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，这导致了第二代AR抑制剂的开发，这些抑制剂已证明可适度改善生存期。除了导致异常AR信号传导的改变之外，在转移性前列腺癌标本中经常观察到许多其他分子改变，包括肿瘤抑制因子PTEN和TP 53的丢失以及涉及ERG的基因组重排。已经开发了几种靶向PI 3 K通路的新疗法，目的是提高晚期恶性肿瘤患者的生存率。我们最近已经证明，PI 3 K和AR途径通过相互反馈相互交叉调节，由此抑制一个激活另一个，维持肿瘤细胞存活。重要的是，我们已经表明，PI 3 K和AR信号传导的组合药理学抑制在临床前模型中导致几乎完全的前列腺癌消退。基于这些数据，以及最近完成的BOLERO 2试验的成功，证明了靶向PI 3 K和ER途径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，评估了PI 3 K和AR抑制在去势抵抗性前列腺癌患者中的作用。目前提案的长期目标是定义对PI 3 K/AR抑制的反应和抗性的分子生物学，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，我们将使用GEM模型和一种新的方法来研究个体患者来源的前列腺癌类器官（细胞系），这些类器官来源于PI 3 K/AR抑制剂临床试验患者的活检标本。目标1将重点评价对PI 3 K的临床前应答 和AR抑制剂，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模型和已经衍生的新细胞系来解决ERG在促进对PI 3 K和AR通路联合抑制的抗性中所起的作用。目标3的重点将是确定对联合治疗的获得性耐药机制。我们将利用前列腺癌的Pten p53条件无效模型，该模型显示对PI 3 K和AR抑制的初始显著反应，随后是疾病进展，以及我们新衍生的前列腺癌类器官。将使用重点和广泛的基因组方法来鉴定与耐药性相关的改变，并对其进行验证。总的来说，这项工作将提高我们对去势抵抗性前列腺癌的分子理解，其中AR和PI 3 K信号传导的改变协调调节细胞存活，指导未来临床试验的发展，并改变我们的个性化医疗方法。

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.