# Integrating in vivo and in silico models of prostate cancer-bone interactions to overcome anti-tumor therapy resistance

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $203,567

## Abstract

PROJECT SUMMARY/ABSTRACT
Bone metastasis is the most frequent and lethal complication in prostate cancer patients. The interaction
between prostate cancer and stromal cells has recently emerged as a key player in supporting disease
progression and therapeutic response (and relapse). A major challenge in addressing this cooperation, however,
is due to the lack of suitable experimental systems that exploit a bone-centric approach for testing treatment
options. Consequently, the establishment of novel models that account for bone-epithelial interplays, including
multiscale computational models integrated with experimental evidence, is central to improve the outcome of
men with prostate cancer lesions in bone. In this context, we recently developed a strategy based on multiphoton
microscopy monitoring of prostate cancer in bone combined to an Agent-Based Model of Bone Metastasis
named A(BM)2, which consists of cancer cells growing within an acellular bone compartment. The A(BM)2 was
applied to the study of Radium 223 (223Ra), a bone-targeting radioisotope approved for the treatment of
metastatic prostate cancer. 223Ra induces profound but zonally confined cancer cell lethality at the bone interface
with no perturbation of the tumor core. Therefore, micro-tumors are eradicated or significantly reduced while
macro-tumors persist and expand due to low tissue penetrance of alpha radiation (~100 µm). The relative
inefficacy in controlling large tumors points to application of 223Ra in early bone-metastatic disease or in
combinatorial regimens for major lesions. Our initial findings gained the confidence of clinicians at Genitourinary
Medical Oncology Department, MD Anderson, which are planning a clinical trial to test efficacy of 223Ra in
oligometastatic prostate cancer patients. We here hypothesize that 223Ra will synergize with an agent targeting
the core of established lesions, thus impairing the main resistance niche. Accordingly, we will explore the
combination of 223Ra with cabozantinib, a kinase inhibitor that targets tumor blood vessels, prolongs progression
free survival, and exerts a profound impact on microenvironment remodeling. To this purpose, we will refine our
A(BM)2 by adding tumor vessels and bone stromal cells (osteoblasts, osteoclasts), retrieving their
pathophysiological features by advanced ex vivo multiphoton microscopy experiments. The therapy response to
223Ra and cabozantinib will be precisely integrated in the mathematical model based on own data and further
preclinical evidence made available by Genitourinary Medical Oncology Department. To generate confidence in
the A(BM)2, the response to cabozantinib will be initially simulated, followed by combinatorial experiments with
223Ra. This strategy will explore an extensive number of possible combinations, including different tumor sizes,
drug doses, treatment schedules and onset of resistance mechanisms and the best predicted outcome will be
further validated with ad hoc in vivo p...

## Key facts

- **NIH application ID:** 10525319
- **Project number:** 1R21CA267312-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Stefano Casarin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $203,567
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525319

## Citation

> US National Institutes of Health, RePORTER application 10525319, Integrating in vivo and in silico models of prostate cancer-bone interactions to overcome anti-tumor therapy resistance (1R21CA267312-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10525319. Licensed CC0.

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