Metastatic Castration-Resistant Prostate Cancer (mCRPC) is inevitably fatal. Agents that block androgen receptor (AR) signaling
are the mainstay of therapy for mCRPC, but these agents only increase patient survival by a few
months in most cases. Tumors evolve to evade these AR-directed therapies, culminating in patient death.
Newly developed therapies for mCRPC patients generate DNA damage specifically in tumor cells that have inactivated a crucial DNA repair pathway.
We and others have shown that tumors acquire "reversion" mutations can confer resistance to this therapy. However, reversion mutations
incompletely explain therapy resistance, as they are not present in all patients with resistance, and they are only
detected in a minority of tumor cells that harbor PARPi resistance.
We are defining the factors that mediate PARP inhibitor and Androgen-targeted therapy resistance through analysis of
solid and liquid biopsy samples from patients who progressed on PARP inhibitor therapy. These studies
will define the tumor-intrinsic factors that mediate tumor genome evolution resulting in PARPi resistance.
BRCA2 reversion mutations identified in mCRPC harboring PARPi therapy resistance.
This project is defining the causes and consequences of structural variation and epigenetic alterations in prostate tumors.
This project, a long-term collaboration with the AACR/Stand Up 2 Cancer West Coast Dream Team, is linking methylation
and structural variation to advanced prostate tumor biology by analysis of patient tumor biopsies. A current focus is to
define how the epigenome is altered in advanced prostate cancer, and how this information can lead to novel biomarkers and therapeutic strategies.
The DNA methylation landscape of advanced prostate cancer
Zhao SG*, Chen WS*, Li H* et al. Nature Genetics in press