Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Metastasis is responsible for more than 90% of prostate cancer-related mortality and remains a considerable challenge in developing effective and durable therapies. Interestingly, 80% of all patients with metastatic prostate cancer (PC) develop bone metastases, dropping their 5-year survival to 26-30%, which underscores the need to reveal, understand, and exploit the unique cellular pathways, mechanisms, and oncogenic events that drive the initiation, formation, and maintenance of PC bone metastases. Essential to the development and preclinical screening of novel therapeutic technologies, there is an urgent need for a reliable and convenient in vitro/in vivo cellular model that recapitulates the unique PC bone metastatic environment. Prostate-Specific Membrane Antigen (PSMA) is expressed on the epithelium of nearly all PCs and increases with progression to castration resistance and metastatic disease. Tumor vascularity has a major impact on tumor growth and drug responsiveness with respect to tumor oxygenation and permeability of chemotherapeutics. PC cell-vascular endothelial cell (EC) crosstalk induces expression of PSMA on the surface of tumor vasculature in PC and in renal cell carcinoma and breast, lung, gastric, colorectal, pancreatic, and bladder cancers . Consequently, PSMA-targeted therapies (radiotherapeutics as well as small-molecule and antibody drug-conjugates) are actively being pursued and are anticipated to modulate PC tumor vasculature and diseases involving pathological angiogenesis. Our long-term goal is to develop a flexible 3D bioprinted tumor microenvironment model that can serve as a preclinical screening platform to enhance the development of novel therapeutic agents for various cancers. This study aims to develop a well-defined in vitro model that mimics the molecular, cellular, and metabolic interplay in the bone-tumor microenvironment of metastatic PC and confirm that it is similarly responsive as the clinical condition is to novel targeted diagnostic and therapeutic agents. The rationale for undertaking the proposed research is that developing a reproducible predictive PC tumor-bone model will accelerate therapeutic development for PC and minimize clinical failures.
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).
