PCAPIP · Towards understanding non-canonical phosphatidylinositol kinases in the maintenance of prostate metabolism.

Towards understanding non-canonical phosphatidylinositol kinases in the maintenance of prostate metabolism.

A strong body of evidence suggests that a large network of signaling enzymes, called lipid kinases, can add phosphate tags onto components of cellular membranes and are essential hubs for regulating cell metabolism. The most established is PI3K that can be specifically inhibited with drugs that are being tested in combination with AR treatments for PCa. Preclinical studies have revealed a direct connection between AR and PI3K signaling; however, clinical trials targeting both pathways have lacked efficacy, leading scientists to predict there are other related enzymes functioning to influence critical tumor survival programs. Herein, I propose exploring PI5P4K lipid kinases in PCa. This family of enzymes is closely related to PI3K and early work has implicated them as druggable cornerstones of tumorigenesis in other cancer types. This is the first project to examine PI5P4K function in the biology of the prostate. Preliminary data shows that PI5P4K protein is present in PCa tissue and cell models generated from patient tumors. Digging deeper, I have found a potentially important inverse relationship between PI5P4K expression and levels of AR pathway activity using genetic manipulation of PI5P4K levels in prostate cells. Perhaps most promising, I discovered that inhibiting PI5P4K in AR dependent PCa results in the exit of cell replication programs that tumors use to grow in size. I believe PI5P4K lipid kinases are unexplored cornerstones of cell metabolism and aim to be the first to establish their role in prostate biology. My hypothesis is that PI5P4K is a critical regulator of AR signaling that supports PCa cell survival by influencing metabolic stress cooping mechanisms. To test this I have the following objectives: (1) Establish the biological phenotype associated with PI5P4K expression in prostate cells, (2) Examine how targeting PI5P4K influences the molecular and tumorigenic characteristics of PCa, and (3) Uncover how PI5P4K supports changes to androgen dependence through control of prostate cell metabolism. In attempt to answer these questions I generated the first prostate-specific knock-out mouse model PI5P4K in both normal prostate and in combination with an established model of aggressive cancer. As well, advanced metabolomics technology was used to measure how PI5P4K influences metabolic networks that drive the survival of cancer cells. This first-in-class study aims to establish the role of a novel pathway that could be a key control in the progression to untreatable PCa.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз