Novel synthetic lethality strategy for TP53 mutant colorectal cancer

项目摘要/摘要 肿瘤抑制因子p53基因(TP53)在大多数结直肠腺癌中存在基因改变 (CRC)，并导致预后不良。TP53编码的P53蛋白是DNA损伤的关键元件 由DNA损伤反应激活并控制基因组完整性的检查点。尽管几十年来 研究产生了大量关于p53突变的功能后果的信息，治疗努力 针对突变型p53的靶向已被证明基本上没有结果。P53基因缺陷的结直肠癌现有的治疗方案是 无效并引起毒副作用，强调需要更好的治疗方法。我们开发了一种 概念上新的治疗策略，用于选择性靶向P53基因缺陷的癌细胞 他们独特的DNA修复缺陷。我们的临床前研究表明，p53缺陷的肿瘤会积聚 胸苷类似物(即三氟胸苷，其成分)掺入DNA时的DNA损伤 FDA批准的名为TAS102的药物)。胸腺嘧啶核苷类似物不会中断DNA复制，而是 提示需要依赖于p53的检查点的DNA修复。我们发现P53缺失的细胞缺乏 依赖于P53的检查点选择性地积累DNA断裂。重要的是，这种DNA损伤是强烈的 被导致细胞死亡的聚(ADP)核糖聚合酶(PARP)抑制剂增强。这种新颖的诱导剂-- 放大策略在多种临床前模型中得到了广泛的验证。我们的临床前数据显示 TAS102联合PARP抑制剂(PARPI)的抗肿瘤活性优于任一种药物 在P53缺失的癌症模型中是单独存在的。基于我们的临床前数据，我们开发出了人类第一个阶段I FDA批准的两种药物TAS102和PARPI他唑巴治疗晚期结直肠癌的临床试验。因此，我们 假设TAS102与PARPI他唑巴联合治疗是一种有效的生物标记物驱动治疗 适用于p53基因缺陷的结直肠癌患者。目前的提案旨在定义我们的组合的有效性 首次在晚期结直肠癌患者中采用基础、翻译、 和临床科学家。这项研究将产生生物标志物来指导临床实施，并进一步 使用患者从我们正在进行的临床试验中提取的材料来开发我们的诱导-放大策略。 这项研究将使用最先进的下一代测序方法来定义基因组范围的变化 以响应CRC模型中的TAS102-PARPI组合。重要的是，我们将检查抗肿瘤药物 我们新的两药联合疗法对p53缺陷型结直肠癌患者的疗效。共同努力，这项工作将提供 对我们两种药物治疗行动的机械性见解，并将作为更好的发展平台 治疗。我们的研究对数千名侵袭性P53基因缺陷的结直肠癌患者具有重要意义。

PROJECT SUMMARY/ABSTRACT Genetic alterations in the tumor suppressor p53 gene (TP53) are found in most colorectal adenocarcinomas (CRC) and contributes to poor prognosis. The p53 protein encoded by TP53 is a key element of DNA damage checkpoints that are activated by DNA damage response and control genome integrity. Although decades of research generated immense information on the functional consequences of p53 mutations, therapeutic efforts targeted to mutant p53 have proven largely unfruitful. Existing therapeutic options for p53-deficient CRC are ineffective and cause toxic side effects stressing the need for better therapeutics. We developed a conceptually novel treatment strategy for selectively targeting p53-deficient cancer cells that takes advantage of their unique DNA repair deficiencies. Our preclinical research revealed that p53-deficient tumors accumulate DNA damage upon incorporation into DNA of a thymidine analogue (i.e., trifluorothymidine, a component of FDA-approved drug called TAS102). The thymidine analogue does not interrupt DNA replication but rather prompts DNA repair that requires p53-dependent checkpoint. We found that p53-deficient cells lacking the p53-dependent checkpoint selectively accumulate DNA breaks. Importantly, this DNA damage is strongly enhanced by inhibitors of poly (ADP) ribose polymerase (PARP) leading to cell death. This novel inducer- amplifier strategy was extensively validated in multiple preclinical models. Our preclinical data demonstrated a superior anti-tumor activity of TAS102 in combination with PARP inhibitor (PARPi) compared to either drug alone in p53-deficient cancer models. Based on our preclinical data, we developed a first-in-human Phase I clinical trial for advanced CRC with two FDA-approved drugs TAS102 and PARPi talazoparib. Thus, we hypothesize that the combination of TAS102 with PARPi talazoparib is an effective biomarker-driven treatment for patients with p53-deficient CRC. The current proposal is aimed to define the efficacy of our combination therapy strategy for the first time in humans with advanced CRC in a collaborative effort of basic, translational, and clinical scientists. The study will generate the biomarkers to guide clinical implementation and further development of our inducer-amplifier strategy by using patient-derived material from our ongoing clinical trial. The study will employ state-of-the art next-generation sequencing approaches to define genome-wide changes in response to the TAS102-PARPi combination in CRC models. Importantly, we will examine the antitumor efficacy of our novel two-drug therapy in p53-deficient CRC patients. Together, this work will provide mechanistic insights in the action of our two-drug therapy and will serve as a platform for development of better treatments. Our study matters for thousands of patients with aggressive p53-deficient CRC.