Targeting a Lipid Kinase Regulator of Nuclear Akt in Breast Cancer
Abstract
The p53 gene (TP53) is mutated in more than half of all human tumors. Similarly, a molecule known as Akt that regulates cell growth is abnormally active in the majority of cancers. Mutant p53 and Akt drive tumor progression and metastasis, the spread of tumor cells to distant organs. TP53 mutations occur in 80% of triple-negative breast cancers (TNBCs), an aggressive type of breast cancer that is not hormonally driven and is defined by the lack of three receptors (estrogen receptor, progesterone receptor, and HER2) which are commonly expressed in other types of breast cancer. Abnormal activation of Akt is also a common feature of TNBC. TNBC disproportionately strikes young African American and Hispanic women, and often spreads rapidly to the lungs and brain despite treatment. Although there are a few alternatives to chemotherapy recently approved for TNBC, there is an urgent need to develop new therapies for this deadly disease. Recently, my colleague, Dr. Richard Anderson, and I discovered a new pathway that directly links mutant p53 and Akt, two key cancer genes that were not known to interact. We discovered that a molecule called inositol polyphosphate multikinase (IPMK) modifies mutant p53 and enables it to bind and activate Akt. Importantly, we also showed that inhibiting IPMK blocks nuclear Akt and triggers breast cancer cells to die, thereby pointing to IPMK as a promising drug target in breast tumors with mutant p53 and/or abnormally active Akt. This work was published in the prestigious journal Nature Cell Biology and received extensive media attention. Notably, IPMK has not been studied in breast cancer. We also recently discovered that a U.S. Food and Drug Administration (FDA)-approved antidepressant vilazodone, an IPMK inhibitor, blocks the nuclear Akt pathway, suggesting we may be able to repurpose this drug to treat breast cancer. In the proposed experiments, Dr. Anderson and I will partner and bring our different backgrounds to study IPMK as a new drug target and vilazodone as a potential breakthrough drug in breast cancer. Dr. Anderson is an expert in basic cell biology who has made landmark discoveries about the Akt pathway, and I am an expert in translational breast cancer research who has taken my lab discoveries into clinical trials in breast cancer. Our partnership has been very productive, resulting in two Department of Defense BCRP Breakthrough Awards and several publications, including two in the prestigious journal Nature Cell Biology. We will use our complementary expertise to investigate our hypothesis that inhibiting IPMK with drugs like vilazodone or by genetic strategies will block nuclear Akt activation and cause breast cancer cells to die, thereby stopping breast tumor growth and the spread of tumor cells (metastasis) to other organs. As such, our proposal addresses two BCRP Overarching Challenges: Revolutionizing treatment with less toxic and more effective options; and eliminating the mortality of metastatic breast cancer. We will test our hypothesis with three aims. In Aim 1, we will examine the effects of drugs such as vilazodone, which inhibit IPMK, and genetic strategies to turn off the IPMK gene required for the nuclear Akt pathway in TNBC cells. In Aim 2, we will use these same approaches (drugs and genetic strategies) to inhibit IPMK and examine the effects on the growth, survival, and movement of TNBC cells. In Aim 3, we will evaluate the effects of inhibiting IPMK (vilazodone and genetic strategies) to kill TNBC cells and stop the growth and metastasis of breast tumors in mice, using clinically relevant models such as patient-derived tumors and metastatic models of TNBC. Drug toxicity will be carefully investigated. These studies have been carefully designed to obtain critical proof-of-principle data to support a future clinical trial of vilazodone or other IPMK inhibitors in breast cancer. Indeed, we will review data with our clinical collaborator
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310554
Entities
People
- Richard A. Anderson
Organizations
- United States Army
- University of Wisconsin–Madison