TNBC). Methods: NanoBRET, PARylation, and pharmacokinetic/pharmacodynamic assays were performed to examine DSB1559 potency, PARP family selectivity, and in vivo behavior. Immunocompetent FVB/n mice bearing BRCA1-deficient TNBC (CMV-Cre;Brca1f/f;Trp53f/f) tumors were treated daily with PARPi (Olaparib) or PARP1i (DSB1559) for 60 days and followed for survival. CellTiter-Glo and qPCR assays were used to examine DSB1559 effect on cell viability and STING activation, respectively. Results: DSB1559 is a novel and potent PARP1 inhibitor which has superior selectivity for PARP1 compared to Olaparib and PARP1i AZD5305. DSB1559 has highly desirable physico-chemical and in vitro ADME properties, which translate to high oral bioavailability and moderate clearance in rodent PK studies. Additionally, DSB1559 demonstrated superior tumor residence time and tumor/plasma ratio compared to AZD5305. Compared to Olaparib, DSB1559 significantly increased STING activation and reduced cell viability in BRCA1-associated murine TNBC cells. BRCA1-associated TNBC-bearing immune-competent mice treated with DSB1559 had significantly reduced tumor growth and increased overall survival (median survival 74 days) compared to Olaparib (median survival 18 days). Analysis of changes in the tumor microenvironment are ongoing. Conclusions: Taken together, DSB1559 is a highly selective PARP1 inhibitor that demonstrates superior efficacy compared to Olaparib in a BRCA1-associated immune-competent TNBC model. Citation Format: Adam Nelson, Kelly F. Zheng, Carlos Wanderley, Daniel E. Michaud, Phillip M. Cowley, Gillian M. Campbell, Barry E. McGuinness, Alan Wise, Jennifer Guerriero. Investigating PARP1 selective inhibitor DSB1559 efficacy in BRCA1-associated triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7120.