Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein-coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

Identification of an oncogenic network with prognostic and therapeutic value in prostate cancer.

Identifying critical pathways governing disease progression is essential for accurate prognosis and effective therapy. We developed a broadly applicable and novel systems-level gene discovery strategy. This approach focused on constitutively active androgen receptor (AR) splice variant-driven pathways as representative of an intractable mechanism of prostate cancer (PC) therapeutic resistance. We performed a meta-analysis of human prostate samples using weighted gene co-expression network analysis combined with experimental AR variant transcriptome analyses. An AR variant-driven gene module that is upregulated during human PC progression was identified. We filtered this module by identifying genes that functionally interacted with AR variants using a high-throughput synthetic genetic array screen in Schizosaccharomyces pombe This strategy identified seven AR variant-regulated genes that also enhance AR activity and drive cancer progression. Expression of the seven genes predicted poor disease-free survival in large independent PC patient cohorts. Pharmacologic inhibition of interacting members of the gene set potently and synergistically decreased PC cell proliferation. This unbiased and novel gene discovery strategy identified a clinically relevant, oncogenic, interacting gene hub with strong prognostic and therapeutic potential in PC.

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR.

Predation risk modifies behaviour by shaping the response of identified brain neurons.

Interpopulation comparisons in species that show behavioural variations associated with particular ecological disparities offer good opportunities for assessing how environmental factors may foster specific functional adaptations in the brain. Yet, studies on the neural substrate that can account for interpopulation behavioural adaptations are scarce. Predation is one of the strongest driving forces for behavioural evolvability and, consequently, for shaping structural and functional brain adaptations. We analysed the escape response of crabs ITALIC! Neohelice granulatafrom two isolated populations exposed to different risks of avian predation. Individuals from the high-risk area proved to be more reactive to visual danger stimuli (VDS) than those from an area where predators are rare. Control experiments indicate that the response difference was specific for impending visual threats. Subsequently, we analysed the response to VDS of a group of giant brain neurons that are thought to play a main role in the visually guided escape response of the crab. Neurons from animals of the population with the stronger escape response were more responsive to VDS than neurons from animals of the less reactive population. Our results suggest a robust linkage between the pressure imposed by the predation risk, the response of identified neurons and the behavioural outcome.