Identification of non-coding RNAs to therapeutically target undruggable pathways in metastatic lung adenocarcinoma and squamous cell carcinoma

 描述（由申请人提供）：癌症是一种复杂的遗传性疾病。在后基因组时代，人们正在采取新的举措来完全了解患者肿瘤的基因组成，从而实现个性化治疗。虽然许多重要的肿瘤抑制基因和癌基因已经以这种方式被鉴定出来，但重要的是要认识到许多癌症驱动突变的基因都是基因家族的成员。由于对家族中每个基因功能的了解有限，基因家族中冗余功能的存在使得癌症等疾病难以治疗和治愈。 p53家族就是这样的基因家族之一，也是我实验室研究的重点。尽管长期以来人们都知道 p53 的功能在癌症中经常发生改变，但 p53 仍然是一个不可成药的靶标，因为它具有转录因子的功能，而且它缺乏可以轻易抑制的酶活性。我们认为，这种失败与对 p53 家族整体功能了解不足直接相关。为了寻找针对癌症的 p53 的新方法，我的实验室一直致力于了解 p53 家族（包括 p63 和 p73 基因）相互关联的生物学功能。使用我实验室生成的新型小鼠模型，我们在理解和识别 p63 和 p73 在转移（Su 等人，Nature 2010）、干细胞维持（Su 等人，Cell Stem Cell 2009；Chakravarti 等人，PNAS 2014）和代谢（Su 等人，Cell Metabolism 2012）中的新功能方面取得了长足的进步。这些小鼠模型还揭示了 p63 和 p73 在肿瘤代谢中的新功能，并使我们能够操纵 p63 和 p73 的特定亚型来治疗靶向 p53 缺陷和突变的肿瘤（Venkatanarayan 等人，Nature 2014，印刷中）（参见附录）。在本提案中，我们的目标是进一步使用这些小鼠模型和几种新颖的高通量模式来了解 p53 家族调控的非编码 RNA 在癌症转移和肿瘤代谢中的生物学功能。我们将整合这些知识，努力使用非编码 RNA 合理地靶向 p53 通路。针对 p53 通路的发现可能会更广泛地应用于其他“不可成药”的靶标。通过R35机制的支持将极大地促进这项原本不可能实现的大型任务。

 DESCRIPTION (provided by applicant): Cancer is a complex genetic disease. In the post-genomic era, new initiatives are underway to completely understand the genetic makeup of a patient's tumor to personalize treatment. While many important tumor suppressors and oncogenes have been identified in this manner, it is important to recognize that many genes that are driver mutations in cancer are members of gene families. The existence of redundant functions in gene families has made diseases like cancer challenging to treat and cure due to the limited knowledge about the functions of each gene within the family. The p53 family is one such gene family and is the focus of the research in my laboratory. Despite long-standing knowledge that the p53 function is frequently altered in cancer, p53 has persisted as an undruggable target because of its function as a transcription factor and because it lacks an enzymatic activity that can be readily inhibited. In our view, this failure is directly tied to inadequate understanding of how the p53 family functions as a whole. In an effort to identify novel ways of targeting p53 in cancer, my laboratory has been focused on understanding the interrelated biological functions of the p53 family, which includes the p63 and p73 genes. We have made great strides in understanding and identifying novel functions for p63 and p73 in metastasis (Su et al., Nature 2010), stem cell maintenance (Su et al., Cell Stem Cell 2009; Chakravarti et al., PNAS 2014), and metabolism (Su et al., Cell Metabolism 2012) using novel mouse models generated in my laboratory. These mouse models have also revealed novel functions of p63 and p73 in tumor metabolism and have allowed us to manipulate particular isoforms of p63 and p73 to therapeutically target p53 deficient and mutant tumors (Venkatanarayan et al., Nature 2014, in press)(See Appendix). In this proposal, we aim to further use these mouse models and several novel high throughput modalities to understand the biological functions of non-coding RNA regulated by the p53 family in cancer metastasis and tumor metabolism. We will integrate this knowledge in an effort to rationally target the p53 pathway using non-coding RNAs. Discoveries made to target the p53 pathway can be potentially applied more broadly to other "undruggable" targets. Support through the R35 mechanism will greatly facilitate this large undertaking that would not otherwise be possible.