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

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 策略将具有高治疗指数，因为我们针对的是正常情况下可消耗的蛋白质 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， 未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。

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.