Targeting the oncogenic mutant p53 signaling in colorectal cancer therapy

结直肠癌治疗中针对致癌突变体 p53 信号传导

• 批准号: 8665720
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 31.67万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-18 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665720
• 关键词: ABCB1 gene; Address; Cancer Patient; Cell Death; Cell Death Induction; Cells; Clinic; Colon Carcinoma; Colorectal Cancer; Detection; Disease Progression; Disease Resistance; Dose; Drug Efflux; Drug Kinetics; Drug Targeting; Ellipticines; FDA approved; Family; Family member; Frequencies; Gene Targeting; Goals; High Pressure Liquid Chromatography; Human; Image; In Vitro; Lead; Libraries; Luciferases; Mass Spectrum Analysis; Modeling; Molecular; Mus; Mutate; Mutation; Oncogenic; P-Glycoprotein; Pathway interactions; Phenotype; Population; Pre-Clinical Model; Prodigiosin; Protein p53; Pump; Radiation; Radiation therapy; Recurrence; Regimen; Relapse; Reporter; Resistance; Role; SW480; Safety; Schedule; Signal Transduction; Stem cells; System; TP53 gene; Testing; Toxic effect; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; Translating; Tumor Stem Cells; Tumor Suppressor Proteins; Tumorigenicity; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; design; drug development; drug discovery; ellipticine; gain of function; in vivo; mutant; neoplastic cell; novel; novel strategies; protein p73; public health relevance; restoration; self-renewal; small molecule; stem; stem cell population; subcutaneous; therapeutic target; therapy resistant; transcription factor; tumor; tumor xenograft

Abstract Wide type (Wt) p53 is a tumor suppressor that is mutated or inactivated in more than 50% of colorectal cancers. Mutant P53 represents an oncogenic gain of function phenotype. P53 mutations are known to contribute to disease progression and resistance to chemotherapy and radiotherapy. Therefore, mutant P53 is considered as a major target for drug development. p53 family member p73 is rarely mutated in cancer cells and can elicit a p53-like tumor suppressive function. Thus, small molecules that can activate the p53 family member p73 represent a novel approach for p53 pathway restoration in mt p53 expressing tumors. Our lab has been working on the p53 pathway for the past 20 years. We have been involved with the discovery of endogenous p53 targets and drug discovery for targeting the p53 pathway. Our long term goal is to provide therapy for colorectal cancer patients with safe and efficacious small molecules that restore wild type (wt) p53 function in tumors with p53 mutations. P53 is also considered to be one of the key factors in regulating the cancer stem cell (CSC) population. CSCs are a smaller population of stem/progenitor cells capable of self- renewal that are responsible for long-term sustenance of the tumor, local tumor recurrence and metastatic relapse. CSCs are resistant to conventional chemotherapy since they possess various drug efflux mechanisms such as P-glycoprotein pumps (P-gp) (MDR1). Wt p53 is known to act as a transcriptional repressor of the MDR1 gene. Our hypothesis is that restoration of wt p53 function can not only target bulk tumor cells but also therapy resistant CSCs. p53 pathway restoration in CSCs would be associated with reduced P- gp pump activity and reduced therapy efflux that would support greater efficacy and reduced toxicity from p53 restoration compounds. We have previously established a functional cell-based screen for identifying small molecule compounds targeting mutant p53 protein. Through this screen we identified Prodigiosin, its related compound and CB-7587351 (Chembridge library # 7587351) as potent p53-family transcriptional activators. These compounds can restore wild-type p53 function in colon cancer cells harboring mt p53 in a p73-dependent manner. We will further address p53 pathway restoration in mt p53 expressing colorectal cancer with the following specific aims: Specific Aim1. Evaluate Prodigiosin and its related compound as a lead compound to target mt p53 in therapy of colorectal cancer and its tumor stem cells. Specific Aim2. Evaluate novel compound CB-7587351 as a lead compound to target mt p53 in therapy of colorectal cancer and its tumor stem cells. Specific Aim3. Test in vivo efficacy, pharmacokinetics and safety of p53 pathway restoration in preclinical models of colorectal cancer and its tumor stem cells harboring mt p53. Our proposed studies of p53 pathway restoration will represent a unique regimen that may help overcome resistance and toxicity associated with current chemotherapy. Selective inhibition of mt p53 expressing colon cancer stem cells may help resolve issues associated with therapy resistance and tumor recurrence.

抽象的 宽类型（WT）p53是一种肿瘤抑制剂，在超过50％的结直肠内突变或灭活 癌症。突变p53代表功能表型的致癌增益。 p53突变已知 有助于疾病进展和对化学疗法和放射疗法的抗性。因此，突变体p53是 被认为是药物开发的主要目标。 p53家族成员p73在癌细胞中很少突​​变 并可以引起p53样肿瘤抑制功能。因此，可以激活p53家族的小分子 成员p73代表了一种表达肿瘤的MT p53中p53途径恢复的新方法。我们的实验室有 在过去的20年中，一直在p53途径上工作。我们参与了发现 内源性p53靶标和用于靶向p53途径的药物发现。我们的长期目标是提供 恢复野生型（WT）p53的安全有效的小分子的结直肠癌患者的治疗 在具有p53突变的肿瘤中功能。 p53也被认为是调节的关键因素之一 癌症干细胞（CSC）种群。 CSC是能够自我的茎/祖细胞群的较小 负责长期维持肿瘤，局部肿瘤复发和转移性的更新 复发。 CSC对常规化学疗法具有抗性，因为它们具有各种药物排出机制 例如P-糖蛋白泵（P-GP）（MDR1）。 WT P53被称为 MDR1基因。我们的假设是，恢复WT p53功能不仅可以靶向大块肿瘤细胞 而且还具有耐药性CSC。 CSC中的p53途径恢复与p-的降低有关 GP泵活动和减少治疗外排，这将支持更大的疗效并降低毒性 从p53恢复化合物。我们以前已经建立了一个基于功能的单元格屏幕 鉴定靶向突变体p53蛋白的小分子化合物。通过此屏幕，我们确定了 Protigiosin，其相关化合物和CB-7587351（Chembridge Library＃7587351）作为有效的p53家族 转录激活剂。这些化合物可以在携带的结肠癌细胞中恢复野生型p53功能 MT p53以p73依赖性方式。我们将进一步介绍MT P53中的P53途径恢复 结直肠癌具有以下特定目的：特定AIM1。评估Protigiosin及其相关 在结直肠癌及其肿瘤干细胞治疗中，化合物是靶向MT p53的铅化合物。 特定的AIM2。评估新型化合物CB-7587351作为铅化合物，以靶向MT p53 结直肠癌及其肿瘤干细胞。特定的AIM3。测试体内功效，药代动力学和安全性 p53大肠癌及其具有MT p53的肿瘤干细胞的临床前模型中的p53途径恢复。 我们对p53途径恢复的拟议研究将代表一种独特的方案，可能有助于克服 与当前化学疗法有关的耐药性和毒性。选择性抑制MT p53表达结肠 癌症干细胞可能有助于解决与耐药性和肿瘤复发有关的问题。