The core foundation of precision medicine, and in turn, precision oncology, is a personalized approach to treatment that focuses on targeting specific molecular features that impact how cancer cells proliferate and spread. Targeted therapies, often exploiting specific proteins present on the surface of cancer cells, provide additional avenues for patients whose tumors express these targets, leading to more favorable outcomes than standard therapy alone. In prostate cancer, “PSMA [prostate specific membrane antigen] is the most comprehensively validated cell surface target,” said Dr. Erolcan Sayar, a postdoctoral research fellow in the Haffner Lab, part of Fred Hutch’s Human Biology Division. In recent years, great strides have been made in targeting PSMA for treatment, with radioligand therapy 177Lu-PSMA-617 receiving FDA approval for treating patients with advanced prostate cancer. “However, the expression levels of PSMA can vary among different tumors and even within the same tumor. The impact of heterogeneous PSMA expression on treatment options is primarily related to the use of PSMA-targeted therapies. These therapies, such as PSMA-targeted radionuclide therapy (e.g., 177Lu-PSMA-617), rely on the presence of PSMA on the surface of cancer cells for their effectiveness. Prior clinical trials have suggested that patients with low or heterogenous PSMA expression show reduced therapeutic benefit from PSMA-directed therapies,” explained Dr. Sayar. Based on this, Dr. Sayar, under the mentorship of Dr. Michael Haffner, led a study recently published in JCI insight, to better understand the heterogeneous expression patterns and molecular underpinnings of PSMA, with the goal of improving treatment options for patients with metastatic castration resistant prostate cancer (mCRPC), a lethal disease state.
For their study, the authors extensively profiled samples derived from patients with mCRPC and determined variable broad expression patterns across different subtypes of the disease. For example, tumors that rely on the androgen receptor for proliferation exhibited diverse PSMA expression patterns, while neuroendocrine tumors had generally lower expression of PSMA at both the mRNA and protein level. Next, to assess both inter- and intra-tumoral heterogeneity, the authors profiled samples derived from multiple distinct metastatic sites within the same patient with mCRPC. “A major advantage of our tissue donation based study is the ability to study multiple metastatic sites in a given patient. This setting allows for the detailed evaluation of inter- and intra-tumoral heterogeneity. We are grateful to the patients and their families for their contributions to the UW Medical Center Prostate Cancer Tissue Donation Program,” expressed Dr. Sayar. They observed substantial intertumoral (between different metastatic sites) heterogenous PSMA expression, in addition to heterogeneous expression of PSMA present intratumorally (between different spatial sites within one metastatic lesion).
Next, the authors set out to understand the molecular mechanisms driving this heterogeneous expression of PSMA. Differential gene expression analyses allowed them to determine a distinct expression profile associated with PSMA low tumors, including the enrichment of genes involved in cell proliferation. By querying the druggable genome database, the authors determined high expression of cell surface targets, for example MUC1, suggesting the presence of druggable targets in PSMA low tumors. The authors further investigated the molecular landscape of PSMA by investigating the relationship between the androgen receptor and PSMA. Although they were able to confirm that androgen receptor signaling can modulate PSMA expression, they also hypothesized that it was not the sole contributor and that epigenetic changes may also have a role to play.
Investigating epigenetic changes associated with PSMA expression resulted in the finding that DNA methylation alterations were tightly linked with PSMA expression, specifically controlled by DNA hypermethylation and active chromatin modifications, such as H3K27ac. Excitingly, treatment of prostate cancer cell lines with DNA methylation and histone acetylation inhibitors increased PSMA expression, a finding they replicated in vivo in patient derived xenograft models. The findings from this study will inform future clinical practice in advanced prostate cancer by demonstrating “that DNA methylation changes are tightly linked to PSMA expression, and the FOLH1 gene regulation is controlled by an interplay of repressive (DNA hypermethylation) and active (H3K27ac) chromatin modifications. Epigenetic changes are known to be at least partly reversible, and we showed that treatment with a variety of HDAC inhibitors resulted in robust increases in PSMA expression in vitro and in vivo. Our data provide a strong rationale for evaluating if HDAC inhibitors and other epigenetic modifiers can enhance PSMA expression to overcome treatment resistance and augment clinical outcomes of PSMA-directed therapies. Indeed, based on our study a clinical trial will open at Fred Hutch (led by Dr. Michael Schweizer) that will explore the used of HDAC inhibitors to increase PSMA expression,” summarized Dr. Sayar.
Going forward “our study sheds light on the epigenetic regulation of PSMA. The finding that DNA methylation and HDACs are involved in PSMA silencing paves the way for novel co-treatment strategies to enhance the efficacy of PSMA-directed therapies. In addition, our profiling efforts of tumors with low PSMA expression showed that there are several other putative cell surface targets that are specifically upregulated in PSMA negative/low tumors,” said Dr. Sayar. “Future efforts in the lab are focused on A) optimizing epigenetic therapies to increase PSMA expression, B) conducting proof-of concept clinical trials in which we critically test the activity of epigenetic drugs in augmenting therapeutic efficacy of PSMA-targeting agents and C) further develop alternative treatment strategies for PSMA negative tumors,” he continued.
This work was supported by funding from the National Institutes of Health, the National Cancer Institute, the US Department of Defense Prostate Cancer Research Program, the Doris Duke Charitable Foundation, the V Foundation, the Prostate Cancer Foundation, the Safeway Foundation, the Richard M. Lucas Foundation the FredHutch/UW Cancer Consortium, the Brotman Baty Institute for Precision Medicine, and the UW/Fred Hutch Institute for Prostate Cancer Research.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Michael Schweizer, Jessica Hawley, Lawrence True, Eva Corey, John Lee, Colm Morrissey, Peter Nelson, and Michael Haffner contributed to this work.
Sayar E, Patel RA, Coleman IM, Roudier MP, Zhang A, Mustafi P, Low JY, Hanratty B, Ang LS, Bhatia V, Adil M, Bakbak H, Quigley DA, Schweizer MT, Hawley JE, Kollath L, True LD, Feng FY, Bander NH, Corey E, Lee JK, Morrissey C, Gulati R, Nelson PS, Haffner MC. Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer. JCI Insight. 2023 Apr 10;8(7):e162907. doi: 10.1172/jci.insight.162907. PMID: 36821396; PMCID: PMC10132157.