PSMA PET as a Biomarker for PI3K Signaling Axis in PTEN-Deficient Prostate Cancer
Abstract
Rationale: Most aggressive prostate cancer samples (>70%) share a common molecular event that involves partial or complete suppression of a key tumor suppressor protein called PTEN. This event leads to up-regulation of another critical pathway, PI3K, and enables the cancer cells to survive and thrive even during treatment (castration and/or anti-androgen therapy). Therefore, several drugs have been developed to suppress the PI3K pathway in hopes of benefitting patients. However, the results from clinical trials with these drugs have been disappointing. While many potential reasons can explain these results, one important contributing factor is the lack of non-invasive tests that can tell whether the drugs are efficient in impeding the PI3K pathway. The only current option is invasive biopsies, which are not always feasible because, in addition to being invasive, the tumors are located in difficult regions and most patients have multiple tumor sites all over the body, which makes biopsy impractical. Objective/Aims: To overcome this critical limitation, we are proposing to develop a non-invasive method based on PET (positron emission tomography) that can determine whether the drug being administered is enough to stop the PI3K signaling in all of the patient’s tumor sites. Our preliminary studies indicate that a well-known marker called PSMA (prostate-specific membrane antigen), for which there is currently a very good PET tracer under development (68Ga-DKFZ-PSMA11), can function as a surrogate for PI3K signaling. The studies we will carry out will conclusively establish that PSMA can indeed be a good surrogate for PI3K signaling; i.e., if the PET signal is high, PI3K is active, and if the signal is low, PI3K is inhibited. The advantage with PET is that we can capture real-time information about all the tumor sites simultaneously. This will be very important because it can also tell whether or not the drug dosing is sufficient for stopping the signaling. This will be done first in prostate cancer cell-based studies, which will allow us to test a wide variety of PI3K inhibitors under different conditions that will simulate genetic and molecular variability observed in patients. Next, we will perform testing in prostate cancer animal models with a number of drugs that will replicate the heterogeneity observed in patients with prostate cancer. Contributions to the Field of Prostate Cancer Research/Clinical Applications: Our work will immediately contribute to an improved understanding of various signaling partners that drive prostate cancer. If successful, our research will provide a new tool to patients with prostate cancer worldwide to test how well both current drugs and drugs under development can stop the PI3K pathway in these aggressive types of prostate cancer and to assess how well certain treatments can prolong life and promote a disease-free life. We believe the impact of our research in the clinic will be immediate and extensive, since treatment centers around the world now have ready access to the PET tracer, 68Ga-DKFZ-PSMA11, and based on our hypothesis and preliminary findings, can immediately test whether new drugs can impede the PI3K pathway.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910536
Entities
People
- Nagavarakishore Pillarsetty
Organizations
- Sloan-Kettering Institute
- United States Army