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2025 Patrice & Precious Motsepe-PCF Young Investigator Award

Rationally Designed Therapeutic Strategies for Effective targeting of DNA-Hypomethylated Prostate Cancers

Pallabi Mustafi, PhD
Fred Hutchinson Cancer Center

Mentors: Michael Haffner; Peter Nelson 

Description:

  • Epigenetics is a major mechanism of controlling gene expression by adding or removing chemical groups on DNA to alter its 3D structure, permitting or preventing access to various genes. Altered epigenetics is a major driver of cancer progression and treatment resistance, by changing the gene expression programs of cancer cells. 
  • Methylation of DNA is one of the most important epigenetic regulatory mechanisms, where high levels of DNA methylation at gene sites shuts down gene expression. However, the impact of low levels of DNA methylation on gene expression are unclear.
  • Dr. Pallabi Mustafi has previously identified a distinct prostate cancer subtype that is characterized by severe low levels of DNA methylation across the genome, and has named these “DNA Hypomethylated Cancers” (DHMCs). This subtype has distinct molecular features and unique vulnerabilities to targeted therapies, particularly AKT inhibitors (AKTi).  These findings suggest an interaction between epigenetic states and AKT signaling, which Dr. Mustafi aims to uncover to enhance therapeutic efficacy.  
  • In this project, Dr. Mustafi will define the clinical and epigenetic context of DHMC through profiling of primary and metastatic castration-resistant prostate cancers; investigate the interaction between AKTi and global DNA methylation states; and will conduct preclinical testing of AKTi therapies in combination with epigenetic therapies. 
  • If successful, this project will define a novel epigenetic subclass of prostate cancer, enhance our understanding of global DNA methylation alterations in prostate cancer, and identify targetable vulnerabilities within this newly identified subtype of prostate cancer. 

What this means to patients: Dr. Mustafi and colleagues have recently identified a new molecular subtype of prostate cancer, characterized by extreme global loss of DNA methylation, which comprises ~30% of cases of castration resistance prostate cancer. This project will define the biology of this molecular subtype and identify possible treatments specifically effective in this subtype.  These findings will provide a robust preclinical foundation for near-term clinical translation, advancing precision medicine for prostate cancer.