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

描述(申请人提供)：发现在去势耐受前列腺癌中存在持久的雄激素信号，这一发现导致了第二代AR抑制剂的开发，并显示出对存活率的适度改善。除了导致AR信号异常的改变外，在转移性前列腺癌标本中还经常观察到其他一些分子改变，包括肿瘤抑制基因PTEN和TP53的丢失，以及涉及ERG的基因组重排。针对PI3K通路的几种新疗法已经开发出来，目的是提高晚期恶性肿瘤患者的存活率。我们最近已经证明，PI3K和AR通路通过相互反馈相互调节，抑制一个通路激活另一个通路，维持肿瘤细胞的存活。重要的是，我们已经证明，在临床前模型中，联合药物抑制PI3K和AR信号导致前列腺癌近乎完全消退。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，我们启动了一项Ib期临床试验，评估对去势耐药前列腺癌患者的PI3K和AR抑制。目前建议的长期目标是确定对PI3K/AR抑制的反应和抵抗的分子生物学，这将为个别患者和临床试验的发展提供信息。为了实现这些目标，我们将使用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的活检标本中的单个患者来源的前列腺癌器官(细胞系)。目标1将重点评估PI3K的临床前反应 并将这些发现与临床观察到的患者反应相关联。目的2将使用前列腺癌的GEM模型和已获得的新的细胞系来说明ERG在促进对PI3K和AR途径联合抑制的抵抗中所起的作用。目标3的重点将是确定联合治疗获得性耐药的机制。我们将利用前列腺癌的Pten P53条件零模型，该模型对PI3K和AR抑制显示出最初的戏剧性反应，然后是疾病进展，以及我们新衍生的前列腺癌有机化合物。重点和广泛的基因组方法将被用来识别与抗性相关的变化，这些变化将得到验证。总的来说，这项工作将提高我们对去势耐药前列腺癌的分子理解，其中AR和PI3K信号的变化协调调节细胞生存，指导未来临床试验的发展，并转变我们的个性化药物治疗方法。

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.