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2020 John Black Charitable Foundation-PCF Young Investigator Award

Alec Paschalis, MD, PhD

Institute of Cancer Research (ICR)

Mentors: Johann de Bono, MD, PhD; Stephen Plymate, MD; Ganesh Raj, MD, PhD

Metabolic Adaptations to Androgen Receptor Blockade and the Prostate Cancer Transcriptome.

Description:

  • Despite recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC), acquired resistant disease remains invariably fatal.
  • Androgen receptor (AR) variants such as AR-V7, which are constantly activated and lack the domains of AR that are targeted by existing AR-directed therapies, have been proposed to be key contributors to the development of treatment resistance in CRPC.
  • Efforts to target AR-V7 directly have, however, proven challenging. Thus there remains an urgent clinical need for novel therapeutic strategies to target AR-V7 to improve the outcomes of patients with advanced prostate cancer.
  • Alec Paschalis is studying the mechanisms that control the expression of AR-V7 in CRPC. In prior studies, Dr. Paschalis has identified that the 2-oxoglutarate (2OG)-dependent oxygenase JMJD6 is potentially a key regulator of AR-V7, and may be a promising new therapeutic target in prostate cancer.
  • In this project, Dr. Paschalis will explore the relationship between metabolism and transcription, and determine the mechanisms by which JMJD6 senses environmental changes and consequently regulates AR-V7 expression and drives prostate cancer growth.
  • Additionally, the potential for targeting JMJD6 as a novel therapeutic strategy in CRPC will be validated in preclinical models.
  • If successful, this project will elucidate major mechanisms of AR-V7 regulation and begin to identify new ways of treating prostate cancer.

What this means to patients: Dr. Paschalis is studying a novel environmental metabolic sensing pathway that may drive CRPC by altering expression levels of AR-V7.  This project will determine the mechanisms of this pathway and validate the potential for targeting this pathway as a new treatment strategy in CRPC.​