Development and Preclinical Evaluation of a Novel Targeted Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer
Abstract
Prostate cancer is the second leading cause of cancer death among American men. The vast majority of these patients die of the development of metastatic castration resistant prostate cancer (CRPC), a lethal status of the disease. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer development and progression. Although AR-based targeting approaches are continuously being developed and improved, these AR-based treatments are not curative. In contrast, radiation therapy (RT) is one of the two curative treatments for localized prostate cancer. Recently, a prostate specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) has provided a potential curative RT for CRPC. PSMA is a specific cell membrane protein expressed in more than 80% of prostate cancer tissues, and PSMA-based targeted delivery allows specific delivery of therapeutic agents such as chemotherapeutic agents and radioisotopes to prostate cancer cells that express PSMA. TRT is a type of systemic RT to deliver radionuclide to a particular type of cancer cells. Promising results have come from a Phase III clinical trial of 177Lu-PSMA-617 for treatment of metastatic CRPC. However, toxicities associated with PSMA-expressing tissues such as salivary glands are often seen and have become a dosing limiting factor. Thus, improving the existing PSMA-based TRT with less toxicities and increased therapeutic efficacy is strongly desired. Protein arginine methyltransferase 5 (PRMT5) is a novel type of protein that can alter expression of genes by a process known as epigenetic regulation, in which no alteration in DNA of genome is needed. We have recently demonstrated that PRMT5 is a critical regulator of prostate cancer cell growth by controlling the expression level of AR. We have also demonstrated that PRMT5 regulates the expression of genes responsible for radiation-induced DNA damage repair such as DNA double strand break (DSB) repair. Because AR expression and cellular DSB repair ability are important determinants of prostate cancer cell’s response to RT, targeting PRMT5 would allow co-targeting of these two pathways and sensitize prostate cancer cells to RT. Preliminary evaluation of a potent and clinically approved PRMT5 inhibitor JNJ-64619178 (Phase I clinical trial for lymphoma and other solid tumors) also suggests that JNJ-64619178 (JNJ) is a potential radiosensitizer for prostate cancer treatment. It is hypothesized that PSMA-based TRT in combination with the PRMT5 inhibitor JNJ-64619178 will provide a novel, enhanced, and targeted RT for metastatic CRPC. To test this hypothesis, we will synthesize a novel conjugate 177Lu-PSMA-617-JNJ to co-deliver the radionuclide 177Lu and the radiosensitizer JNJ-64619178 to PSMA-expressing prostate cancer cells. We will determine its cellular and tumor uptake, biodistribution, and biological effect on AR expression and DSB repair (Aim 1). We will also conduct a preclinical evaluation in mice to compare its efficacy with 177Lu-PSMA-617 using both single administration and multiple administrations (Aim 2). Contribution to the Field and Timeline for Clinical Applicability: Completion of the proposed research will provide preclinical evidence that 177Lu-PSMA-617-JNJ is an effective and better TRT for metastatic CRPC. Because JNJ-64619178 is currently in a Phase I clinical trial, it is expected that clinical trials could be launched immediately after the completion of the proposed research (3 years). Patients That Can Benefit from the Proposed Research: Because more than 80% of CRPC tissues express PSMA, it is expected that the majority of metastatic CRPC patients will benefit from the proposed research. Additional Benefits: Since current treatment with 177Lu-PSMA-617 is often associated with toxicities (mainly dry mouth due to the expression of PSMA in salivary gland), 177Lu-PSMA-617-JNJ will not onl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110473
Entities
People
- Chang Deng Hu
Organizations
- Purdue University
- United States Army