We aim to determine the molecular features that associate with response and resistance mechanisms to pathway-targeted agents and conventional chemotherapy. Several clinical (translational) trials are underway including studies incorporating neoadjuvant therapies and large-scale tumor genome sequencing. Tissue samples are acquired pre- and post-therapy and molecular correlates of direct drug effects are identified to define tumor and host signatures: (a) predictive of therapeutic response and (b) predictive of disease outcome (relapse). We are also exploring new minimally-invasive approaches to assess the molecular composition of tumors using circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA) biomarkers that allow for iterative sampling of tumor biology and direct therapy.

A major focus involves the identification of synergistic drug combinations. For most solid tumors, single drugs fail to completely eradicate metastatic cancers and resistance is universal. Through collaborative studies, we are employing unique panels of patient-derived xenografts (PDX) and organoid models to identify rational drug combinations capable of producing complete responses.

Questions and Projects

• Are there synergistic combinations of drugs that exploit synthetic lethality and overcome predictable pathways of resistance?
• What contributes to variability in treatment responses across tumors with different genetic/epigenetic landscapes?
• What are the predictable mechanisms of drug resistance?
• What are the microenvironment features that promote drug/therapy resistance? Can they be effectively targeted?
• Why is prostate cancer generally resistant to immune-based therapeutics?
• Are there prostate tissue/cell-specific targets that can be exploited using antibody/T-cell based therapeutics?