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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的宽型 (Wt) p53 是一种肿瘤抑制因子，在超过 50% 的结直肠癌中发生突变或失活癌症。突变体 P53 代表功能表型的致癌增益。已知 P53 突变有助于疾病进展和对化疗和放疗的抵抗。因此，突变体P53是被视为药物开发的主要目标。 p53 家族成员 p73 在癌细胞中很少发生突变并能引发类似p53的肿瘤抑制功能。因此，可以激活p53家族的小分子 p73 成员代表了一种在 mt p53 表达肿瘤中恢复 p53 通路的新方法。我们实验室有过去20年来一直致力于p53通路的研究。我们一直参与发现内源性 p53 靶点和针对 p53 通路的药物发现。我们的长期目标是提供使用安全有效的恢复野生型 (wt) p53 的小分子治疗结直肠癌患者在 p53 突变的肿瘤中发挥作用。 P53也被认为是调节的关键因素之一癌症干细胞（CSC）群体。 CSC 是较小的干细胞/祖细胞群，能够自我负责肿瘤长期维持、局部肿瘤复发和转移的更新复发。 CSCs 对传统化疗具有耐药性，因为它们具有多种药物流出机制例如 P-糖蛋白泵 (P-gp) (MDR1)。已知 Wt p53 作为转录抑制因子 MDR1 基因。我们的假设是，恢复 wt p53 功能不仅可以靶向大量肿瘤细胞还有治疗耐药的 CSC。 CSC 中 p53 通路的恢复与 P-减少有关 gp 泵活性和减少的治疗流出将有助于提高疗效并降低毒性来自 p53 修复化合物。我们之前已经建立了基于功能性细胞的筛选鉴定针对突变 p53 蛋白的小分子化合物。通过这个屏幕我们确定了灵菌红、其相关化合物和 CB-7587351（Chembridge 文库 # 7587351）作为有效的 p53 家族转录激活剂。这些化合物可以恢复结肠癌细胞中野生型 p53 的功能 mt p53 以 p73 依赖的方式。我们将进一步解决 mt p53 表达中 p53 通路的恢复问题结直肠癌有以下具体目标：具体目标1。评估灵菌红素及其相关物质化合物作为靶向 mt p53 的先导化合物，用于治疗结直肠癌及其肿瘤干细胞。具体目标2。评估新型化合物 CB-7587351 作为靶向 mt p53 的先导化合物在治疗中的作用结直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 的肿瘤干细胞临床前模型中 p53 通路的恢复。我们提出的 p53 通路恢复研究将代表一种独特的治疗方案，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耐药和肿瘤复发相关的问题。