Targeting the oncogenic mutant p53 signaling in colorectal cancer therapy

描述(申请人提供)：野生型(Wt)P53是一种肿瘤抑制基因，在超过50%的结直肠癌中发生突变或失活。突变型P53代表癌基因功能表型的获得。已知p53突变会导致疾病进展以及对化疗和放射治疗的耐药性。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，并能引起P53样肿瘤抑制功能。因此，能够激活P53家族成员p73的小分子为mt P53表达肿瘤的P53通路修复提供了一种新的途径。在过去的20年里，我们的实验室一直在研究P53途径。我们参与了内源性P53靶点的发现和靶向P53通路的药物的发现。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，使携带p53突变的肿瘤恢复野生型(Wt)p53功能。P53也被认为是调节肿瘤干细胞(CSC)数量的关键因素之一。CSCs是一种能够自我更新的较小数量的干/祖细胞，负责肿瘤的长期维持、局部肿瘤复发和转移复发。肿瘤干细胞具有多种药物外排机制，如P-糖蛋白泵(P-gp)(Mdr1)，因此对常规化疗耐药。WT p53被认为是mdr1基因的转录抑制因子。我们的假设是，wt p53功能的恢复不仅可以靶向肿瘤细胞，还可以靶向治疗耐药的CSCs。CSCs中P53途径的恢复可能与P-gp泵活性降低和治疗外排减少有关，这将支持P53修复化合物的更高疗效和更低的毒性。我们之前已经建立了一种基于细胞的功能筛选，用于鉴定针对突变的P53蛋白的小分子化合物。通过这一筛选，我们确定了灵芝菌素及其相关化合物和CB-7587351(Chembridge库#7587351)是有效的P53家族转录激活剂。这些化合物可以以p73依赖的方式恢复携带mt p53的结肠癌细胞中野生型p53的功能。我们将进一步研究mt P53表达的结直肠癌中P53通路的修复，具体目的如下：特异性Aim1。评价灵芝菌素及其相关化合物作为靶向mt p53的先导化合物治疗结直肠癌及其肿瘤干细胞。特定的AIM2。评价新化合物CB-7587351作为靶向mt p53治疗结直肠癌及其肿瘤干细胞的先导化合物。特定的目标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通路修复的体内疗效、药代动力学和安全性。我们提议的P53途径恢复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。

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.