Exploiting Mechanisms of Response and Resistance to Next Generation Androgen Pathway Antagonists

对去势抵抗性前列腺癌（CRPC）新疗法的临床反应， 配体合成（例如阿比特龙）或阻断雄激素受体（AR）配体结合结构域（LBD）（例如，MDV 3100）令人印象深刻。然而，患者总是进步。如果要实现CRPC的长期控制或治愈，确定对这些新引入的疗法的耐药机制至关重要。 假设：我们的主要假设是，AR轴仍然是对靶向AR途径的新药物的耐药性的主要驱动因素，并且AR-LBD相互作用的日益有效的消除将导致配体非依赖性AR变体（ARV）作为耐药性的重要组分的表达。我们假设AR轴的患者特异性差异决定了对靶向这些途径的药物的敏感性，并且肿瘤内类固醇生成和AR或ARV表达的肿瘤特异性差异可以用作CRPC中靶向AR轴和串扰途径的药物反应的指标。 具体目的1：在以下临床试验中确定阿比特龙抑制肿瘤雄激素的疗效： CRPC，以及类固醇生成、AR或ARV作为进展时耐药机制的作用。 具体目标二：确定AR轴中的肿瘤特异性差异如何影响对靶向AR途径的新型药物的反应和耐药性，包括LBD靶向（例如，阿比特龙，MDV 3100）和非 靶向LBD的AR抑制剂（例如，EPI-002，T6）。这一目标的目的是确定如何表达 AR轴成分与AR通路抑制的抗性相关，以及LBD缺失的ARVs是否 在AR-LBD定向治疗进展的肿瘤中成为关键靶点。 具体目标3。确定CRPC特异性ARv 567变体的转基因表达是否影响 肿瘤进展或对肿瘤中由PTEN缺失驱动的PI 3 K抑制的响应。由于高达40%的原发性前列腺癌和70%的转移性前列腺癌表现出PTEN丢失或PI 3 K/AKT活化（20，21），该目标的目的是确定ARV的诱导将如何改变这种情况下的CRPC进展和/或影响靶向AKT/PI 3 K通路的治疗策略。 我们的总体目标不仅是阐明对特定疗法的反应机制，而且在这样做的过程中，更好地了解AR如何继续保持PCa治疗的主要靶点，继续逃避越来越有效的药物和多靶向治疗策略。

Clinical responses to new therapies for castration resistant prostate cancer (CRPC) which potently inhibit ligand synthesis (e.g. abiraterone) or block the androgen receptor (AR) ligand binding domain (LBD) (e.g.,MDV3100) have been impressive. However, patients invariably progress. Defining mechanisms of resistance to these newly introduced therapies is crucial if long-term control or cure of CRPC is to be achieved. Hypothesis: Our primary hypothesis is that the AR axis remains a primary driver of resistance to new agents targeting the AR pathway, and that increasingly potent abrogation of the AR-LBD interaction will result in expression of ligand independent AR variants (ARVs) as important components of resistance. We hypothesize that patient-specific differences in the AR-axis dictate sensitivity to agents targeting these pathways, and that tumor-specific differences in intratumoral steroidogenesis and expression of AR or ARVs can be exploited as indicators of response to agents targeting the AR axis and crosstalk pathways in CRPC. Specific Aim 1: Determine the efficacy of abiraterone in suppressing tumor androgens in a clinical trial of CRPC, and the role of steroidogenesis, AR or ARVs as mechanisms of resistance at progression. Specific Aim 2: Determine how tumor-specific differences in the AR-axis influence response and resistance to novel agents targeting the AR pathway, including LBD-targeted (e.g., abiraterone, MDV3100) and non- LBD-targeted AR inhibitors (e.g., EPI-002, T6). The goals of this Aim are to determine how the expression of AR-axis components associates with resistance to AR pathway inhibition, and whether LBD-deleted ARVs emerge as key targets in tumors that progressed on AR-LBD directed therapy. Specific Aim 3. Determine whether transgenic expression of the CRPC-specific ARv567 variant influences tumor progression or response to PI3K inhibition in tumors driven by the loss of PTEN. As up to 40% of primary and 70% of metastatic prostate cancers exhibit PTEN loss or PI3K/AKT activation (20,21), the goals of this Aim are to determine how induction of ARVs will alter CRPC progression in this setting and/or influence treatment strategies targeting the AKT/PI3K pathway. Our overarching goal is not only to elucidate mechanisms of response to specific therapies, but in so doing, to better understand how the AR, despite continuing to remain the dominant target of therapy in PCa, continues to elude increasingly potent agents and multi-targeted treatment strategies.