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Leveraging Epigenomics to Target Acquired Vulnerabilities in Treatment Resistant Prostate Cancer

Principal Investigator:
Matthew Freedman, MD (Harvard: Dana-Farber Cancer Institute)

Co-Investigators: Mark Pomerantz, MD (Dana-Farber Cancer Institute), Wilbert Zwart, PhD (The Netherlands Cancer Institute), Sylvan Baca, MD, PhD (Dana-Farber Cancer Institute), Tesa Severson, PhD (Netherlands Cancer Institute)

Description:

  • Epigenetics are chemical modifications on DNA that control which genes can and cannot be expressed, and enable the human body to have many different cell types using an identical genome. Alterations in epigenetic patterns play a major role in cancer.
  • Dr. Freedman and team are investigating the role of epigenetic alterations in the development of resistance to anti-androgen therapy and progression to neuroendocrine prostate cancer (NEPC), a highly aggressive form of treatment-resistant prostate cancer.
  • The team previously identified patterns of epigenetic changes in prostate cancer samples that tracked with development of metastasis, metastatic castration resistant prostate cancer (mCRPC) and NEPC. 35 master transcription regulators, including FOXA1, HOXB13, and ASCL1, were found to collectively regulate the genes affected by the epigenetic changes, suggesting they are major drivers of prostate cancer progression and may be promising therapeutic targets.
  • In this project, the team will investigate whether targeting any of these transcription regulators in preclinical prostate cancer models will prevent the development of resistance to anti-androgen therapy and progression to NEPC.
  • For 25 of the 35 transcriptional regulators, candidate small molecule inhibitors are available. These will be assessed for their efficacy and safety as potential prostate cancer treatments.
  • The team will also create a metastatic prostate cancer epigenomic resource for the research community, to accelerate translational research on the development of treatment resistance and NEPC. This resource will be comprised of genomic, gene expression, and epigenetic data from patient samples across the advanced prostate cancer disease spectrum.
  • If successful, this project will enable the identification of novel therapeutic targets and treatments to prevent progression to metastatic treatment resistant prostate cancer.

What this means to patients: Once prostate cancer has progressed to a metastatic treatment-resistant state, there are no curative treatment options yet discovered. Dr. Freedman and team have identified a set of transcriptional regulators that control the conversion of prostate cancer to metastatic and treatment-resistant states, and are testing whether these may serve as promising treatment targets. This will lead to new treatments that prevent development of advanced, lethal prostate cancer. The team is also developing a prostate cancer research resource, which will enable other researchers to more rapidly uncover novel biology and treatment opportunities for prostate cancer patients.