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2023 Rob & Cindy Citrone – PCF Young Investigator Award

Precision Prevention and Treatment for Aggressive Prostate Cancer with PTEN Loss

Sinéad Flanagan, MB BCh BAO, MPH.
Harvard T.H. Chan School of Public Health

Mentors: Lorelei Mucci ScD, Konrad Stopsack MD MPH, Tamara Lotan MD.

Description:

  • Phosphatase and tensin homolog (PTEN) is the most commonly inactivated tumor suppressor gene in prostate cancer and its loss is strongly associated with increased risk for metastases and death from prostate cancer.
  • PTEN is also a critical negative regulator of insulin signaling through its role in the phosphoinositide 3-kinase (PI3K) pathway. Abnormally high insulin levels (hyperinsulinemia) induced by diet and lifestyle are associated with increased risk of prostate cancer development and progression.
  • In terms of PTEN, hyperinsulinemia has also been shown to accelerate prostate cancer progression in PTEN-deficient mouse models. Moreover, cholesterol metabolism and PI3K signaling are tightly linked, and statin therapy post-diagnosis may be specifically beneficial in the presence of PTEN loss.
  • Dr. Flanagan hypothesizes that tumors with PTEN loss are amenable to primary prevention and responsive to precision interventions involving insulin-modulating dietary and lifestyle changes and/or statin therapy following a prostate cancer diagnosis.
  • An ongoing, well-annotated, US population-based cohort study, with over three decades of long-term follow-up, along with an associated tumor biorepository, will be leveraged. Since 1986, this cohort study has prospectively collected clinical, dietary, and lifestyle data at regular intervals from more than 50,000 men initially free of cancer. Prostate tumor samples have been obtained from over 1,800 participants diagnosed with prostate cancer during this period and will undergo evaluation for genetically validated PTEN status.
  • The impact of a low-insulinemic diet and lifestyle on the incidence of prostate cancer with PTEN loss and whether such insulin-modulating dietary and lifestyle changes, along with statin use, can prevent progression to metastasis and death in prostate cancer patients with PTEN loss will be investigated.
  • If successful, this project will determine the potential benefits of a low-insulinemic diet and lifestyle for the primary prevention of prostate cancer with PTEN loss, while evaluating PTEN as a biomarker to identify patients with prostate cancer who are more likely to benefit from an insulin-lowering diet and lifestyle or statin therapy.

What this means to patients: Prostate cancers commonly lose PTEN, a critical tumor suppressor gene that negatively regulates the insulin signaling pathway. Dr. Flanagan and team will determine whether a low-insulinemic diet and lifestyle, and/or statin use, can prevent the development or progression of prostate cancer with PTEN loss. This will set the stage for clinical trial testing of diet and lifestyle-based strategies, which have also shown proven cardiovascular benefits, for the prevention and treatment of this highly aggressive form of prostate cancer.