Preclinical analyses of advanced prostate cancer in genetically-engineered mice

描述（由申请人提供）：我们的提案专注于通过调查性研究改善晚期前列腺癌男性的治疗选择。我们开发了一种新的实验模式，将基因工程小鼠（GEM）去势抵抗前列腺癌模型的临床前分析与复杂的跨物种计算分析相结合，以确定药物反应的主要调节因子。我们将把这一策略应用于阿比特龙的研究，阿比特龙是一种雄激素生物合成抑制剂，已被证明可以提高晚期前列腺癌患者的生存率。然而，尽管阿比特龙在临床试验中显示出令人鼓舞的结果，但并非所有患者都对阿比特龙有反应

DESCRIPTION (provided by applicant): Our proposal is focused on improving treatment options for men with advanced prostate cancer through investigative research. We have been developed a novel experimental paradigm, which combines preclinical analyses in genetically-engineered mouse (GEM) models of castration-resistant prostate cancer with sophisticated cross-species computational analyses to identify master regulators of drug response. We will apply this strategy to study Abiraterone, which is an inhibitor of androgen biosynthesis that has been shown to improve survival of men with advanced prostate cancer. However, although Abiraterone has shown promising results in clinical trials, not all patients respond to Abiraterone and most of those who do respond initially eventually fail treatment. Therefore, there is a critica need to pursue preclinical investigations to understand the mechanisms of action of Abiraterone in specific tumor contexts, and to define biomarkers predictive of response and resistance. Toward this end, our studies will focus on the following critical questions: (Aim 1): In which tumor contexts is Abiraterone responsive? We will perform preclinical studies using our GEM models, with the goal of identifying responsive and non-responsive tumors. Using gene expression signatures from these responsive and non-responsive tumors, we will perform cross-species computational analyses to identify master regulators that predict response to Abiraterone. Candidate master regulators will be validated to human prostate cancer, as well as to assess their functional relevance for response to Abiraterone in vivo. The goal of these studies is to elucidate mechanisms of Abiraterone response and biomarkers that predict its efficacy. (Aim 2): Can the efficacy of Abiraterone be improved by co-targeting with anti-androgens? We will perform preclinical studies in GEM models to evaluate the efficacy of Abireratone in combination with the anti-androgen, MDV3100. Using molecular signatures from mice treated with the individual versus combinatorial agents, we will identify master regulators that inform on the mechanisms of the drug interaction and as biomarkers of multi-drug response. Candidate master regulators will be validated to human prostate cancer, as well as in functional studies to asses their efficacy for drug action in vivo. The goal of these studies is to inform on mechanisms underlying the interaction of Abiraterone and anti-androgens, and to identify biomarkers of multi-drug response. (Aim 3): Why does treatment with Abiraterone fail? Considering mechanisms of intrinsic versus acquired resistance, we will establish GEM models that are resistant to Abiraterone treatment. Using molecular signatures from mice prior to or immediately following Abiraterone treatment or following tumor recurrence, we will identify master regulators of drug resistance. These will be validated to human prostate cancer, and to assess their ability to affect resistance to drug treatment. The goal of these studies is to eludicate mechanisms of Abiraterone resistance, and to identify biomarkers of resistance.