Functional Analysis of p53 Polymorphic Variants

项目摘要 这份修订后的续签申请要求在15-19年为致力于以下目的的提案提供资金 了解P53肿瘤抑制基因亚型对癌症风险和治疗的影响。 中心前提是分析与癌症相关的p53肿瘤的遗传亚型 抑制子可以为肿瘤抑制因子在癌症中的关键功能提供关键的洞察力。建议数 研究重点是非洲特有的Pro47Ser P53低多态性(以下简称S47)，它存在于 在美国有80万非洲裔人，这会增加这些人患癌症的风险 个人。P53的S47变体在一小部分P53靶基因的反式激活中存在缺陷， 尤其是那些对铁性上睑下垂敏感的患者。建议的总体假设 研究表明，通过了解P47S和其他与癌症相关的亚型的生物学，有两个 取得了重要成果：第一是确定了P53的关键肿瘤抑制功能，这是 仍然是未知的。第二，我们可以使用老鼠模型来更好地了解癌症 风险，并发现优越的癌症治疗方法，为拥有这些变种的个人。 在目标1中，我们将调查我们的发现，S47小鼠的肿瘤微环境具有更强的免疫性。 抑制，由于髓系来源的抑制细胞(MDSCs)积累增加。MDSC是 强大的免疫抑制细胞，直接限制免疫检查点抑制剂的疗效。我们会 在WT和S47小鼠身上测试免疫检查点抑制剂的有效性，我们将测试联合治疗 我们的目标是MDSC。在目标2中，我们提供了P47S和另外两个与癌症相关的P53的数据 亚型Y107H和G334R，已经减弱了反式激活染色质修饰物PADI4的能力 错误折叠和采用突变型P53构象的倾向增加。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&lt；6x10-6，或 7.5)。为此，我们研究了S47在小鼠膀胱癌模型中的功能，目的是 更好地理解这种重大关联背后的原因。然后我们遵循我们发布的 成功识别在S47膀胱中显示改善疗效的新型化疗药物 癌症，与西雅图相比。这些综合研究建立在大量已发表和初步数据的基础上， 以及P53亚型的新小鼠模型和贯穿始终的人类数据整合。这些 研究对于我们了解少数族裔癌症的遗传基础的长期目标是至关重要的。 改善非洲人后裔的个人化医疗方法。

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.