Interrogating the Intersection of PSMA and PI3K Pathway Signaling as a Novel Treatment Approach in Treatment-Resistant Prostate Cancer
Abstract
Scientific Objective and Rationale: Despite advances in treatment, metastatic prostate cancer is a lethal disease that remains the second leading cause of cancer-related death in men. Chemotherapy and hormone therapy are the most effective treatments for men with metastatic prostate cancer and can cause tumors to shrink, improve symptoms from the cancer, and help men live longer with the cancer. Unfortunately, these treatments are not effective for all men with metastatic prostate cancer, and even when they do work, every patient’s cancer will eventually develop resistance to all therapies and become lethal. In recent years, researchers have identified multiple new targeted therapies that can be effective in metastatic prostate cancers after hormonal therapy stops working. These therapies target specific molecular changes in a patient’s cancer cells, leading to fewer side effects compared to chemotherapy. One type of therapy takes advantage of DNA changes present in more than 50% of metastatic prostate cancers, which can cause abnormal activation of a protein known as phosphatidylinositol 3- kinase (PI3K). Another type of therapy takes advantage of a protein called prostate-specific membrane antigen (PSMA), which is found in high levels on the surface of prostate cancer cells. While these both represent additional non-chemotherapy options for metastatic prostate cancer, each therapy is effective in less than half of patients who have the target, and even when they work, a cancer will inevitably develop treatment resistance, usually over the course of months. Data from prostate cancer cell lines in the lab suggests that these two proteins work together in ways that could promote treatment resistance, so combining treatments may be more effective for some patients than either one alone. However, the tests that we currently use to identify which individual patient would benefit from one of these therapies alone, both together or through a completely different approach, are not very effective. Because of this, patients may be exposed to side effects from a drug that will not control their cancer. We have taken advantage of the fact that cancer DNA and cells can be isolated from a simple blood draw in patients with metastatic cancer, sometimes called a liquid biopsy, to develop a unique set of tests to measure the activity of these proteins and related signaling pathways in cancer cells in the blood of metastatic prostate cancer patients, and through the incredible generosity of our patients, we have found differences in protein activity that could explain why some patients respond to each drug and some do not and could potentially predict which treatment approach will be effective for an individual patient. The goals of this project are (1) to use our liquid biopsy blood tests to determine which patients will benefit from each type of therapy on its own, and to understand why some patients benefit and some do not and (2) to use prostate cancer cells grown in the lab as well as liquid biopsy tests in prostate cancer patients to understand whether combining these PI3K and PSMA targeted therapies will increase the effectiveness of these therapies and whether we can use the liquid biopsy blood tests to determine which patients will benefit from the combination of both therapies. Applicability: If successful, this project will help men with metastatic prostate cancer, who are at the highest risk of developing therapeutic resistance and dying from prostate cancer, through the development of a new combination therapy approach to overcome PI3K- and PSMA-targeted therapy resistance, with integrated liquid biopsy testing to select patients most likely to benefit, increasing effectiveness and reducing unnecessary exposure to side effects from ineffective therapies. In addition to directly helping these patients, this research will contribute to the field of prostate cancer research by increasing our understanding of the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310164
Entities
People
- Marina Sharifi
Organizations
- United States Army
- University of Wisconsin–Madison