Analysis of the p53 in vivo using a unique mouse model

描述(申请人提供)：尽管不同的癌症有明显的异质性，但几乎所有癌症都存在P53网络的功能失活。然而，在任何特定的肿瘤细胞类型的进化过程中，哪些信号负责触发P53，当这种情况发生时，这种激活对每个肿瘤细胞和整个肿瘤可能产生什么直接后果，以及这些信号是否被已建立的癌症保留，这些在很大程度上仍然是未知的。尽管如此，这些都是对特定肿瘤中P53功能如何被禁用以及每种肿瘤类型中P53修复的治疗效果如何的深远影响的考虑。后者与恢复P53功能的实用药理策略的出现直接相关。我们将使用一种独特的小鼠模型，在该模型中，内源性P53功能可以在非活动状态和功能状态之间进行可逆切换，以探索不同癌症对P53修复的不同反应。在目标1中，我们将使用单一致癌机制 (激活的RAS)，以探讨肿瘤组织类型如何影响对P53修复的反应。在目标2中，我们将使用分别由RAS、Myc或RAS和Myc共同驱动的同源散发性肺癌模型，以确定致癌病变如何改变单一肿瘤组织类型中P53修复的反应。在目标3中，我们将调查P53修复疗法是否以及如何失败。在P53修复后，肿瘤是通过从P53耐药的祖细胞群体再生还是通过选择和生长耐药突变体而出现的，这种情况随着肿瘤组织类型的变化而变化，以及如何避免这种耐药？为了解决这些问题，我们将使用我们特征良好的可切换的p53 E5-myc淋巴瘤模型，并将相同的研究策略扩展到Aim 1中使用的RAS诱导的实体瘤模型。 公共卫生相关性：虽然不同的癌症非常不同，但几乎所有的癌症都涉及P53途径的失活。因此，在肿瘤中恢复P53功能可能是一种高效、普遍适用和肿瘤选择性的治疗策略。我们已经开发出一种独特的可切换敲入小鼠，使我们能够在体内模拟任何肿瘤类型的P53功能恢复。我们将利用这只小鼠来探索P53的治疗效果、效用和作用机制，以及肿瘤类型如何决定这一点，为优化P53修复在癌症治疗中的作用提供基础。

DESCRIPTION (provided by applicant): Despite the apparent heterogeneity of different cancers, functional inactivation of the p53 network is common to almost all. However, which signals are responsible for triggering p53 during evolution of any specific tumor cell type, when this happens, what the immediate consequences of such activation might be for each tumor cell and for the whole tumor, and whether such signals are retained by established cancers, all remain largely unknown. Nonetheless, these are considerations with a profound impact on how p53 function is disabled in specific tumors and how therapeutically effective p53 restoration might be in each tumor type. This latter is of immediate relevance with the advent of practicable pharmacological strategies for re-instating p53 function. We will use a unique mouse model in which endogenous p53 function can be reversibly toggled between inactive and functional states to explore the diversity of responses to p53 restoration in differing cancers. In Aim 1, we will use a single oncogenic mechanism (activated Ras) to explore how tumor tissue type influences the response to p53 restoration. In Aim 2, we will use homologous sporadic models of lung cancer driven respectively by Ras, Myc, or Ras and Myc together, to determine how the oncogenic lesion modifies the response to p53 restoration within a single tumor tissue type. In Aim 3, we will investigate whether and how p53-restoration therapy fails. Do tumors recurring after p53 restoration arise by regeneration from a p53-refractory progenitor population or by selection and outgrowth of resistant mutants, how does this vary with tumor tissue type, and how might such resistance be averted? To address these questions we will use our well-characterized switchable p53 E5-myc lymphoma model and extend the same investigative strategy into the Ras-induced solid tumor models employed in Aim 1. PUBLIC HEALTH RELEVANCE: Although different cancers are very diverse, almost all involve inactivation of the p53 pathway. Hence, restoration of p53 function in cancers may be a highly effective, generally applicable and tumor-selective therapeutic strategy. We have developed a unique switchable knock-in mouse that enables us to model p53 functional restoration in any tumor type in vivo. We will use this mouse to explore the therapeutic efficacy, utility and mechanism of action of p53 and how this is dictated by tumor type, providing a basis for optimizing p53 restoration in cancer treatment.