# Influence of bone microenvironment on drug resistance in prostate cancer bone metastasis

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2022 · $346,350

## Abstract

In the United States, over 80% of prostate cancer patients die with bone metastases.
Second line hormonal therapies such as enzalutamide only improve overall patient
survival by a few months in about 50% of the patients, and almost all patients develop
drug resistance. Thus, there is an urgent need to determine the mechanisms of drug
resistance and to develop new approaches for overcoming such resistance and for
better treatment of prostate cancer bone metastasis.
Enzalutamide is a small-molecule inhibitor of the androgen receptor (AR). Our
preliminary study demonstrated that although enzalutamide inhibited the tumor growth of
castration-resistant prostate cancer C4-2B cells when xenografted orthotopically or
subcutaneously, it had no effect on the growth of C4-2B tumors in the bone and the
development of bone lesions. This data highlights a crucial role of the microenvironment
in enzalutamide resistance in prostate cancer bone metastasis. Interestingly, we found
that enzalutamide significantly and specifically reduced the TGF-β type II receptor
(TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate
cancer patients who had undergone the second line hormonal therapies such as
enzalutamide. To determine the role of TGFBR2 in the osteoblasts during bone
metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout
specifically in the osteoblasts. We found that Tgfbr2 KO in osteoblasts significantly
promoted prostate cancer bone metastasis. Based on these results, we hypothesize
that reduction of TGFBR2 in osteoblasts caused by enzalutamide results in resistance to
the drug in prostate cancer bone metastasis. The objectives of this proposal are to
determine how enzalutamide decreases osteoblast TGFBR2 and thus promotes prostate
cancer bone metastasis and to identify novel approaches to counteracting the
enzalutamide resistance.

## Key facts

- **NIH application ID:** 10242964
- **Project number:** 5R01CA230744-04
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Xiaohong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,350
- **Award type:** 5
- **Project period:** 2019-04-19 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242964

## Citation

> US National Institutes of Health, RePORTER application 10242964, Influence of bone microenvironment on drug resistance in prostate cancer bone metastasis (5R01CA230744-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242964. Licensed CC0.

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