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

利用下一代雄激素途径拮抗剂的反应和耐药机制

• 批准号: 9135214
• 负责人: ELAHE A MOSTAGHEL
• 金额: $ 19.94万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9135214
• 关键词: Anabolism; Androgen Receptor; Androgens; Binding; Biological Markers; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Enzymes; Exhibits; Exposure to; Goals; Growth; Hour; Individual; Length; Ligand Binding Domain; Ligands; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Mitotic; Neoplasm Metastasis; New Agents; PI3 gene; PI3K/AKT; PTEN gene; Pacific Northwest; Pathway interactions; Patients; Pre-Clinical Model; Proto-Oncogene Proteins c-akt; Receptor Cross-Talk; Receptor Signaling; Recurrence; Research Design; Resistance; Role; Steroid biosynthesis; Tissues; Transgenic Organisms; Up-Regulation; Variant; abiraterone; base; castration resistant prostate cancer; effective therapy; inhibitor/antagonist; men; neoplastic cell; next generation; novel; novel therapeutics; predicting response; prevent; resistance mechanism; response; targeted agent; targeted treatment; transcriptome; treatment response; treatment strategy; tumor; tumor growth; tumor progression

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.

对抑制前列腺癌（CRPC）的新疗法的临床反应，该疗法有效抑制 配体合成（例如abiraterone）或阻止雄激素受体（AR）配体结合结构域（LBD）（例如MDV3100）令人印象深刻。但是，患者总是进展。如果要实现长期控制或治愈CRPC，则定义对这些新引入疗法的抗性机制至关重要。 假设：我们的主要假设是，AR轴仍然是针对AR途径的新试剂的抗性的主要驱动力，并且越来越有效的AR-LBD相互作用的废除将导致表达配体独立AR变体（ARV）作为重要的耐药性成分。我们假设AR轴上的患者特异性差异决定对靶向这些途径的药物的敏感性，并且可以将肿瘤特异性的肿瘤特异性差异和AR或ARV的表达差异作为对靶向CRPC中ARAX和Crosstalk途径的反应的指标。 具体目标1：确定阿比罗酮在抑制肿瘤雄激素中的功效 CRPC，以及类固醇生成，AR或ARV的作用作为进展时抗性的机制。 具体目标2：确定AR轴的肿瘤特异性差异如何影响针对AR途径的新型药物的反应和抗性，包括靶向LBD的途径（例如Abiraterone，MDV3100）和非 - 靶向LBD的AR抑制剂（例如Epi-002，T6）。这个目标的目标是确定如何表达 AR轴组件与AR途径抑制的抗性以及LBD删除的ARV相关联 在AR-LBD定向疗法上进展的肿瘤的关键靶标。 特定目标3。确定CRPC特异性ARV567变体的转基因表达是否会影响 由PTEN损失驱动的肿瘤抑制肿瘤进展或对PI3K抑制作用。由于多达40％的原发性和70％的转移性前列腺癌表现出PTEN损失或PI3K/AKT激活（20,21），因此该目标的目标是确定ARV诱导将如何改变此环境中CRPC的进展并影响针对AKT/PI3K PATHWAY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，尽管如此，尽管继续保持PCA治疗的主要疗法目标，但仍继续揭示出越来越有效的药物和多目标治疗策略。