Exploiting PI3K Pathway Inhibitor Therapy in Prostate Cancer

在分子靶向癌症治疗的评估中的限速步骤是匹配靶向肿瘤的能力。 正确的抑制剂和正确的病人。成功需要对患者的肿瘤组织进行分子分析， 发现生物标志物，预测敏感性的具体代理。该项目解决了这个问题， 前列腺癌，重点是PI 3-激酶（PI 3 K）通路的抑制剂。该项目建立在进展的基础上 Sawyers博士和Wu博士在资助研究mTOR抑制剂的前5年期间， 在开发基因工程前列腺小鼠模型和使用这些模型来评估 信号通路抑制剂。因为这个项目中的概念显然已经成熟，可以用于临床翻译，我们 将Sawyers博士最近搬迁到纪念斯隆-凯特琳癌症中心（MSKCC）视为一项资产， 提供访问由霍华德谢尔和彼得博士指导的杰出的临床前列腺癌组 Scardino，这将补充加州大学洛杉矶分校的临床项目。该项目将使用三个具有良好特征的 基因工程前列腺癌模型（PTEN，MYC，AKT）：（i）定义和测量途径- 使用小鼠模型和人肿瘤组织和血清中的特异性前列腺癌生物标志物特征 患者和（ii）评估PIS激酶途径抑制剂单独治疗和与激素联合治疗。 依赖性和激素难治性前列腺癌小鼠模型。这些发现将指导设计， 在前列腺癌中进行PI 3激酶通路抑制剂的新辅助临床试验， MSKCC和UCLA，并评估循环肿瘤细胞（CTC）作为癌基因组读数的效用， 前列腺癌患者。

A rate-limiting step in the evaluation of molecularly targeted cancer therapeutics is the ability to match the right inhibitor with the right patient. Success requires molecularly profiling of tumor tissue from patients and the discovery of biomarkers that predict sensitivity to specific agents. This project addresses this question in prostate cancer with the focus on inhibitors of the PI3-kinase (PI3K) pathway. The project builds on progress by Drs. Sawyers and Wu during the first 5 years of funding studying mTOR inhibitors and capitalizes on their expertise in developing genetically engineered prostate mouse models and using these models to evaluate signaling pathway inhibitors. Because the concepts in this project are clearly ripe for clinical translation, we view Dr. Sawyers' recent relocation to Memorial Sloan-Kettering Cancer Center (MSKCC) as an asset, providing access to an outstanding clinical prostate cancer group directed by Drs. Howard Scher and Peter Scardino, that will complement the clinical program at UCLA. The project will use three well-characterized genetically engineered prostate cancer models (PTEN, MYC, AKT) to: (i) define and measure pathway- specific, prostate cancer biomarker signatures in tumor tissue and serum using mouse models and human patients and (ii) evaluate PIS kinase pathway inhibitor therapy alone and in combination using hormone- dependent and hormone refractory prostate cancer mouse models. These findings will guide the design and execution of neoadjuvant clinical trials of PI3 kinase pathway inhibitors in prostate cancer, collaboratively at MSKCC and UCLA, and assess the utility of circulating tumor cells (CTCs) as oncogenomic readouts in prostate cancer patients.