Novel synthetic lethality strategy for TP53 mutant colorectal cancer

TP53突变结直肠癌的新型合成致死策略

基本信息

批准号：
10718572
负责人：
CHRISTOS Fountzilas
金额：
$ 58.6万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718572
关键词：
Amplifiers Antineoplastic Agents BRAF gene Biological Markers Blood Cancer Model Cell Death Cells Chromatin Chromatin Structure Clinical Clinical Data Clinical Trials Colorectal Adenocarcinoma Colorectal Cancer Combined Modality Therapy DNA DNA Damage DNA Repair DNA Repair Disorder DNA biosynthesis DNA damage checkpoint Data Deoxyuridine Development Dose Elements Evaluation FDA approved Future G2 Phase Genes Genetic Transcription Genomics Human Malignant Neoplasms Metabolism Modeling Molecular Abnormality Mutation Neoplasm Metastasis Oncogenic Patient Selection Patients Pharmaceutical Preparations Pharmacotherapy Phase Phase I Clinical Trials Poly(ADP-ribose) Polymerase Inhibitor Pre-Clinical Model Predictive Value Prognosis Randomized Refractory Regimen Research Resistance Sampling Scientist Solid Neoplasm Stress TP53 gene Testing Therapeutic Thymidine Time Tissues Trifluridine Validation Work analog biomarker driven biomarker identification biomarker selection cancer cell clinical application clinical biomarkers clinical efficacy clinical implementation cohort design first-in-human follow-up gene repair genome integrity genome-wide improved inhibitor therapy insight mutant next generation sequencing novel novel drug combination novel strategies novel therapeutic intervention patient population phase 3 study pre-clinical pre-clinical research predict clinical outcome predictive marker prospective repaired replication stress response response biomarker side effect therapeutically effective transcriptome treatment planning treatment strategy tumor tumor progression uptake

项目摘要

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.

项目概要/摘要大多数结直肠腺癌中均发现肿瘤抑制 p53 基因 (TP53) 的遗传改变 (CRC) 并导致不良预后。 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。虽然几十年来研究产生了有关 p53 突变的功能后果、治疗努力的大量信息针对 p53 突变体的研究已被证明基本上没有成果。 p53 缺陷型 CRC 的现有治疗选择是无效并引起毒副作用，强调需要更好的治疗方法。我们开发了一个选择性靶向 p53 缺陷癌细胞的概念性新颖治疗策略他们独特的DNA修复缺陷。我们的临床前研究表明，p53 缺陷的肿瘤会积累胸苷类似物（即三氟胸苷，胸苷的一种成分）掺入 DNA 后会造成 DNA 损伤 FDA 批准的药物称为 TAS102）。胸苷类似物不会中断 DNA 复制，而是提示需要 p53 依赖性检查点的 DNA 修复。我们发现 p53 缺陷细胞缺乏 p53 依赖性检查点选择性地积累 DNA 断裂。重要的是，这种 DNA 损伤非常严重聚（ADP）核糖聚合酶（PARP）抑制剂增强该作用，导致细胞死亡。这种新颖的诱导剂—— 放大器策略在多个临床前模型中得到了广泛验证。我们的临床前数据表明与任一药物相比，TAS102 与 PARP 抑制剂 (PARPi) 联合使用具有优异的抗肿瘤活性单独在 p53 缺陷的癌症模型中。根据我们的临床前数据，我们开发了首个人体 I 期药物使用FDA批准的两种药物TAS102和PARPi talazoparib治疗晚期结直肠癌的临床试验。因此，我们假设 TAS102 与 PARPi talazoparib 的组合是一种有效的生物标志物驱动的治疗适用于 p53 缺陷的 CRC 患者。目前的提案旨在确定我们组合的功效在基础、转化、和临床科学家。该研究将生成生物标志物来指导临床实施并进一步通过使用来自我们正在进行的临床试验的患者来源的材料来开发我们的诱导剂放大器策略。该研究将采用最先进的下一代测序方法来定义全基因组变化响应 CRC 模型中的 TAS102-PARPi 组合。重要的是，我们将检查抗肿瘤我们的新型两种药物疗法对 p53 缺陷的 CRC 患者的疗效。这项工作将共同提供我们的两种药物疗法的作用机制见解，并将作为开发更好的平台治疗。我们的研究对数千名患有侵袭性 p53 缺陷型 CRC 的患者很重要。