The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer

PGC1beta 和 ERRalpha 作为结直肠癌治疗新靶点的作用

• 批准号: 10164730
• 负责人: Kurt Fisher
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164730
• 关键词: 5' -AMP-activated protein kinase; Adipose tissue; Animal Model; Biogenesis; Biology; Brain; Breast; Brown Fat; Cancer Etiology; Cancer cell line; Cecum; Cessation of life; Colon; Colonic Neoplasms; Colorectal Adenocarcinoma; Colorectal Cancer; Cyclic AMP-Dependent Protein Kinases; Data; Development; Development Plans; Disease; Distant; Distant Metastasis; EGF gene; ERR1 protein; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptor alpha; Ethics; Event; Faculty; Gender; Gene Expression; Genes; Genetic Transcription; Growth; Heart; Homeostasis; Human; In Vitro; KRAS2 gene; Knock-out; Knowledge; Leadership; Ligand Binding; Ligand Binding Domain; Ligands; Liver; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Mentorship; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Mitochondria; Modeling; Molecular; Mus; Muscle; Mutate; Mutation; Neoplasm Metastasis; Normal Cell; Nuclear Orphan Receptor; Oncogenic; PPAR gamma; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Play; Post-Translational Protein Processing; Primary Neoplasm; Prognosis; Protein Family; Protein Kinase; Proteins; Publications; Regulation; Research; Research Training; Resistance; Response Elements; Role; Scientist; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Solid Neoplasm; Survival Rate; Testing; Therapeutic; Therapeutic Index; Tissues; Training; Transcription Coactivator; United States; Woman; Work; Xenograft Model; Xenograft procedure; bioinformatics tool; career development; cell growth; colon cancer cell line; cross reactivity; delta protein; design; estrogen-related receptor; genome-wide; human tissue; implantation; improved; in vivo; inhibitor/antagonist; member; men; metastatic colorectal; mouse model; mutant; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; promoter; ras Proteins; ras-Related G-Proteins; side effect; skills; targeted treatment; transcription factor; translational impact; treatment strategy; tumor; tumor growth; tumor metabolism; tumorigenesis

Abstract Significance: This proposal has the potential to impact a large number of patients since colorectal cancer (CRC) is the 3rd leading cause of cancer deaths in both genders. K-Ras is mutated in approximately 40% of all CRCs and this mutation makes tumors resistant to EGFR-targeted therapies. Our studies aim to develop novel strategies for treatment of tumors with K-Ras mutations. Additionally, we propose that our treatment strategies will have a high therapeutic index, since we are targeting proteins that are expendable for normal growth, but required for malignancy. We also anticipate that our findings will be applicable to other tumors with mutant Ras proteins, which constitute up to 30% of all human malignancies. Background: We have determined that 5' AMP-activated protein kinase (AMPK), peroxisome proliferator- activated receptor gamma coactivator 1-beta (PGC1β), and estrogen-related receptor alpha (ERRα) are novel regulators of tumor metabolism in K-Ras mutant CRCs. PGC1β is a transcriptional co-activator and ERRα is a transcription factor that are present in highly metabolic tissues, such as heart, skeletal muscle, brain and brown adipose tissue, where they interact to transcribe genes involved in metabolism and mitochondrial biogenesis. PGC1β and ERRα are dramatically over-expressed in CRC cell lines and human liver metastases compared to non-transformed human colon epithelial cells (HCECs) and normal human colon tissue, respectively. AMPK, a critical regulator of energy homeostasis, is a potent regulator of PGC1β, ERRα, and tumor survival. Research Plan: In this application, we present preliminary data on the critical role of AMPK, PGC1β, and ERRα as novel regulators of tumor metabolism and survival in K-Ras mutant CRCs and we hypothesize that these are promising targets for the development of novel treatment strategies because they are expendable for normal cell growth. To test this hypothesis, first, we will examine the role of PGC1β and ERRα downstream effector Ras-related GTP-binding protein D (RagD), a positive regulator of mTORC1 signaling and tumor growth. Second, we will characterize the critical regulatory role of AMPK on PGC1β activity. Lastly, we will assess the role of PGC1β, ERRα, and an ERRα inhibitor in metastatic disease using the orthotopic cecal implantation mouse model of metastasis. This proposal will advance our knowledge of these underexplored metabolic effectors that are required for K-Ras mutant CRCs and have the potential for the development of several types of novel therapeutics. Career Development: I have worked closely with my mentors to create a scientific and career development plan designed to help me transition to independence as a physician-scientist. Specifically, I will gain valuable training in metabolic regulation of cancer growth, models of metastasis, leadership skills, grantsmanship, and ethical research. My mentorship committee consists of outstanding faculty members with expertise in mentoring junior faculty members, CRC research, and training of physician-scientists.

摘要 意义：这一建议有可能影响大量结直肠癌患者， (CRC)是男女癌症死亡的第三大原因。K-Ras在大约40%的 所有的CRC和这种突变使肿瘤耐EGFR靶向治疗。我们的研究旨在发展 治疗K-Ras突变肿瘤的新策略。此外，我们建议我们的治疗 这些策略将具有很高的治疗指数，因为我们靶向的蛋白质是正常的消耗性蛋白质。 生长，但需要恶性肿瘤。我们还预计，我们的研究结果将适用于其他肿瘤， 突变Ras蛋白，占所有人类恶性肿瘤的30%。 背景：我们已经确定5'AMP-活化蛋白激酶（AMPK），过氧化物酶体增殖物- 活化受体γ辅激活因子1 β（PGC 1 β）和雌激素相关受体α（ERRα）是新的 K-Ras突变型CRC中的肿瘤代谢调节因子。PGC 1 β是一种转录辅激活因子，ERRα是一种转录辅激活因子。 存在于高代谢组织中的转录因子，如心脏、骨骼肌、脑和棕色组织。 脂肪组织，在那里它们相互作用以转录参与代谢和线粒体生物发生的基因。 PGC 1 β和ERRα在CRC细胞系和人肝转移瘤中显著过表达， 非转化的人结肠上皮细胞（HCEC）和正常人结肠组织。AMPK，a 能量稳态的关键调节剂，是PGC 1 β、ERRα和肿瘤存活的有效调节剂。 研究计划：在本申请中，我们提供了AMPK、PGC 1 β和 ERRα是K-Ras突变型CRC中肿瘤代谢和存活的新型调节因子，我们假设 这些是开发新治疗策略的有希望的目标，因为它们是消耗性的， 正常的细胞生长。为了验证这一假设，首先，我们将研究PGC 1 β和ERRα下游的作用， 效应子Ras相关GTP结合蛋白D（RagD），mTORC 1信号传导的正调节剂和肿瘤 增长其次，我们将描述AMPK对PGC 1 β活性的关键调节作用。最后，我们将 使用原位盲肠评估PGC 1 β、ERRα和ERRα抑制剂在转移性疾病中的作用 移植转移小鼠模型。这一建议将促进我们对这些未充分探索的知识 K-Ras突变型CRC所需的代谢效应物，并有可能发展为 几种新型疗法。 职业发展：我与我的导师密切合作，创造了一个科学的职业发展， 计划旨在帮助我过渡到独立作为一个医生科学家。具体来说，我将获得宝贵的 癌症生长的代谢调节、转移模型、领导技能、granuloma，以及 伦理研究。我的导师委员会由杰出的教师组成，他们在以下方面具有专长： 指导初级教员，CRC研究和培训医生科学家。