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 in humans. Thus, this project has the potential for very rapid translation to the clinic for the treatment of mCRPC.
Prostate cancer (PC) is the most commonly diagnosed cancer among U.S. Veterans and virtually all PC deaths are from metastatic, castration-resistant disease, which is currently incurable. PC most frequently metastasizes to the skeleton and causes extensive bone remodeling that greatly contributes to patient morbidity and diminishes the effectiveness of chemotherapies to treat PC. Human metastatic castration- resistant PC contains elevated levels of arginine vasopressin receptor 1a (AVPR1a). Small molecule inhibitors (antagonists) of AVPR1a are available and were found to be safe and effective in human clinical trials for non- cancer disorders. Preliminary data show that such an AVPR1a inhibitor greatly decreased the growth of human castration-resistant PC in two distinct mouse models including one that reproduces human bone metastatic disease. This proposal will evaluate the mechanisms and use of existing and clinically safe AVPR1a antagonists to substantially improve upon the treatment of incurable metastatic castration-resistant PC.
