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

项目 1：高级别癌症：利用 PARPness 治疗卵巢癌

• 批准号: 10005294
• 负责人: GORDON B. MILLS
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005294
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Apoptotic; BRCA1 gene; Biological Assay; Biological Markers; Bos taurus PARP protein; Bypass; CDK4 gene; CHEK1 gene; CHEK2 gene; Cancer Center; Cancer Patient; Cell Line; Cells; Clinical; Clinical Data; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complement; Cyclin B; DNA; Data; Defect; Development; Doctor of Medicine; Equilibrium; Event; FOXM1 gene; Future; Genes; Goals; In Vitro; Knowledge; Lead; MEKs; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methods; Molecular; Molecular Profiling; Mutation; Oncogenes; Outcome; Ovarian Carcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Proteins; RNA; Recurrence; Research Design; Resistance; Retinoblastoma Protein; Role; Sampling; Series; Serous; TP53 gene; Testing; Therapeutic; Woman; arm; base; biomarker development; biomarker performance; cohort; combinatorial; design; druggable target; homologous recombination; improved; improved outcome; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; member; novel; novel drug class; patient population; personalized medicine; pre-clinical; predicting response; prevent; programs; research study; resistance mechanism; response; small hairpin RNA; success; synergism; three-dimensional modeling; tumor

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.

项目1摘要/摘要 不幸的是，高级浆液卵巢癌（HGSOC）几乎没有“可吸毒”改变。那， 探索由同源重组（HR）缺陷引起的治疗责任，第二个 TP53突变后卵巢癌中最常见的畸变是主要的作用。人力资源缺陷引起的 通过种系和躯体BRCA1/2的畸变以及其他途径成员的畸变，导致 合成致死性与抑制聚（ADP-核糖）聚合酶1（PARP）结合使用。但是，至关重要 知识中存在差距，阻碍了我们最佳实施PARP抑制剂的长期目标 （PARPI）包括：1）鉴定患者最有可能受益于PARPI（即“ Parpness”）和2 理性组合疗法的发展可以防止或克服对PARPI的抵抗力。 在我们先前的孢子项目中，我们开发并实施了旨在预测的DNA，RNA和蛋白质测定法 受益于Parpi，并确定了人力资源途径的新成员，提供了扩展的方法 可能受益于PARPI的患者人群。在这个孢子的建议中，我们将完成我们正在进行的 PARPI和磷脂酰肌醇3激酶（PI3K）抑制剂的多臂组合试验并实施 与PARP Plus WEE1I相比，在PARP抗性患者的PARP抗性患者中进行了敏化试验。使用这些 试验，基于细胞系，PDX和动物模型的强初步数据，我们将完善 生物标志物可以预测HGSOC中对PARPI的反应和抗性。我们将进一步发展临床前和 临床数据以证明该孢子中的一系列合理组合试验是合理的。 我们的总体假设是，识别“ parpness”分子概况将扩大 HGSOC的PARPI。作为推论，最佳结果只能通过合理组合疗法与 parpi。这，我们将对细胞系，动物模型和患者样品进行系统分析，合并 使用我们的组合自适应抗性治疗平台以及超深shrna和CRISPR/CAS屏幕 可靶向分子系统地鉴定与PARPI治疗的合理组合。完成我们的 长期目标并检验我们的总体假设，我们提出了两个具体目标：特定目的1： 在卵巢癌中识别和完善来自PARPI益处的生物标志物，并具体目标2：建立 临床前框架，旨在识别和优先考虑卵巢癌的合理组合疗法。 拟议研究的成功实施将有助于：1）开发个性化 基于分子特征的晚期和复发性卵巢癌的妇女的治疗，2） 可能受益于PARP抑制剂的患者的定义，3）识别抗性机制 抑制剂和4）合理组合疗法将增加可能受益和 还可以防止抵抗的出现。该项目的成功实施不仅会改善 临床结果，但将指导未来的临床试验发展以推进该领域。