Integration of circulating tumor cell and nuclear imaging biomarkers to assess LuPSMA response and resistance in advanced prostate cancer patients

/abstract Prostate cancer accounts for 15% of malignancies and is the second leading cause of cancer-related death in men. The incidence of prostate cancer worldwide is expected to rise from 1.4 million annually in 2020 to 2.9 million by 2040. While outcomes for cancer localized to the prostate are generally good, they worsen for metastases (5-year survival: ~30%). Chemo-, hormonal, and immunotherapy options are limited for advanced prostate cancer and cause significant toxicity. Radiopharmaceutical therapy (RPT) is a new, promising systemic treatment that preferentially delivers ionizing radiation to tumors expressing certain molecular targets. Several RPTs targeting the prostate-specific membrane antigen (PSMA) are currently in clinical and research use. PSMA-RPT is effective for some patients, but identifying patients who will respond to PSMA-RPT and understanding why patients develop treatment resistance during PSMA-RPT remains challenging. Thus, there is an unmet clinical need for biomarkers to identify patients with advanced prostate cancer responsive to PSMA-RPT and robustly monitor treatment resistance during RPT-based therapy. PSMA-based molecular imaging shows potential for stratifying patient responders and non-responders for PSMA-RPT but remains imperfect. We and others have shown the potential of liquid biopsy approaches for treatment monitoring in prostate cancer patients, including different types of RPT. In particular, our group has developed a novel circulating tumor cell (CTC) biomarker strategy that allows not only the isolation of rare populations of CTCs in typically acquired clinical blood samples but also maintains their integrity to probe the transcriptomic profile of the CTCs. In preliminary testing, we have found that this novel CTC technology complements PSMA-based molecular imaging for monitoring patients being treated with the RPT agent 177Lu- PSMA-617 (LuPSMA). We have additionally developed novel machine learning approaches to refine and optimize the integration of these biomarkers. Therefore, in response to FOA PAR-21-290, we propose to systematically optimize and understand the integration of CTC and nuclear medicine imaging for LuPSMA assessment. Our overarching hypothesis is that fluid-based CTC and non-invasive imaging biomarkers are complementary and synergistic for assessing patient response to LuPSMA. We will achieve this goal through 2 specific Aims. Aim 1: Correlate pre-treatment CTC profiles with changes in PSMA-avid tumor burden during LuPSMA therapy. Aim 2: Correlate CTC and imaging biomarker dynamics during LuPSMA treatment with progression-free survival. If successful, the outcomes of this work will provide the impetus for widespread assessment of these integrated biomarkers in clinical trials and drive focused preclinical studies to understand RPT biology further. Project Number: 1R01CA302774-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Sheung Chee Thomas Ng (+1 co-PI) | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $684,107 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11205286