Targeting EZH2 for Novel Combination Therapeutic Strategies in Aggressive Variant Prostate Cancer
Abstract
Androgen deprivation therapy (ADT) is the current standard of care for metastatic prostate cancer, however, ADT fails to provide a durable response in 90 percent of patients due to acquired resistance and progression to castration resistance prostate cancer. Aggressive variant prostate cancer (AVPC) is a lethal phenotype that arises upon treatment with ADT, resulting in a lineage switch to a neuroendocrine morphology and the acquisition of molecular alterations that enable the cells to survive independent of AR signalling. Our work, and the work of others, has established that combinatorial loss/mutation of tumor suppressor genes - PTEN, TP53 and RB1 - drive lineage plasticity and therapeutic resistance to ADT. Further, epigenetic regulators, including EZH2, are indicated as driver effectors of lineage plasticity downstream of these key combinatorial genetic events. With the known activation PI3K/AKT/mTOR signalling due to PTEN and the data supporting epigenetic targeting of EZH2, it remains to be determined if co-inhibition of PI3K/AKT/mTOR and EZH2 will provide a significant response in AVPC patients. This project focuses on utilizing preclinical mouse and human models of AVPC to investigate the combinatorial effect of PI3K/AKT/mTOR and EZH2 inhibition on delaying progression to, or reversing, castration resistant disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1227502
Entities
People
- Katherine L Morel
Organizations
- Dana–Farber Cancer Institute