Nima Sharifi

MD

Cleveland Clinic

Kendrick Family Chair for Prostate Cancer Research

PLCO (Learn more about this study)

2016-0015

Jun 1, 2016

Role of diet and metabolism in risk of lethal prostate cancer in a PLCO cohort

Prostate cancer (PCa) and cardiovascular disease (CVD) share many metabolic derangements in cholesterol and sterol metabolism, with dysregulation of parallel biochemical pathways. For example, it is clear that virtually all aspects of cholesterol metabolism, ranging from cholesterol synthesis, deposition of native and oxidized forms into the arterial wall, and reverse cholesterol transport-mediated removal from the arterial wall, are linked to CVD pathogenesis. Similarly, numerous recently published studies have identified elevated cholesterol levels as a clinically relevant target in lethal PCa. Heightened plasma cholesterol levels are associated with increased risk of aggressive prostate cancer, with mechanistic studies suggesting that elevated intracellular cholesterol within PCa cells may contribute to androgen synthesis. Correspondingly, cholesterol-lowering therapies such as statins have similarly recently been associated with protective benefits in PCa, presumably via impacting membrane microdomains and consequent cellular signaling, and possibly steroidogenesis. Multiple molecular processes linked to cholesterol synthesis and cellular cholesterol metabolism of relevance to CVD pathogenesis have likewise recently been linked to lethal PCa.

We have recently described a molecular basis for how products of specific foods (i.e., red meats and other animal products) are converted by gut microbiota to specific chemical entities that perturb cholesterol metabolism and lead to heart attacks and stroke. In this proposal, these and other analytes will be interrogated for their role in the development of lethal prostate cancer.

The primary purpose of this project is to test the hypothesis that alterations in choline and other TMA-related nutrients and their gut microbiota generated metabolites (i.e. TMAO) are associated with risk of lethal PCa.
We believe that this objective will garner potentially clinically useful information for men wondering what dietary modifications they can make, if any, to lower their risk of dying from prostate cancer. A more difficult question to address is whether these metabolic pathways contribute to baseline risk of developing prostate cancer. This challenge stems from the high prevalence of undiagnosed indolent disease as evidenced by autopsy series, which has been posited to account for differences of risk factors for lethal PCa versus overall PCa in epidemiologic studies19,20. For these reasons, we believe it would be most fruitful to directly study lethal prostate cancer as the outcome.

Successful completion of the proposed study will lead to important new insights into the role of choline and gut microbiota driven pathways in the development of lethal PCa.

Aim 1) Test the hypothesis that gut microbiota-dependent metabolism of choline and other trimethylamine (TMA) nutrients such as trimethylamine-N-oxide (TMAO) are linked to lethal PCa risk.

We will perform a targeted metabolomics study using quantitative stable-isotope-dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of all lethal cases of PCa in the PLCO trial intervention arm for which biological samples are available (n=136) compared with men without lethal PCa at the time of case diagnosis (n=408, 1:3 case:control ratio) matched on age and race, to test the hypothesis that choline, L-carnitine, TMA, TMAO, and other related gut microbiota-dependent analytes are associated with lethal PCa risk.

Aim 2) Discover novel pathways linked to lethal PCa development using untargeted metabolomics.

In separate assays, we will use an unbiased metabolomics approach to evaluate for additional putative metabolic markers associated with lethal PCa risk using methods described previously in the cardiovascular disease literature which are described in detail in the full application. We will examine potential differences in metabolites between the aforementioned cases of lethal prostate cancer (n=136) and the controls (n=408) to identify pathways and potential dietary factors based upon nutrient metabolite signatures that potentially contribute to lethal PCa risk.