Project 1: Incorporating antibody drug conjugates into mechanism-based combinations to target metastatic breast cancer

PROJECT SUMMARY The long-term objective of this SPORE project is to identify new, more effective, and less toxic therapeutic approaches for metastatic triple-negative breast cancer (mTNBC), the most aggressive and poor-prognosis breast cancer subtype. Our team of DF/HCC investigators and others have led the clinical development of multiple antibody-drug conjugates (ADCs) for advanced breast cancer, including Sacituzumab govitecan (SG), achieving improved objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) comparted to standard chemotherapy. SG comprises a humanized monoclonal antibody targeting TROP- 2, a tumor antigen expressed in >90% of mTNBC, coupled to the topoisomerase 1 (TOP1) inhibitor SN-38 (the active metabolite of irinotecan). Despite its benefits, only approximately 30% of patients with mTNBC experience a therapeutic response to SG, highlighting the unmet need for new approaches to enhance efficacy. Accordingly, our clinical and translational research program has focused on identifying mechanism- based therapeutic combinations with ADCs that can overcome de novo and acquired drug resistance. We recently completed an investigator-initiated phase 1b/2 clinical trial of SG and PARP inhibitor (PARPi, talazoparib) for mTNBC (NCT04039230), notably delivered via a sequential dosing schedule which we hypothesized would limit toxicity and improve the therapeutic window. While sequential drug administration indeed reduced dose-limiting myelosuppression we observed with concurrent dosing, the combination still had significant hematologic toxicity. In this project, our team of investigators seeks to systematically investigate the rational therapeutic use of next-generation ADC/PARPi combinations, and to test new ADC combinatorial therapies. In Aim 1 we will carry out pre-clinical studies leading to design and implementation of a phase 1b/2 clinical trial of a TROP-2 directed, TOP1 inhibitor-based ADC in combination with a novel PARP1-selective inhibitor, as PARP1 inhibition is known to have a hematopoietic stem/progenitor-sparing effect. We will also establish the association between therapeutic response and pre-treatment and pharmacodynamic biomarkers of DNA damage and repair in the context of ADC/PARP1i versus ADC alone through analysis of clinical trial and other patient samples. In Aim 2 we will systematically test a novel ADC plus targeted therapy combinatorial approach, revealed through systematic CRISPR screens, that has the potential to enhance efficacy through dual effects on repair of TOP1-induced damage and expression of TROP2 itself. Collectively, these studies will implement innovative, mechanism-based clinical trials incorporating ADC-based combinatorial therapy for patients with mTNBC.