Potentiating efficacy of TROP2 targeted antibody-drug conjugates

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Antibody-drug conjugates (ADCs) targeting the TROP2 glycoprotein have transformed treatment options for solid tumors. Sacituzumab Govitecan (SG), an FDA-approved TROP2-directed ADC, demonstrates substantial activity in triple-negative breast cancer (TNBC) and has been given Orphan Drug Designation for PDAC studies. This R01 proposal, “Potentiating Efficacy of TROP2-Targeted Antibody-Drug Conjugates,” seeks to define molecular determinants of ADC response and resistance, and to develop rational strategies that enhance therapeutic benefit. Leveraging a uniquely characterized panel of TNBC and PDAC patient-derived xenografts (PDX) and organoids (PDXO) with comprehensive genomic, transcriptomic, and proteomic profiling, our team integrates multi-omic analyses with high-throughput drug response data. Aim 1 identifies proteogenomic biomarkers that predict SG sensitivity and resistance, enabling development of SG-PREDICTOR, a machine-learning tool for clinical prediction of ADC response. Aim 2 defines cellular and molecular mechanisms of acquired resistance using SG-resistant PDX and PDXO models to uncover alterations in TROP2 expression, internalization, drug efflux, and DNA repair. Aim 3 tests therapeutic strategies to enhance and prolong SG efficacy, including rational drug combinations and next-generation ADC payloads, with validation in vivo. Given the complexity of ADC efficacy, biodistribution within organisms, and necessity for studying systemic toxicities, animal models will be required. Collectively, these studies will identify predictive biomarkers, elucidate resistance mechanisms, and establish therapeutic strategies to optimize TROP2-targeted ADC efficacy in TNBC and PDAC. The anticipated outcomes will directly inform precision oncology, improve patient selection, and guide rational clinical trial design to extend patient survival.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE This project seeks to improve the effectiveness of TROP2-targeted antibody-drug conjugates, such as Sacituzumab Govitecan, in triple-negative breast cancer and pancreatic ductal adenocarcinoma. By identifying molecular predictors of response, uncovering mechanisms of resistance, and developing rational therapeutic strategies, these studies will enable more precise and durable treatments for patients with these aggressive cancers.