Targeting the Noncanonical Phosphoinositide Kinases in p53-Mutant Breast Cancer
Abstract
The goal of this project is to continue to define the role(s) of a novel class of “druggable” phosphoinositide kinases: the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) in the growth of breast cancers with p53 mutations. Our previous studies found that a subset of breast cancers express high levels of these enzymes and that they are essential for the growth of p53 mutant breast cancer cells. Moreover, we showed that deficiency in these enzymes dramatically reduced tumor formation and increased tumor-free survival in mice lacking p53; however, at the time, it was not clear to us exactly how the PI5P4Ks promoted the growth of p53-deficient cancer cells. Excitingly, our recent studies shed light on this question, suggesting that these enzymes enhance the ability of cancer cells to adapt to nutrient scarcity commonly found in the tumor microenvironment. Collectively, our new studies suggest that PI5P4K inhibitors could effectively treat cancers with mutations in p53 by interfering with metabolism. However, additional research is needed to dissect the distinct roles of the PI5P4Ks and their relationship with p53 in tumor metabolism. The research proposed in this application is focused on determining the role(s) of these enzymes in p53-deficient cancers, especially in breast cancer. Overall, given the high frequency of p53 mutations in human cancers and how difficult it is to directly target p53 with drugs, our findings will provide vital information for developing successful PI5P4K inhibitors for p53-mutant cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910614
Entities
People
- Brooke M Emerling
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army