Functional Analysis of p53 Polymorphic Variants

项目摘要 修订后的更新申请要求为15 - 19年的提案提供资金， 了解p53肿瘤抑制基因的遗传亚型对癌症风险和治疗的影响。 中心前提是，分析p53肿瘤的癌症相关遗传亚型， 抑制因子的研究可以对这种肿瘤抑制因子在癌症中的关键功能提供重要的见解。拟议 研究的重点是非洲特有的Pro47Serp53亚型（以下简称S47），它存在于超过1000个国家和地区。 800，000名非洲裔美国人，并增加了这些人的癌症风险 个体p53的S47变体在一小部分p53靶基因的反式激活中有缺陷， 特别是那些赋予对铁下垂敏感性的药物。所提出的总体假设 研究表明，通过了解P47S和其他癌症相关的亚型的生物学， 取得了重要的成果：第一个是鉴定了p53的关键肿瘤抑制功能， 仍然未知。第二，我们可以使用小鼠模型来更好地了解癌症 风险，并发现上级癌症治疗，为个人谁拥有这些变异。 在目标1中，我们将研究我们的发现，即S47小鼠中的肿瘤微环境更具免疫性。 抑制性的，由于髓源性抑制细胞（MDSC）的积累增加。mdsc是 直接限制免疫检查点抑制剂功效的强效免疫抑制细胞。我们将 在WT和S47小鼠中测试免疫检查点抑制剂的功效，我们将测试联合治疗 我们的目标是MDSC。在目标2中，我们提出的数据表明，P47S，像其他两个癌症相关的p53， 亚型Y107 H和G334 R，反式激活染色质修饰剂PADI 4的能力受损，沿着 具有增加的错误折叠和采用突变p53构象的倾向。我们将调查 这两种活性与p53抑制肿瘤的相关性。在目标3中，我们提供了PheWAS数据，表明 S47等位基因是非裔美国人膀胱癌的一个高度显著的危险因素（p <6x10 - 6，或 7.5）。在这个目标中，我们研究了S47在膀胱癌小鼠模型中的功能， 更好地理解这种重要关联背后的原因。然后，我们遵循我们发布的 成功的方案来识别在S47膀胱中显示出改善疗效的新型化疗药物 癌症，与WT相比。这些综合研究建立在大量已发表和初步数据的基础上， 沿着p53亚型的新型小鼠模型和人类数据的整合。这些 研究对于我们了解少数癌症的遗传基础的长期目标至关重要。 差异，并改善针对非洲裔个人的个性化医疗方法。

Project Summary This revised renewal application requests funding for years 15-19 for a proposal that is devoted to understanding the impact of genetic hypomorphs of the p53 tumor suppressor on cancer risk and therapy. The central premise is that the analysis of cancer-associated genetic hypomorphs of the p53 tumor suppressor can lend critical insight into the key functions of this tumor suppressor in cancer. The proposed research focuses on the African-specific Pro47Ser p53 hypomorph (hereafter S47) that exists in over 800,000 African-descent individuals in the United States and confers increased cancer risk in these individuals. The S47 variant of p53 is defective in the transactivation of a small subset of p53-target genes, particularly those that confer sensitivity to ferroptosis. The overarching hypothesis of the proposed research is that by understanding the biology of P47S and other cancer-associated hypomorphs, two important outcomes are met: the first is the identification of key tumor suppressor functions of p53, which are still not known. The second is that we can use mouse models in order to better understand cancer risk, and uncover superior cancer therapies, for the individuals who possess these variants. In Aim 1 we will investigate our finding that the tumor micro-environment in S47 mice is more immuno- suppressive, due to increased accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs are potent immunosuppressive cells that directly limit the efficacy of immune checkpoint inhibitors. We will test the efficacy of immune checkpoint inhibitors in WT and S47 mice, and we will test combination therapy in which we target MDSCs. In Aim 2 we present data that P47S, like two other cancer-associated p53 hypomorphs Y107H and G334R, has impaired ability to transactivate the chromatin modifier PADI4, along with increased propensity to misfold and adopt a mutant p53 conformation. We will investigate the relevance of both activities to tumor suppression by p53. In Aim 3 we provide PheWAS data indicating that the S47 allele is a highly significant risk factor for bladder cancer in African Americans (p< 6x10-6, OR 7.5). In this aim we investigate the function of S47 in mouse models of bladder cancer, with the goal of better understanding the reasons underlying this significant association. We then follow our published successful protocols to identity novel chemotherapeutic drugs that show improved efficacy in S47 bladder cancer, compared to WT. The combined studies build upon a wealth of published and preliminary data, along with novel mouse models for p53 hypomorphs and the integration of human data throughout. These studies are paramount for our long term goal of understanding the genetic basis of minority cancer disparities, and improving personalized medicine approaches for individuals of African descent.