New Therapeutics

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?
Image of supraphysiological androgens and the PARP inhibitor olaparib
Supraphysiological androgens and the PARP inhibitor olaparib induce DNA damage in prostate cancers that express the androgen receptor.


  • Nguyen HM et al. LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease and Serve as Models for Evaluating Cancer Therapeutics. Prostate. 2017 May;77(6):654-671. PMID: 28156002
  • Nyquist MD et al. Exploiting AR Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155. Mol Cancer Res. 2017 May; 15(5):521-531. PMID: 28119432
  • Wu YM et al. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell. 2018 Jun 14;173(7):1770-1782.e14.
  • Mostaghel EA et al. Contribution of Adrenal Glands to Intra-Tumor Androgens and Growth of Castration Resistant Prostate Cancer. Clin Cancer Res. 2018 Sep 4. PMID: 30181386.