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.

摘要 野生型（Wt）p53是一种肿瘤抑制因子，在超过50%的结直肠癌中突变或失活。 癌的突变型P53代表致癌性功能获得表型。已知P53突变 有助于疾病进展和对化疗和放疗的抵抗。因此，突变型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 并可引发p53样肿瘤抑制功能。因此，可以激活p53家族的小分子 成员p73代表了在表达MT p53的肿瘤中恢复p53途径的新方法。我们的实验室 在过去的20年里一直在研究p53通路。我们参与了 内源性p53靶点和靶向p53途径的药物发现。我们的长期目标是提供 用恢复野生型（WT）p53的安全有效的小分子治疗结肠直肠癌患者 在p53突变的肿瘤中发挥作用。P53也被认为是调节细胞凋亡的关键因素之一。 癌症干细胞（CSC）群体。CSC是一个较小的干/祖细胞群体，能够自我调节， 更新，负责肿瘤的长期维持，局部肿瘤复发和转移 复发CSC对常规化疗具有抗性，因为它们具有各种药物外排机制 如P-糖蛋白泵（P-gp）（MDR 1）。已知野生型p53作为转录抑制因子， MDR 1基因。我们的假设是野生型p53功能的恢复不仅可以靶向肿瘤细胞， 还包括治疗抗性CSC。CSC中p53通路的恢复与P- gp泵活性和减少的治疗外排，这将支持更大的疗效和降低的毒性 p53修复化合物。我们先前已经建立了一个功能性细胞为基础的屏幕， 鉴定靶向突变型p53蛋白的小分子化合物。通过这个屏幕我们发现 灵菌红素、其相关化合物和CB-7587351（Chembridge library #7587351）作为强效p53家族 转录激活因子。这些化合物可以恢复结肠癌细胞中野生型p53的功能， 以p73依赖的方式MT p53。我们将进一步研究p53通路在mtp 53表达中的恢复， 结直肠癌，具有以下特定目标：特定目标1。评价灵菌红素及其相关药物 化合物作为靶向MT p53的先导化合物用于治疗结肠直肠癌及其肿瘤干细胞。 具体目标2。评价新型化合物CB-7587351作为靶向mt p53的先导化合物治疗以下疾病： 大肠癌及其肿瘤干细胞。具体目标3。测试体内功效、药代动力学和安全性 结直肠癌及其携带mt p53的肿瘤干细胞的临床前模型中p53通路的恢复。 我们提出的p53通路恢复的研究将代表一种独特的方案，可能有助于克服 与当前化疗相关的耐药性和毒性。选择性抑制表达mt p53的结肠 癌症干细胞可能有助于解决与治疗抗性和肿瘤复发相关的问题。