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：
9033082
负责人：
WAFIK S. EL-DEIRY
金额：
$ 36.58万
依托单位：
RESEARCH INST OF FOX CHASE CAN 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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033082
关键词：
ABCB1 gene Address Cell Death Cell Death Induction Cells Clinic Colon Carcinoma Colorectal Cancer Detection Disease Progression Disease Resistance Dose Drug Efflux Drug Kinetics Drug Targeting FDA approved Family Family member Frequencies Gene Targeting Goals Health 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 colon cancer patients design drug development drug discovery ellipticine gain of function in vivo knock-down mutant neoplastic cell novel novel strategies protein p73 restoration self-renewal small molecule stem stem cell population subcutaneous targeted cancer therapy therapeutic target therapy resistant transcription factor tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Wild (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.

描述（由申请人提供）：野生（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。突变体 P53 代表功能表型的致癌增益。已知 P53 突变会导致疾病进展以及对化疗和放疗的抵抗。因此，突变型P53被认为是药物开发的主要靶点。 p53家族成员p73在癌细胞中很少发生突变，并且可以引发类似p53的肿瘤抑制功能。因此，能够激活p53家族成员p73的小分子代表了在表达mt p53的肿瘤中恢复p53通路的新方法。我们的实验室在过去 20 年里一直致力于 p53 通路的研究。我们一直致力于内源性 p53 靶标的发现以及针对 p53 通路的药物发现。我们的长期目标是为结直肠癌患者提供安全有效的小分子治疗，以恢复 p53 突变肿瘤中野生型 (wt) p53 的功能。 P53也被认为是调节癌症干细胞（CSC）群体的关键因素之一。 CSC是较小的干细胞/祖细胞群，能够自我更新，负责肿瘤的长期维持、局部肿瘤复发和转移性复发。 CSC 对传统化疗具有抵抗力，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 是 MDR1 基因的转录抑制因子。我们的假设是，恢复 wt p53 功能不仅可以靶向大量肿瘤细胞，还可以靶向治疗耐药的 CSC。 CSC 中 p53 途径的恢复与 P-gp 泵活性的降低和治疗外流的减少有关，这将支持 p53 恢复化合物的更大功效和更低的毒性。我们之前已经建立了基于功能性细胞的筛选，用于鉴定针对突变 p53 蛋白的小分子化合物。通过此筛选，我们鉴定出灵菌红、其相关化合物和 CB-7587351（Chembridge 文库 # 7587351）是有效的 p53 家族转录激活剂。这些化合物可以以 p73 依赖性方式恢复携带 mt p53 的结肠癌细胞中的野生型 p53 功能。我们将进一步解决表达 mt p53 的结直肠癌中 p53 通路的恢复问题，具体目标如下：具体目标 1。评估灵菌红及其相关化合物作为靶向 mt p53 的先导化合物在结直肠癌及其肿瘤干细胞治疗中的作用。具体目标2。评估新型化合物 CB-7587351 作为靶向 mt p53 的先导化合物在结直肠癌及其肿瘤干细胞治疗中的作用。具体目标3。在结直肠癌及其携带 mt p53 的肿瘤干细胞的临床前模型中测试 p53 通路恢复的体内功效、药代动力学和安全性。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。