Project 1: High Grade Cancers: Capitalizing on PARPness in Ovarian Carcinoma

项目1摘要/摘要 不幸的是，在高级别浆液性卵巢癌(HGSOC)中几乎没有“可用药”的改变。因此， 同源重组缺陷引起的治疗责任探讨之二 在卵巢癌中最常见的突变是TP53基因突变，现已占据主导地位。造成的人力资源缺陷 通过生殖系和体细胞BRCA1/2异常以及其他通路成员的异常导致 合成致死性与抑制聚(ADP-核糖)聚合酶-1(PARP)相结合。然而，至关重要的是 知识上的差距阻碍了我们实现最佳实施PARP抑制剂的长期目标 (PARPI)包括：1)确定最有可能受益于PARPI的患者(即“PARPness”)和2) 能够预防或克服对PARPI耐药性的合理联合治疗的发展。 在我们之前的孢子项目中，我们开发并实施了dna、rna和蛋白质分析，旨在预测 受益于PARPI以及确定的人力资源途径的新成员，提供了扩大 可能受益于PARPI的患者群体。在这份孢子提案中，我们将完成正在进行的 PARPI和磷脂酰肌醇3激酶(PI3K)抑制剂的多臂联合试验 PARP耐药患者Wee1抑制与PARP加Wee1i的再增敏试验。使用这些 试验，基于来自细胞系、PDX和动物模型的强大初步数据，我们将完善 预测HGSOC对PARPI反应和耐药性的生物标志物。我们将进一步发展临床前和 临床数据证明在这个孢子上进行了一系列合理的组合试验。 我们最重要的假设是，确定一个“PARPness”分子图谱将扩大 HGSOC中的PARPI。作为推论，最佳结果只有通过合理的联合治疗才能体现出来 帕尔皮。因此，我们将对细胞系、动物模型和患者样本进行系统分析，结合 通过我们的组合适应性耐药治疗平台和超深shRNA和CRISPR/CAS筛查 到靶向分子，以系统地确定与PARPI治疗的合理组合。为了实现我们的目标 长期目标和检验我们的总体假设，我们提出了两个具体目标：具体目标1： 确定和提炼PARPI在卵巢癌中受益的生物标记物和特定目标2：建立 卵巢癌合理联合治疗的确定和优先顺序的临床前框架。 拟议研究的成功实施将有助于：1)发展个性化 基于分子图谱的晚期和复发卵巢癌妇女的治疗，2)扩大的 定义可能受益于PARP抑制剂的患者，3)确定对PARP的耐药机制 抑制剂，以及4)合理的联合治疗，将增加患者可能受益和 还可以防止出现抗药性。这一项目的成功实施不仅将改善 临床结果，但将指导未来临床试验的发展，以推动该领域的发展。

Project 1 SUMMARY/ABSTRACT Unfortunately, there are few “druggable” alterations in high-grade serous ovarian cancer (HGSOC). Thus, exploration of therapeutic liabilities engendered by defects in homologous recombination (HR), the second most common aberration in ovarian cancer after TP53 mutation, has taken a dominant role. HR defects caused by germline and somatic BRCA1/2 aberrations, as well as aberrations in other pathway members, lead to synthetic lethality in combination with inhibition of poly (ADP-ribose) polymerase–1 (PARP). However, crucial gaps in knowledge exist that hinder our long-term goal of optimal implementation of PARP inhibitors (PARPi) including: 1) the identification of patients most likely to benefit from PARPi (i.e., “PARPness”) and 2) the development of rational combination therapies able to prevent or overcome resistance to PARPi. In our prior SPORE project, we developed and implemented DNA, RNA and protein assays designed to predict benefit from PARPi as well as identified new members of the HR pathway, providing approaches to expand the population of patients likely to benefit from PARPi. In this SPORE proposal, we will complete our ongoing multi-arm combination trial with PARPi and phosphatidylinositol 3 kinase (PI3K) inhibitors and implement a resensitization trial in PARP resistant patients of Wee1 inhibition compared to PARP plus Wee1i. Using these trials, based on strong preliminary data from cell line, PDX and animal models, we will refine the utility of biomarkers to predict response and resistance to PARPi in HGSOC. We will further develop the preclinical and clinical data to justify a series of rational combination trials in this SPORE. Our overarching hypothesis is that the identification of a “PARPness” molecular profile will expand the utility of PARPi in HGSOC. As a corollary, optimal outcomes will only manifest by rational combination therapy with PARPi. Thus, we will perform a systematic analysis of cell lines, animal models and patient samples, combined with our combinatorial adaptive resistance therapy platform and ultra-deep shRNA and CRISPR/CAS screens to targetable molecules to systematically identify rational combinations with PARPi therapy. To accomplish our long term goals and to test our overarching hypothesis, we propose two specific aims: Specific Aim 1: To identify and refine biomarkers of benefit from PARPi in ovarian cancer and Specific Aim 2: To establish a preclinical framework to identify and prioritize rational combination therapies in ovarian cancer. The successful implementation of the proposed studies will contribute to: 1) development of personalized treatment of women with advanced and recurrent ovarian cancer based on molecular profiles, 2) an expanded definition of patients likely to benefit from PARP inhibitors, 3) identification of resistance mechanisms to PARP inhibitors, and 4) rational combination therapies that will increase the spectrum of patients likely to benefit and also prevent the emergence of resistance. Successful implementation of this project will not only improve clinical outcomes but will direct development of future clinical trials to advance the field.