Defining Response and Resistance to PI3K and AR inhibition in Prostate Cancer

描述（由申请人提供）：发现去势抵抗性前列腺癌中存在持续的雄激素信号传导，导致第二代AR抑制剂的开发，该抑制剂已证明可适度改善生存率。除了导致异常AR信号的改变外，转移性前列腺癌标本中还经常观察到许多其他分子改变，包括肿瘤抑制因子PTEN和TP53的缺失，以及涉及ERG的基因组重排。一些针对PI3K通路的新疗法已经被开发出来，目的是提高晚期恶性肿瘤患者的生存率。我们最近证明，PI3K和AR通路通过相互反馈相互交叉调节，即抑制一个激活另一个，维持肿瘤细胞存活。重要的是，我们已经在临床前模型中表明，PI3K和AR信号的联合药物抑制导致前列腺癌几乎完全消退。基于这些数据，以及最近完成的BOLERO2试验的成功证明了靶向PI3K和ER通路在乳腺癌中的治疗效果，我们已经启动了一项Ib期临床试验，评估PI3K和AR抑制对去势抵抗性前列腺癌患者的作用。当前提案的长期目标是确定对PI3K/AR抑制的反应和耐药的分子生物学，这将为个体患者和临床试验的发展提供信息。为了实现这些目标，我们将采用GEM模型和一种新的方法来研究来自PI3K/AR抑制剂临床试验患者活检标本的个体患者衍生的前列腺癌类器官（细胞系）。目的1将侧重于评估PI3K的临床前反应

DESCRIPTION (provided by applicant): The discovery that persistent androgen signaling is present in castrate resistant prostate cancer has led to the development of second generation AR inhibitors that have demonstrated modest improvements in survival. In addition to alterations leading to aberrant AR signaling, a number of other molecular alterations are frequently observed in metastatic prostate cancer specimens, including loss of the tumor suppressors PTEN and TP53, and genomic rearrangements involving ERG. Several novel therapies targeting the PI3K pathway have been developed, with the goal of improving survival in patients with advanced malignancies. We have recently demonstrated that the PI3K and AR pathways cross- regulate each other by reciprocal feed-back whereby, inhibition of one activates the other, maintaining tumor cell survival. Importantly, we have shown that combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in pre-clinical models. Based this data, and the success of the recently completed BOLERO2 trial demonstrating therapeutic efficacy of targeting the PI3K and ER pathways in breast cancer, we have initiated a phase Ib clinical trial evaluating PI3K and AR inhibition in patients with castrat resistant prostate cancer. The long-term objective of the current proposal is to define the molecular biology of response and resistance to PI3K/AR inhibition that will be informative for individual patients and the development of clinical trials. To accomplish these aims we will employ the use of GEM models and a novel methodology for the study of individual patient derived prostate cancer organoids (cell lines) derived from biopsy specimens of patients on clinical trials of PI3K/AR inhibitors. Aim 1 will focus on evaluating pre-clinical response to PI3K and AR inhibitors in individual prostate cancer organoids and correlate these findings with the patient response observed in the clinic. Aim 2 will address the role ERG plays in promoting resistance to combined PI3K and AR pathway inhibition using GEM models of prostate cancer and novel cell lines that have been derived. The focus of Aim 3 will be to identify mechanisms of acquired resistance to combination therapy. We will utilize the Pten p53 conditional null model of prostate cancer that displays an initial dramatic response to PI3K and AR inhibition followed by disease progression, as well as our newly derived prostate cancer organoids. Focused and broad genomic approaches will be used to identify alterations associated with resistance which will be validated. Collectively, this work will improve our molecular understanding of castrate resistant prostate cancer where alterations in AR and PI3K signaling coordinately regulate cell survival, guide the development of future clinical trials, and transform our approach to personalized medicine.