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2024 Michael and Lori Milken Family Foundation – PCF Young Investigator Award

Establishing an Indication for Pyruvate Kinase Activator Therapy in Prostate Cancer

Daniel Schmidt, MD, PhD
Harvard: Beth Israel Deaconess Medical Center

Mentors: Matthew Vander Heiden, MD, PhD; Steven Balk, MD, PhD

Description:

  • Prostate cancer growth is fueled by a hypermetabolic state that depends on acquiring extracellular nutrients for proliferation, but no therapies target these altered metabolic requirements. Prostate cancer expresses exclusively the PKM2 isoform of pyruvate kinase (PK), the enzyme that catalyzes the final step of glycolysis. Prior data has shown that PKM2 must be in a low activity state for prostate cancer growth, while PKM2 activation inhibits tumor growth. 
  • Dr. Daniel Schmidt’s project will test the hypothesis that pharmacologic activation of PK could be an effective treatment for prostate cancer and will explore mechanisms of action and strategies to further increase efficacy of this approach.
  • The therapeutic efficacy of PK activators when combined with androgen deprivation and radiation therapy will be tested in prostate cancer models, and mechanisms of action will be identified.  
  • Tumor cell factors that confer sensitivity to PK activators will be identified and used to develop a molecular signature of sensitivity to PK activator therapy. 
  • Metabolic mechanisms, such as uptake of serine, will be identified that can be targeted to sensitize prostate cancer cells to PK activator therapy. 
  • If successful, this project will determine the potential of PK activators for treating prostate cancer and define the context in which PK activators are most likely to benefit prostate cancer patients. 

What this means to patients: Altered tumor metabolism is hallmark of prostate cancer but has been understudied as a possible treatment strategy. Dr. Schmidt’s project will determine the therapeutic benefit of combining PK activator therapy with androgen deprivation or radiotherapy, identify molecular features that predict for treatment response, and identify strategies to improve the efficacy of PK activator therapy by co-targeting serine import. The outcome of these preclinical studies will directly inform design of a PK activator clinical trial in prostate cancer.