Deconstructing the multi-faceted roles of Rb in tumor progression

项目总结 Rb肿瘤抑制因子在相对较小的肺组织中突变失活 腺癌，但一般情况下，Rb通路在大多数情况下是失活的。此方案 为针对Rb上游负调控因子，即细胞周期蛋白依赖的治疗奠定基础 激活RB的肿瘤抑制功能。目前，多项临床试验正在进行中，以测试 这种疗法的有效性和显著的临床益处已经在某些癌症类型中被发现。 然而，即使在这些情况下，治疗的持久性也是不确定的，目前还不清楚RB是否 重新激活将对许多其他类型的肿瘤有效，包括肺腺癌。再加上这一点 不确定性是一个令人惊讶的认识，即Rb，或一般的Rb途径，在致癌Kras- 驱动肺腺癌的原因尚不清楚。因此，我们的项目有两个主要目标：目标1专注于 确定两种基因工程小鼠肺中Rb突变的功能后果 腺癌模型和人肺癌标本中。相比之下，这项提案的目标2侧重于 使用我们实验室最近开发的一种基因工具来模拟Rb再激活疗法，这种工具既可以 Rb在肿瘤发展过程中的条件失活，以及Rb的可诱导和准确的重新激活 一旦癌症被确定。在我们的初步发现的推动下，我们在目标1中的首要假设是 Rb的丢失通过消除两种截然不同的屏障来加速肺腺癌的进展 序列限制腺瘤-癌的转变，然后是转移能力的开始。在目标2中， 我们的初步见解表明，Rb修复在已建立的肺中的主要作用 腺癌是重建抑制的染色质结构，导致晚期肿瘤逆转。 转移性基因表达程序的分级和抑制。 我们希望我们的研究将揭示驱动Rb途径突变选择的机制， 建立Rb通路修复治疗肺腺癌的疗效。此外，我们的研究将 强调RB途径在疾病相关环境中利用的特定生化程序，这些程序可能是 经过治疗刺激，重述这一关键的肿瘤抑制因子的自然功能。这些见解 可能广泛适用于许多含有Rb途径突变的肿瘤类型。

PROJECT SUMMARY The Rb tumor suppressor is mutationally inactivated in relatively small fraction of lung adenocarcinomas, but the Rb pathway in general is likely inactivated in the majority of cases. This scenario sets the stage for therapies targeting the upstream negative regulators of Rb, namely cyclin dependent kinases, to reactivate Rb's tumor suppressive functions. Currently, multiple clinical trials are underway to test the efficacy of such therapies and significant clinical benefits have been discovered in certain cancer types. However, even in these cases the therapeutic durability is uncertain and it is currently unknown whether Rb reactivation will be effective in many other tumor types including lung adenocarcinoma. Adding to this uncertainty is the surprising realization that the role of Rb, or the Rb pathway in general, in oncogenic Kras- driven lung adenocarcinomas is unclear. Therefore, our project has two major goals: Aim 1 focuses on determining the functional consequences of Rb mutations in both genetically engineered mouse lung adenocarcinoma models and in human lung cancer specimens. In contrast, Aim 2 of this proposal focuses on modeling Rb reactivation therapy using a genetic tool recently developed in our laboratory that allows both, the conditional inactivation of Rb during tumor development, and the inducible and accurate reactivation of Rb once cancers are established. Fueled by our preliminary findings, our overarching hypothesis in Aim 1 is that loss of Rb accelerates lung adenocarcinoma progression by removing two distinct barriers that work in sequence to limit the adenoma-carcinoma transition, and then the onset of metastatic competency. In Aim 2, our initial insights suggest the hypothesis that the major role of Rb restoration in established lung adenocarcinomas is to reestablish repressive chromatin structures that lead to the reversal of advanced tumor grades and repression of pro-metastatic gene expression programs. We expect that our study will uncover the mechanisms that drive selection of Rb pathway mutations, and establish the therapeutic efficacy of Rb pathway restoration in lung adenocarcinoma. Further, our study will highlight specific biochemical programs utilized by the Rb pathway in disease relevant contexts that could be therapeutically stimulated to recapitulate the natural functions of this critical tumor suppressor. These insights may be broadly applicable to the many tumor types that harbor Rb pathway mutations.