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

有效抑制去势前列腺癌(CRPC)新疗法的临床反应 配体合成(如阿比特龙)或阻断雄激素受体(AR)配体结合域(LBD)(如MDV3100)已令人印象深刻。然而，患者总是会进步的。如果要实现对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轴仍然是抵抗针对AR途径的新药物的主要驱动因素，并且AR-LBD相互作用的日益有效的取消将导致作为抗性重要组成部分的配体非依赖性AR变体(ARV)的表达。我们假设，患者在AR轴上的不同决定了对靶向这些通路的药物的敏感性，肿瘤内类固醇合成和AR或ARV表达的肿瘤特异性差异可以作为CRPC中靶向AR轴和串扰通路的药物反应的指标。 具体目的1：阿比特龙抑制肿瘤雄激素的临床试验 CRPC，以及类固醇生成、AR或ARV作为进展中耐药机制的作用。 具体目标2：确定AR轴中肿瘤特异性差异如何影响针对AR途径的新药物的反应和耐药性，包括LBD靶向(例如，阿比特龙，MDV3100)和非LBD靶向药物 LBD靶向AR抑制剂(例如EPI-002、T6)。这一目标的目标是确定如何表达 AR轴成分与AR通路抑制的抵抗有关，以及LBD是否缺失ARV 在AR-LBD定向治疗进展的肿瘤中成为关键靶点。 特定目的3.确定CRPC特异性ARv567变体的转基因表达是否影响 PTEN缺失驱动的肿瘤进展或对PI3K抑制的反应。由于多达40%的原发前列腺癌和70%的转移性前列腺癌存在PTEN缺失或PI3K/AKT激活(20，21)，这一目标的目的是确定ARV的诱导如何改变这种情况下的CRPC进展和/或影响针对AKT/PI3K通路的治疗策略。 我们的首要目标不仅是阐明对特定疗法的反应机制，而且在这样做的同时，更好地理解AR是如何尽管仍然是PCa的主要治疗靶点，但仍然躲避越来越有效的药物和多靶点治疗策略。

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.