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).