Friday, May 9, 2025
5/9/2025
Fluorescence image guided surgery, adjuvant PDT, and the immune response - Abstract. Prostate cancer (PCa) is the most prevalent cancer among men in the United States and radical prostatectomy remains one of the three treatment options for these patients. Screening with serum prostate specific antigen (PSA) allows for 78% of prostate cancers to be diagnosed at the early localized stage, facilitating therapy with radical prostatectomy (RP) or radiation therapy. However, ∼ 20% patients present with high-risk PCa, i.e., positive surgical margins (PSM) discovered after surgery during pathology of resected tissues. These patients with high-grade tumors also have a high risk of biochemical recurrence (>60%) and will ultimately develop lethal metastatic disease. Surgical approaches to prostate cancer are also associated with significant morbidity, e.g. incontinence (3-74%) and impotence (30-90%) due to the close proximity of the prostate gland to critical nerves and muscles. Therefore, there remains an unmet clinical need to improve surgical techniques for identifying and removing all cancerous tissue without damaging surrounding tissues during prostatectomy and to prevent relapse. The goal of this study is to provide a means to address both unmet needs, i.e., to more completely remove cancers and at the same time generate an immune response to help prevent local recurrence and metastatic disease. In the proposed study we will develop a precisely targeted theranostic agent, PSMA-1-Pc413, for both fluorescence guided surgery and photodynamic therapy (PDT) to effectively treat prostate cancer. The overall approach is to use the highly expressed and tumor selective prostate specific membrane antigen (PSMA) biomarker to target a highly fluorescent and potent photosensitizer, Pc4, to prostate cancer tumors. Following IV injection and recognition of the PSMA receptor on prostate cancer cells, PSMA-1-Pc413 will be used for fluorescence image guided surgery to remove the PCa from the flank of mice. Following excision, the surgical field will be irradiated with light to stimulate PDT to remove any non-visible or non- resectable cancerous cells. Furthermore, PDT may stimulate a local and even systemic immune response limiting local recurrence and metastatic disease. We will first test our hypothesis in immune competent syngeneic mouse prostate cancer models. Since efficacy trials in mice are not always predictive of human results, we will also test the approach in an orthotopic canine prostate cancer model; dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. After probe injection, PDT will be performed and the canine prostate gland and any extra-glandular cancer tissues will be resected. Correlation of the probe to cancerous tissues and the impact of PDT on cancer and surrounding normal tissues will be assessed using histopathology. Targeting and PDT studies in dogs will substantially encourage the potential to use this agent in dogs with spontaneous forming prostate cancers (beyond the scope of these studies) and clinical translation of the developed agent. Our innovative, combined theranostic approach, if successful, will significantly alter the way prostatectomies are performed in the future by: 1)increasing surgical efficacy; 2) prolonging progression-free survival; and 3) decreasing morbidity. No such approach has been reported for PCa.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).