Frontiers in Bone Metastatic Models for Prostate Cancer

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.