Career Enhancement Program (CEP)

Title: Novel FAP-targeted Approach to Metastatic Prostate Cancer

Despite recent breakthroughs in disease detection and treatment, the most aggressive types of prostate cancer remain limited. The recent development of prostate-specific membrane antigen (PSMA)-directed imaging and therapy has made a significant impact on the lives of prostate cancer patients, mainly through (1) detection of cancer that was previously not seen until further advanced, and (2) by prolonging survival in patients with advanced disease through PSMA-targeted therapies. How-ever, the vast majority of patients with advanced prostate cancer relapse after initial favorable response to PSMA-targeted therapies. On average, these therapies prolong life by 4 months. Hence, novel diagnostic and therapeutic approaches that complement the current methods are needed to enhance the treatment of advanced prostate cancer. Fibroblast activation protein (FAP) is a molecule found in aggressive prostate cancer tumors. Preliminary research studies support that by targeting FAP, there is potential for the detection and treatment of prostate cancer. Hence, FAP-directed diagnostic tools and therapies must undergo a systematic evaluation. To this end, this proposal will demonstrate that FAP can be used as a target to detect prostate cancer, and that FAP can become a target for future therapies. Successful completion of this research proposal will justify future larger research studies to demonstrate that FAP-targeting diagnostic tools and therapies can make a difference in the lives of patients with advanced prostate cancer. 

 

Title: Imaging and Circulating Biomarkers for Early Identification of Treatment Response and Resistance in Neuroendocrine Prostate Cancer Treated with Targeted Radiopharmaceutical Therapies

Neuroendocrine prostate cancer is an aggressive form of prostate cancer with a poor prognosis and limited treatment options. A potential novel treatment approach for these cancers is to us a drug targeted specifically to a molecule expressed by these cancer cells labeled with a radioactive isotope. The radioactive isotope is then able to deliver radiation therapy targeted directly to the cancer. While such a treatment shows much, it is complicated to give, expensive, there are safety concerns when giving it, and it may still be an ineffective treatment for these patients whose cancers progress rapidly. This proposal aims to test tools that will help identify patients who are most appropriate for this treatment, and to identify response and resistance to this drug early in the course of therapy. We specifically propose to test two potential tools. The first is a tool that automatically looks at the response of each area of cancer within the body by comparing an image taken before therapy began and an image taken mid-way through the treatment course. The second tool identifies cancer cells circulating freely within the patient’s blood. The cancer’s expression of specific genes can be determined from these cells. This genetic information can potentially identify cancers that will best respond to this therapy, and can also be used to identify cancers responding to the therapy or progressing in spite of it. If the work in this proposal demonstrates that these tools can identify patients best suited for this targeted radioisotope therapy and identifies cancers responding and not responding early in the course of therapy, care for the patients with this aggressive form of cancer could be better personalized, to ensure they are receiving an appropriate and effective therapy for their cancer.  

Title: The role of ctDNA and CTCs in guiding initiation of salvage radiation therapy

Prostate cancer is the most common cancer in men, and is often treated by surgery. However, in 20-50% of cases, prostate cancer can recur after surgery. When this happens salvage radiation is used to treat the prostate cancer – but only cures the cancer in approximately 50% of men. One of the reasons for this low cure rate could be the lack of clear guidance on when patients should get radiation. Our proposal is investigating a blood test to help identify when men with recurrent prostate cancer after surgery should get radiation therapy. This blood test examines both the DNA and intact cancer cells in a patient’s blood. We first need to run a pilot clinical trial to determine if this blood test can accurately detect prostate cancer, and help predict how aggressive the cancer will be. Ultimately, we plan to use this blood test to run national clinical trials personalizing treatments for men with recurrent prostate cancer. 

 

Title: Interrogating the molecular signatures of Aggressive Variant Prostate Cancer via longitudinal liquid biopsy

Despite advances in treatment, metastatic prostate cancer is a lethal disease that remains the second leading cause of cancer-related death in men. Prostate cancers start out highly dependent on hormone signaling from androgens such as testosterone. A type of medication called androgen signaling inhibitors (ASIs)which block androgen hormone signaling are a very effective treatment for most men with metastatic prostate cancer, and can cause tumors to shrink, improve symptoms, and help men live longer with their cancer. Unfortunately, every patient’s cancer will eventually become resistant to ASI therapy and start to grow again and become lethal. About one out of five metastatic prostate cancers develop resistance to ASI is by becoming independent of androgen hormone signaling, and once this transition to androgen independence occurs, the cancer becomes very aggressive, rapidly lethal, and with limited effective treatments. In recent years, researchers have identified some molecular changes associated with this transition, including DNA changes in the prostate cancer cells that activate different types of signaling in the cancer cells including the pro-growthphosphatidylinositol-3-kinase (PI3K) pathway. However, there is still much that we do not understand about how and why this transition happens, so there are often delays or uncertainty in identifying when this change has occurred. The challenges in accurately identifying this transition in patients with metastatic prostate cancer has also been a barrier to developing treatments to prevent this transition or treat the cancer effectively after this transition occurs.  

To address this need for better ways to identify and understand the transition to androgen independent aggressive disease (AVPC), we leveraged a large dataset of RNA level profiling of metastatic prostate cancer tissue samples with known clinical outcomes that allows us to look beyond DNA changes into broad signaling pathway patterns that give insight into prostate cancer cell behavior. Using this approach, we found a signaling pathway pattern of low levels of androgen response (consistent with androgen insensitivity) and high levels of pro-growth pathways including the PI3K pathway associated with clinically aggressive prostate cancer. We think that this pattern, a type of molecular signature, will be a more sensitive and specific way to identify AVPC than what was previously available.  

To utilize this molecular signature to understand how, why and when prostate cancers transition to AVPC, 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,” and developed a platform to identify our AVPC molecular signature in cancer cells from the blood of patients with metastatic prostate cancer, which we have tested successfully in a small pilot cohort of metastatic prostate cancer patients. This would allow us to monitor for the development of the AVPC molecular signature over time in patients receiving ASIs for metastatic prostate cancer, as well as to understand how our molecular signature relates to clinical outcomes. Additionally, we can use our platform to understand whether increases in the pro-growth PI3K pathway are seen in conjunction with the AVPC molecular signature, as we expect from our tissue sample dataset, which would suggest that drugs that block the PI3K pathway, which are currently in testing in metastatic prostate cancer, may be an effective strategy to treat AVPC, as well as to evaluate for other possible drug targets for cancer cells with the AVPC signatures.  

The goals of this project are (1) test our liquid biopsy platform in a larger cohort of patients with metastatic prostate cancer to understand how often we see the AVPC molecular signature when patients develop ASI resistance, if we can detect the AVPC signature emerging before clinical ASI resistance is identified, and to understand the characteristics of tumor cells with the AVPC signature in the blood and (2) to evaluate the PI3K pathway activity in AVPC and non-AVPC tumor cells in the blood to understand whether targeting this pathway may be an effective strategy in AVPC. Success of this work will lay the groundwork for larger studies utilizing these tests to gain a better understanding of the molecular drivers of AVPC development, and to develop clinical trials testing whether identifying the AVPC transition early via the liquid biopsy test and changing to a different and more effective treatment approach improves outcomes for men living with metastatic prostate cancer.