Synergistic Combination Treatment of Prostate Cancer Using CD46-Targeted Antibody-Drug Conjugate and Radioimmunotherapy
Abstract
Despite important research advances, late-stage, metastatic, castration-resistant prostate cancer is a disease with poor outcomes. For this reason, there is a need to develop improved therapeutic strategies to treat prostate cancers effectively. Additionally, many current cancer treatments have side effects that create difficulties for patients and decrease quality of life. Therefore, tumor-specific therapy preventing the side effects on normal body organs is vital. A therapeutic dose of the drugs can be delivered to destroy tumor cells by targeting specific proteins expressed on the tumor tissue. The goal of this grant application is to develop a treatment strategy for patients with prostate cancer. A high dose of a single drug is needed to get a good response for therapy, but this results in a toxic reaction to the body organs. We plan to combine the two-prostate cancer-targeted molecules to achieve a synergistic response for tumor killing at a lower dose. This combination therapy will result in a synergistic anti-tumor response with lower side effects. Therefore, this study contributes to the overarching challenge to develop treatments that improve outcomes for men with lethal prostate cancer. Recently, the concept of theranostics has revolutionized prostate cancer care, by combining high-sensitivity scanning together with targeted therapy. The current theranostic agents for prostate cancer are based on the presence of prostate cancer membrane antigen (PSMA) on tumor. However, many patients do not show the presence of PSMA. As we target the novel biomarker CD46, this therapeutic strategy could also help these patients with low or no PSMA on the tumor tissue. We are combining the CD46 targeted actinium-225 labeled antibody with an already known therapeutic molecule in clinical trials (CD46 ADC). We have conducted preliminary studies on combining these therapies with very promising results. Specifically, when used in combination, these two molecules show synergistic response at the lower doses as compared to their individual response. However, this needs to be confirmed with additional experiments using different tumor models, for example, tumors collected from patients and tumor spreading (metastasizing) to other body organs. Additionally, we have planned to carry out the toxicity study for individual drug molecules, as well as for combination therapy. As of now, we will be working with mouse models, but the results of these studies will form a solid ground for designing the therapy for men with prostate cancer. Another important fact of this study is the use of patient tumor tissues and metastatic tumor models in mice. The primary tumor at one location is different from the metastasized tumor in other body organs. We have adopted the strategy to make these metastatic tumor models in mice to study the effect of our combination therapy. This way, we will have knowledge about the action of combination therapy in advanced diseases, where it will be used in patients. The anti-cancer effect of therapeutic molecules will be studied in these advanced tumor models to find out the ways to improve anti-cancer response for men with advanced or metastatic tumors. We will study the molecular mechanism of the synergistic anti-cancer response. The mechanistic information will be utilized to change the doses of individual drugs to achieve maximum therapy response with minimum toxicity or side effects. Current experiments are at the preclinical stage; thus it will take 2 years to collect all of the data and analyze the results. However, the CD46 ADC is currently under a clinical trial at UCSF; thus, data from this study will help us to expedite our experiments and possibly work on human trials. The Principal Investigator, Dr. Anil Bidkar, is already working on some projects in Dr. Flavell’s lab at the Radiology Department, University of California, San Francisco. With the current proposal, Dr. Bidkar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310139
Entities
People
- Anil Parsram Bidkar
Organizations
- United States Army
- University of California, San Francisco