Research: 2018 – Windsor

Project Title:
Suppression of prostate-specific membrane antigen (PSMA) in poor prognostic neuroendocrine prostate cancer differentiation, imaging and therapy
Investigators:
Dr. Lisa A. Porter, University of Windsor, Biological Sciences
 
Dr. Lisa Porter received her BSc in Biology & Pharmacology (McMaster University) and her PhD in Medical Sciences (McMaster University). She conducted her postdoctoral fellowship in Chemistry & Biochemistry at the University of California San Diego. She began as a tenure track Assistant Professor in Biological Sciences at the University of Windsor in 2004. Currently she is a tenured Professor in Windsor and is the Translational Director of the Windsor Cancer Research Group. Porter has received many awards including a CIHR new investigator award, an Assumption University Research Chair and was an inaugural member of the College of New Scholars, Artists and Scientists of the Royal Society of Canada. Porter holds grants from the CIHR and NSERC and has a team of approximately 20 trainees spanning from undergraduates, MSc/PhD, post-doctoral and research associates. Her research focuses on the biological mechanisms driving progression for specific cancers with a focus on breast, brain, liver and more recently prostate. Her lab has developed several cell and animal models that will be critical to the advance of this program, this includes 3 full patents on technology that uniquely positions the Porter lab to conduct studies on Spy1 function. She also has close collaborative ties with the Windsor Cancer Centre and Henry Ford Hospital and is currently the PI on 2 investigator lead clinical trials.
Project Abstract:
The primary male sex hormone testosterone regulates development of male reproductive tissues. Testosterone binds to the androgen receptor (AR) triggering a cascade of signals that ultimately cues cells to grow and divide. In a majority of prostate cancers, AR levels are elevated which drives formation of prostate cancer tumors. Anti-androgen drugs have been developed to inhibit this mechanism. However, in some prostate cancers the AR can be suppressed, making anti-androgen therapy ineffective. These patients are found to be more resistant to all therapies. Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is over-expressed in a majority of prostate tumors as well as in metastatic lesions. Imaging prostate cancer using PSMA is a very useful approach. However, a few clinical reports suggest that PSMA-targeted imaging is not able to detect some aggressive tumors. With Ride for Dad funding in 2018 we have provided convincing data demonstrating that indeed PSMA is not a reliable marker for some of patients, and we have begun to propose more rigorous options for these patients. This proposal will determine how PSMA is suppressed and it will be the first to investigate the alternative options for PSMA-imaging for some of the most aggressive prostate cancers.
Scientific Abstract:
Prostate adenocarcinoma (PCa) can progress to an aggressive treatment resistant subtype termed neuroendocrine prostate cancer (NEPC). The majority of NEPC tumors are androgen receptor (AR)-negative and they express common NE markers. Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is over-expressed in a majority of PCa tumors as well as in metastatic lesions. Recent clinical reports however suggest that PSMA-targeted imaging is not able to detect NEPC tumors. Determining how PCa tumors progress to become resistant to therapy and become PSMA-suppressed is a high priority. Our lab has characterized a novel cell cycle regulator, coined Spy1, which is found in many aggressive forms of cancer. We have provided convincing data demonstrating that indeed PSMA is not a reliable marker for NEPC and we have begun to propose more rigorous options for this aggressive form of PCa. We have exciting data to support that elevated Spy1 levels correlate with suppressed AR expression. In this work, we evaluate the role of Spy1 in PCa progression, PSMA-suppression and address whether PSMA-loss and Spy1 amplification could represent a novel marker for NEPC patients. This research could lead to higher success rates of NEPC diagnosis and survival of patients with NEPC.
Impact on prostate cancer patients:
Emerging data from prostate cancer clinical trials demonstrate that up to 30% of men eventually evolve or progress to neuroendocrine prostate cancer (NEPC). Patients with this class of prostate cancer do not respond to hormonal therapy; they have high metastasize rate, and have a poor prognosis with an average survival of less than one year. This project will test a novel diagnostic approach for accurate and timed detection of progression to NEPC. In addition, this work will be the first to test this promising approach as a therapeutic that could offer new hope for patients with this aggressive form of cancer.