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.

Grant Number: 1R21CA282396-01A1
NIH Institute/Center: NIH
Principal Investigator: Leslie Caromile