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

鉴定非编码 RNA 以治疗转移性肺腺癌和鳞状细胞癌中不可成药的途径

• 批准号: 10132250
• 负责人: Elsa R Flores
• 金额: $ 93.88万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132250
• 关键词: Adenocarcinoma Cell; Biological Process; Cell Maintenance; Cellular Metabolic Process; Complex; Disease; Failure; Family; Gene Family; Genes; Genetic Diseases; Genomics; Knowledge; Laboratories; Lung Adenocarcinoma; Malignant Neoplasms; Metabolism; Modality; Nature; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Protein Isoforms; Research; Squamous cell carcinoma; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Untranslated RNA; base; driver mutation; genetic makeup; in vivo; member; mouse model; mutant; novel; personalized medicine; public health relevance; stem cells; therapeutic target; transcription factor; tumor; tumor metabolism

 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.

 描述（由申请人提供）：癌症是一种复杂的遗传疾病。在后基因组时代，新的举措正在进行中，以完全了解患者肿瘤的基因组成，以个性化治疗。虽然许多重要的肿瘤抑制因子和癌基因已经以这种方式被鉴定，但重要的是要认识到许多作为癌症中驱动突变的基因是基因家族的成员。基因家族中冗余功能的存在使得癌症等疾病的治疗和治愈具有挑战性，这是由于对家族中每个基因功能的了解有限。p53家族就是这样一个基因家族，也是本实验室研究的重点。尽管长期以来人们都知道p53的功能在癌症中经常改变，但p53仍然是一个不可忽视的靶点，因为它具有转录因子的功能，而且缺乏容易被抑制的酶活性。在我们看来，这种失败与对p53家族作为一个整体如何发挥作用的理解不足直接相关。为了确定在癌症中靶向p53的新方法，我的实验室一直专注于了解p53家族（包括p63和p73基因）的相关生物学功能。我们在理解和鉴定p63和p73在转移中的新功能方面取得了很大进展（Su et al.，Nature 2010）、干细胞维持（Su et al. Cell Stem Cell 2009; Chakravarti等人，PNAS 2014）和代谢（Su et al. Cell Metabolism 2012）使用在我的实验室中产生的新型小鼠模型。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的特定同种型以治疗性靶向p53缺陷型和突变型肿瘤（Venkatanarayan等人，Nature 2014，in press）（见附录）。在这项提议中，我们的目标是进一步使用这些小鼠模型和几种新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，努力合理地使用非编码RNA靶向p53通路。靶向p53通路的发现可能更广泛地应用于其他“不可治疗”的靶点。通过R35机制提供的支持将极大地促进这一否则不可能实现的重大任务。