Peptide-Drug Conjugate as Bone-Targeted Therapy for Bone-Metastatic Prostate Cancer
Abstract
This project addresses the Area of Emphasis on develop treatments that improve outcomes for men with lethal prostate cancer. Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions. Development of bone metastases significantly decreases survival time (5-year survival rate: ~30%). Currently, PCa bone metastases remain incurable. Considering the morbidity associated with late-stage disease, there is an urgent need to develop novel strategies. One unique feature of PCa bone metastasis is the induction of aberrant bone overgrowth. Recent studies showed that tumor cells secreted BMP4 converts tumor-associated endothelial cells to become EC-to-OSB hybrid cells, which then become osteoblasts. EC-OSB hybrid cells in turn elicit paracrine effects on tumor cells to support PCa progression in bone. These studies revealed that EC-to-OSB hybrid cells are a unique cell type in PCa-induced bone lesion, suggesting it may serve as a target for treating PCa bone metastasis. In this proposed research, we will develop and test a new type of therapeutic that could help treat PCa patients with bone metastasis. The proposed new therapeutic, peptide-drug conjugates (PDCs), is a chemical combination of two types of molecules – a peptide capable of selectively binding PCa-induced EC-OSB hybrid cells and a high potency chemotherapy drug that is toxic to cancer cells. Conjugation of bone targeting peptides to high potency medicines can provide tissue-specific delivery to concentrate the pharmacology at a preferred site. Therefore, PDCs can maximize therapeutic effects and reduce off-target toxicities to normal tissues. The successful development of PDCs as targeted therapeutics to specifically target and destroy PCa-induced bone lesions can improve the quality of life of patients by preventing the adverse side effects of existing chemotherapy. At the end of this project, we will obtain proof in vitro that this approach works. We expect that another 4 years will be needed for further optimization and animal testing before putting into human clinical trials. If successful, PDC will make chemotherapy more efficacious and much safer and will have a tremendous impact on the improvement of survival rate and quality of life of patients with PCa bone metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310203
Entities
People
- Tsung Shih
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army