# A Novel Drug Target for Aggressive Prostate Cancer

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2020 · —

## Abstract

Metastatic castration resistant prostate cancer (mCRPC) commonly occurs in the skeleton and soft tissues
and is hallmarked by enhanced expression of androgen receptor (AR) and constitutively active AR variants
such as AR-V7. Transcriptome analyses of AR-V7 in CRPC cells identified increased expression of the
vasoconstrictor and G protein-coupled receptor, arginine vasopressin receptor-1a (AVPR1a). Analysis of
public human databases revealed significantly higher levels of AVPR1a mRNA in human specimens of
mCRPC compared to primary PC tumors. Selective depletion of AVPR1a decreased CRPC cell proliferation.
Conversely, expression of AVPR1a in androgen dependent PC conferred castration resistant growth in vitro
and in vivo. Consistent with a potential role of AVPR1a signaling in mCRPC, the physiologic ligand for
AVPR1a, arginine vasopressin (AVP), stimulated CRPC cell migration and invasion. Most importantly,
inhibition of AVPR1a using relcovaptan, a clinically safe, effective and orally available AVPR1a antagonist,
resulted in decreased CRPC growth in two distinct in vivo xenograft models, one representing newly emergent
CRPC and the other a model of late stage bone metastasis. In the latter model, relcovaptan also diminished
mCRPC-stimulated formation of bone lesions in vivo. PC-induced bone remodeling is a major cause of pain
and pathological fracture in men with mCRPC. Based on these preliminary results, this proposal will
investigate the hypothesis that AVPR1a is a therapeutic target for the most deadly form of PC, metastatic
disease. The objectives of this proposal are to delineate the mechanisms by which AVPR1a is regulated and
drives mCRPC and to evaluate the therapeutic potential of a safe and effective AVPR1a antagonist in
mCRPC. The following specific aims will be addressed: Aim 1. Dissect cross talk between AVPR1a and
AR/AR-V7; Aim 2. Interrogate the role of AVPR1a in mCRPC invasion and early metastasis; Aim 3. Determine
the role of AVPR1a in mCRPC late metastatic growth in the bone microenvironment. These objectives will
assess relcovaptan in conjunction with standard of care androgen deprivation therapy and chemotherapy in
robust CRPC animal models representing the continuum from early invasion to late metastatic growth. Even
“optimal” chemotherapy regimens, often the last line of options for the medical oncologist in treating mCRPC,
have limited efficacy and considerable toxicity. Compounds that can work in combination with lower dose
chemotherapy are an urgent and unmet clinical need. AVPR1a antagonists such as relcovaptan may be useful
not only in inhibiting progression and growth of mCRPC but also in preventing excessive osteoclast activity,
bone resorption and pathological fracture associated with mCRPC. The prior examination of relcovaptan in
human clinical trials (for non-cancer disorders) means that this compound can be more rapidly tested in
mCRPC clinical trials because dose, safety and efficacy have already been established i...

## Key facts

- **NIH application ID:** 9864013
- **Project number:** 5I01BX002773-03
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Kerry L Burnstein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864013

## Citation

> US National Institutes of Health, RePORTER application 9864013, A Novel Drug Target for Aggressive Prostate Cancer (5I01BX002773-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864013. Licensed CC0.

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