# Interplay between tumor and microenvironment in bone metastasis

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $470,956

## Abstract

Prostate cancer (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer
death in men over the age of fifty. Bone is the primary site of metastasis in patients whose CaP progresses
beyond organ confinement. The absence of curative therapies for metastatic CaP emphasizes the imperative to
develop innovative technologies for target-specific delivery of therapeutic agents as well as novel treatment
strategies that are efficacious with minimal toxicity. Our investigative team seeks to address different aspects of
CaP bone metastasis through a highly integrated and focused research effort that will enhance our
comprehension of the mechanisms underlying CaP progression and improve therapeutic strategies to eradicate
bone metastases and prevent relapse. Our early work using a subtraction hybridization screen identified two
unique genes, i.e., melanoma differentiation associated gene-9 (mda-9) and mda-7/IL-24 from terminally
differentiating human melanoma cells. Subsequent research established MDA-9 as a key promoter of cancer
invasion and metastasis, whereas MDA-7/IL-24 was recognized as a broad-spectrum anti-cancer therapeutic.
Using a newly developed syngeneic pre-clinical model of CaP bone metastasis, we will investigate the interplay
between CaP bone metastases and the bone niche orchestrated by MDA-9 and evaluate therapeutic activity of
‘first-in-class’ small molecule inhibitor of MDA-9 (i.e., PDZ1i) for targeting both metastatic CaP cells and the bone
niche. By exploiting the exquisite ability and high efficiency of T cells to locate and destroy disseminated cancer
cells, especially those in normally inaccessible sites, i.e., bone, we will engineer CaP-reactive T cells to produce
MDA-7/IL-24, a unique cancer-selective apoptosis-inducing cytokine, for improved capacity to attack potentially
antigenically heterogenous bone metastases. Last, based on the ability of PDZ1i to reprogram the immune niche
in the tumor microenvironment, we will combine engineered T cells producing next-generation MDA-7/IL-24
(“Superkine MDA-7/IL-24“, “S7M”), having enhanced secretion and stability, with MDA-9-targeted therapy for
synergistic elimination of CaP bone lesions. We anticipate that the insights garnered from these studies will
enable a more precise molecular understanding of bone metastasis development for target discovery, rational
design of improved cellular immunotherapy, and combinatorial treatment modalities optimized to achieve a
maximum therapeutic potential. Successful completion of this multidisciplinary, synergistic research program will
provide a rapid path to translate these technologies and strategies into the clinic to safely and effectively manage
this most common skeletal complication of CaP.

## Key facts

- **NIH application ID:** 10197281
- **Project number:** 1R01CA259599-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PAUL B FISHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $470,956
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197281

## Citation

> US National Institutes of Health, RePORTER application 10197281, Interplay between tumor and microenvironment in bone metastasis (1R01CA259599-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197281. Licensed CC0.

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