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

摘要 重要意义：这项提议有可能影响大量结直肠癌患者 无论男女，结肠癌(CRC)都是导致癌症死亡的第三大原因。K-RAS基因突变在大约40%的 所有的癌基因和这种突变使肿瘤对EGFR靶向治疗产生抗药性。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 战略将有一个很高的治疗指数，因为我们的目标是正常情况下可消耗性的蛋白质 生长，但恶性是必需的。我们还预计，我们的发现将适用于其他具有 突变的RAS蛋白，占人类所有恶性肿瘤的30%。 背景：我们已经确定了5‘AMP激活的蛋白激酶(AMPK)、过氧化物酶体增殖物- 活化的受体γ共激活因子1-β(pgc1β)和雌激素相关受体α(errα)是新发现的 K-RAS突变癌细胞的肿瘤代谢调节。Pgc1β是转录共激活因子，Errα是一种 存在于高代谢组织中的转录因子，如心脏、骨骼肌、脑和棕色 脂肪组织，在那里它们相互作用，转录参与新陈代谢和线粒体生物发生的基因。 PGc1β和ERRα在结直肠癌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(HCECs)和正常人结肠组织。AMPK，a 能量平衡的关键调节因子是Pgc1β、ERRα和肿瘤生存的有效调节因子。 研究计划：在本申请中，我们提供有关AMPK、Pgc1、β和 ERRα作为K-RAS突变癌中肿瘤代谢和生存的新调节因子，我们假设 这些都是开发新的治疗策略的有希望的目标，因为它们可以用于 正常的细胞生长。为了验证这一假设，首先，我们将检查pgc1β和ERRα下游的作用 效应Ras相关GTP结合蛋白D(RagD)--mTORC1信号正向调节因子与肿瘤 成长。第二，我们将表征AMPK对前列腺素C_1β活性的关键调节作用。最后，我们将 应用原位盲肠评价前列腺素C_1β、ERRα和ERRα抑制剂在转移性疾病中的作用 移植瘤小鼠模型的建立。这项建议将促进我们对这些未被开发的 K-RAS突变型CRC所需的代谢效应因子，并有可能发展为 几种新的治疗方法。 职业发展：我与我的导师们密切合作，创造了科学的职业发展 旨在帮助我过渡到独立成为一名内科科学家的计划。具体地说，我将获得宝贵的 关于癌症生长的代谢调节、转移模型、领导技能、勇气和 伦理研究。我的导师委员会由杰出的教职员工组成，他们具有以下专业知识 指导初级教员、CRC研究和培训内科科学家。

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.