Friday, May 9, 2025
5/9/2025
Augmenting PSMA expression to enhance PSMA directed therapeutic efficacy - PROJECT SUMMARY/ABSTRACT Despite treatment advances over the past decade, metastatic prostate cancer (PC) remains a fatal disease. As such, there is an acute need for additional treatment options. The development of therapeutics that specifically target cell surface antigens represent an attractive approach. PSMA is a cell surface glycoprotein that is highly expressed on PC and because PSMA is relatively restricted to prostatic tissues, it represents an ideal theranostic target (i.e. useful for both ‘therapy’ and ‘diagnostics’). 177Lu-PSMA-617, a PSMA-directed radioligand, was recently approved by the FDA. While this is clearly a welcome treatment option, the median PFS has been reported to be <9 months and objective responses only occur in ~50% of patients. As such, strategies to augment the efficacy of PSMA-directed therapies are needed. Given that pre-clinical and clinical data has shown that high, uniform expression of PSMA is associated with optimal outcomes, one approach to augment the activity of 177Lu-PSMA-617 would be to administer a drug shown to increase PSMA expression. Our preliminary data from the University of Washington Rapid Autopsy (UW-RA) program has shown that a substantial proportion of men who die from metastatic castration-resistant PC (mCRPC) harbor tumors that have minimal to no PSMA expression. Mechanistic studies exploring the mediators of PSMA expression have demonstrated that epigenetic modifications represent key regulators of PSMA expression, with DNA hypermethylation of the FOLH1 (PSMA gene) and closed chromatin states associated with PSMA negative tumors. Importantly, we have demonstrated that the epigenetic changes resulting in PSMA repression are reversible and treatment with a variety of HDAC inhibitors results in robust increases in PSMA expression in vitro and in vivo. In this proposal we will conduct a first in field clinical trial testing a novel epigenetic ‘priming’ strategy designed to increase PSMA expression. We will use innovative technologies and unique biospecimens to refine our priming strategy and develop iterative approaches to maximize clinical benefit to PSMA-directed therapies. In Aim 1 we will evaluate the effect of the HDAC inhibitor vorinostat on PSMA expression as determined by PSMA PET imaging. We will also conduct detailed correlative work to assess imaging, blood and tissue-based predictive biomarkers. In Aim 2 we will refine our epigenetic ‘priming’ strategy and conduct preclinical studies that will inform iterative clinical trials. Finally, in Aim 3 we will utilize the UW-RA program to collect metastatic tissue from men who died from mCRPC and received 177Lu-PSMA-617. This will enable us to determine other regulators of PSMA expression and determine mechanisms of resistance to 177Lu-PSMA-617. Importantly, because these patients will also have baseline PSMA and FDG-PET imaging, we will be able to evaluate the dependency of PET imaging features on molecular phenotype. Collectively, these studies will be important to guide the clinical development of PSMA theranostics and will provide novel approaches to overcome primary and secondary resistance to PSMA-directed therapies.
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