# Convergence of Endothelin-1 and Androgen Signaling in Prostate Cancer Bone Metastasis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Prostate cancer is the most common deadly cancer of men. Bone metastasis is a painful complication of
advanced prostate cancer associated with significant morbidity. Endothelin-1 (ET-1) is a prostate cancer-
secreted factor that activates the osteoblast endothelin A receptor (ETAR) causing osteoblast proliferation and
pathologic new bone formation. In turn, osteoblasts send chemotactic and growth cues back to the prostate
cancer cells. Preliminary data have unexpectedly demonstrated that ablation of both ET-1 and androgen action
in osteoblasts is necessary to reduce bone lesion growth in castrate-resistant prostate cancer (CRPC).
Furthermore, osteoblast generation of active androgens from adrenal dehydroepiandrosterone (DHEA) further
fuels osteoblast-directed prostate cancer progression in bone.
 The goals of this proposal are to investigate the actions of ET-1 and androgen on tumor burden in an
animal model prostate cancer bone metastasis in three specific aims. Aim 1 will examine the effects of
castration and DHEA replacement combined with ETAR blockade in a “humanized” animal model of prostate
cancer bone metastasis. Scid mice will undergo castration or sham surgery, and treatment with the ETAR
antagonist zibotentan or a vehicle control. The effects of sustained-release DHEA to negate the effects of
combined zibotentan and castration on the development of prostate cancer skeletal lesions will be tested. It is
expected that DHEA treatment, in castrated mice treated with ETAR blockade, will increase the development
and/or size of prostate cancer lesions in bone compared to control mice not receiving DHEA. Aim 2 will
examine the effects of Hsd3b7 knockout on the progression of prostate cancer bone lesions in DHEA-treated
mice. It is hypothesized that the protein encoded by Hsd3b7 is responsible for osteoblast conversion of DHEA
to androstenedione, and androstenediol to testosterone. It is expected that knockout of Hsd3b7 will negate the
effects of DHEA on the development of prostate cancer lesions in castrated mice treated with ETAR blockade.
Aim 3 will determine if combined ETAR blockade and androgen depletion prevents the initiation of skeletal
lesions, the progression of established lesions, or both. The combination of castration and ETAR
pharmacologic blockade reduced the number of skeletal lesions in a mouse model of bone metastasis
compared to either alone. The timing of androgen depletion and ETAR blockade required to reduce skeletal
tumor burden is unknown. Male scid mice will undergo castration or sham surgery before inoculation of tumor
cells or at the point when skeletal lesions have been established. It is expected that the combination of
androgen depletion and ETAR blockade will prevent both the initiation and the progression of established
lesions.
 ADT is the standard treatment in men with metastatic prostate cancer, but disease progression to CRPC
and bone metastases in most men mark the fatal form of the disease. The clinical imp...

## Key facts

- **NIH application ID:** 9890433
- **Project number:** 2I01BX001370-05A2
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** GREGORY A CLINES
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2013-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890433

## Citation

> US National Institutes of Health, RePORTER application 9890433, Convergence of Endothelin-1 and Androgen Signaling in Prostate Cancer Bone Metastasis (2I01BX001370-05A2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9890433. Licensed CC0.

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