Therapeutic Targeting of a Lipid Kinase Regulator of Mutant p53 in Breast Cancer
Abstract
The p53 gene (TP53) is mutated in more than half of all human tumors. Mutant p53 drives both tumor formation and metastasis, the spread of tumor cells to distant organs. TP53 mutations occur in 80% of triple-negative breast cancers (TNBC), an aggressive type of breast cancer defined by lack of three receptors (estrogen receptor, progesterone receptor, and HER2) that are commonly expressed in other types of breast cancer. TNBC disproportionately strikes young African-American and Hispanic women, spreading rapidly to their lungs and brain despite treatment. Unfortunately, there are no alternatives to chemotherapy for TNBC because these tumors lack the receptors that have been successfully targeted in other types of breast cancer. Hence, there is an urgent need to develop new therapies for this deadly disease. Despite the widespread occurrence of TP53 mutations in cancer, there are no FDA-approved drugs that target p53. Recently, my colleague Dr. Richard Anderson and I discovered a new regulator of mutant p53, a molecule called PIPKIa. PIPKIa binds to mutant p53 and regulates its function by recruiting molecules called small heat shock proteins (sHSPs) that stabilize mutant p53 and allow it to drive tumor formation and metastasis. Importantly, we also showed that inhibiting PIPKIa causes mutant p53 to be destroyed in tumor cells, thereby pointing to PIPKIa as a promising drug target in breast tumors with mutant p53. This work was funded by our BCRP Breakthrough Award and published in the prestigious journal Nature Cell Biology. Unfortunately, there are still no potent and specific drug inhibitors of PIPKIa available for clinical trials. Hence, we propose to partner with Dr. Thomas Chung and his pharma-experienced drug discovery team at the Sanford Burnham Prebys Medical Discovery Institute to identify better PIPKIa inhibitors by screening several hundreds of thousands of their compounds. Notably, we have already started this collaboration and made significant progress in establishing a suitable drug screen for this purpose. We hypothesize that selective inhibitors of PIPKIa will be more effective at killing TNBC cells with TP53 mutations and less toxic to normal cells. As such, our proposal addresses two of the BCRP Overarching Challenges, including revolutionizing treatment with less toxic and more effective options and eliminating the mortality of metastatic breast cancer. We will test our hypothesis in three aims. In Aim 1, Dr. Cryns will determine whether turning off PIPKIa in TNBC cells with TP53 mutations stops them from growing and spreading to different organs (metastasizing) by killing the tumor cells. These studies will be conducted in cultured TNBC cells and in mouse models. In Aim 2, Dr. Chung and his team will screen >350,000 compounds to identify potent and selective inhibitors of PIPKIa. Dr. Cryns will then test the ability of promising PIPKIa inhibitors to stop the growth and kill breast cancer cells. In Aim 3, Dr. Cryns will test promising PIPKIa inhibitors against breast tumors in mice to determine if they stop growth by killing the tumor cells but not affecting normal cells. Dr. Chung will also investigate the mechanism by which these inhibitors work. Impact: We have discovered a new regulator of mutant p53 (PIPKIa) that is an exciting new drug target to kill breast tumor cells with TP53 mutations. In the proposed studies, we will identify potent and selective inhibitors of PIPKIa and test their activity in halting breast tumor growth. These studies will pave the way for a clinical trial of PIPKIa inhibitors in breast cancer. As such, our findings could revolutionize therapeutic approaches to the broad spectrum of breast cancers driven by TP53 mutation, including aggressive TNBC, by identifying and developing PIPKIa inhibitors as a novel treatment strategy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110129
Entities
People
- Vincent Cryns
Organizations
- United States Army
- University of Wisconsin–Madison