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Initial CDAS Request Approval
Feb 6, 2024
Identifying molecular mechanisms underlying insulinemic dietary pattern effect on aggressive prostate cancer
Prostate cancer is common in countries with Western diets and represents a heterogeneous collection of subtypes with varying etiology and clinical behavior. Although a role for diet is suspected, no dietary factor (micronutrient, macronutrient, food group, or dietary pattern) has been convincingly associated with risk. We developed the hypothesis-oriented empirical dietary index for hyperinsulinemia (EDIH), representing the pattern of foods consumed as part of the diet that influences circulating C-peptide, a biomarker of β-cell secretory activity and insulin resistance. In 3 large cohorts, we showed that higher EDIH score was associated with greater risk of aggressive or lethal prostate cancer, and with greater risk of progression among men with non-metastatic disease. However, the specific mechanisms driving the effect of a high-EDIH dietary pattern on aggressive prostate tumor behavior have not yet been investigated. Insulin and insulin-like growth factor-1(IGF1) are potent activators of phosphoinositide-3-kinase (PI3K), a lipid kinase coordinating the utilization of glucose. PI3K pathway activation is modulated by PTEN (tumor suppressor gene), and we have shown that loss of tumor PTEN or high IGF1 receptor protein expression significantly increases the risk of lethal prostate cancer. In addition, the gene fusion TMPRSS2:ERG is the most common somatic event in primary prostate cancer, and ERG overexpression is often accompanied by PTEN loss in prostate cancer. Based on our preliminary data, we hypothesize that a habitual high-EDIH dietary pattern increases ligand-receptor density leading to chronic activation of the PI3K pathway, and the metabolic impact of the high-EDIH diet on PI3K pathway activation is stronger in tumors with PTEN loss and/or with ERG rearrangements. To test this hypothesis, we will assess tumor tissue molecular markers among 3,271 men with prostate cancer in the Health Professionals Follow-up Study (HPFS, n=51,529), Physicians’ Health Study (PHS, n=29,071), and Prostate Lung Colorectal and Ovarian (PLCO, n=76,678) cancer cohorts. We will: characterize the association of the insulinemic (EDIH) dietary pattern with major components of insulin/IGF1 signaling, including PTEN and ERG in prostate tumor tissue; evaluate the extent to which the association of EDIH on prostate cancer survival differs between molecular subtypes; and determine the influence of EDIH on prostate cancer survival and the extent to which it is modified by polygenic risk for dysfunctional insulin signaling and host characteristics. Unravelling the biological mechanisms driving the impact of the EDIH dietary pattern on aggressive disease will inform approaches for modifying dysregulated pathways in a targeted manner and that are more effective, low-cost, and scalable.
Aim 1: Identify major components of insulin/IGF1 signaling in prostate tumor tissue associated with the insulinemic (EDIH) dietary pattern. We hypothesize that among cancer-free men at baseline, higher vs. lower EDIH is associated with: (a) greater risk of tumors with higher expression of insulin receptor (IR) and IGF1R, (b) higher aggressiveness, i.e., greater proliferative activity (Ki-67) and greater de-differentiation (high Gleason grade), and (c) greater risk of developing tumors with PTEN loss or with TMPRSS2:ERG fusions compared to tumors with intact PTEN or that are ERG-negative.
Aim 2: Evaluate the extent to which the association of EDIH with PCa survival differs between molecular subtypes. (a) We hypothesize that among men diagnosed with PCa, higher vs lower post-diagnosis EDIH is associated with greater progression of tumors with PTEN loss or with TMPRSS2:ERG fusions compared to tumors with intact PTEN or that are ERG-negative. (b) We further hypothesize that a dietary change from high pre-diagnosis EDIH to low post-diagnosis EDIH impacts cancer progression and survival by tumor molecular subtypes - PTEN intact/loss and/or ERG positive/negative.
Aim 3: Determine the influence of EDIH on PCa survival and the extent to which it is modified by polygenic risk for dysfunctional insulin signaling and host characteristics. Among men diagnosed with PCa, we hypothesize that men consuming higher vs lower post-diagnosis EDIH dietary pattern have worse survival after diagnosis, (a) especially among men with higher polygenic risk scores (PRS) for dysfunctional insulin signaling than those with lower PRS (b) and among men with higher-than-normal waist circumference.
Fred Tabung (The Ohio State University Comprehensive Cancer Center)
Edward Giovannucci (Harvard T. H. Chan School of Public Health)
Lorelei Ann Mucci (Harvard T. H. Chan School of Public Health)
Konrad Stopsack (Harvard T. H. Chan School of Public Health)