Copper reduction as a novel therapy in BRAF-mutant positive cancers

铜还原作为 BRAF 突变阳性癌症的新疗法

• 批准号: 8565703
• 负责人: Donita C Brady
• 金额: $ 9.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8565703
• 关键词: Ablation; Address; Affinity; BRAF gene; Basic Science; Binding; Biochemical; Biological Assay; Cancer Biology; Cell Line; Cells; Chelating Agents; Chelation Therapy; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Communities; Copper; Critiques; Development; Diagnosis; Disorder by Site; Doctor of Philosophy; Drug usage; Educational workshop; Environment; Exposure to; Extramural Activities; FDA approved; Faculty; Feedback; Fellowship; Fostering; Foundations; Funding; Funding Mechanisms; Future; Genetic; Genetically Engineered Mouse; Goals; Grant; Health; Hepatolenticular Degeneration; Human; Individual; Institutes; Interview; Investigation; Journals; Large Intestine Carcinoma; MAP Kinase Gene; MAP2K1 gene; MAPK1 gene; MAPK3 gene; MEKs; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of thyroid; Manuscripts; Mediating; Melanoma Cell; Mentored Research Scientist Development Award; Mentors; Mentorship; Metastatic Melanoma; Molecular and Cellular Biology; Mus; Mutate; Mutation; Nature; North Carolina; Occupations; Oncogenic; Paper; Papillary thyroid carcinoma; Pathway interactions; Patients; Penicillamine; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Protein-Serine-Threonine Kinases; Publications; Regulation; Research; Research Personnel; Research Project Grants; Resistance; Resistance development; Resources; Role; Services; Signal Transduction; Skin Cancer; Techniques; Therapeutic; Thyroid carcinoma; Time; Training; Translating; Triethylenetetramine; Tumor Biology; Universities; Work; Writing; Xenograft procedure; anticancer research; cancer therapy; career; career development; cell transformation; chelation; effective therapy; experience; graduate student; human BRAF protein; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; interest; kinase inhibitor; knock-down; loss of function; medical schools; meetings; melanocyte; melanoma; member; mouse model; mutant; novel; post-doctoral training; pre-clinical; preclinical study; prevent; programs; protein function; public health relevance; research study; response; responsible research conduct; skills; small hairpin RNA; small molecule; symposium; tetrathiomolybdate; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): My training as a cancer biologist began at the University of North Carolina at Chapel Hill (UNC- CH), first as an undergrad in the lab of Channing J. Der, Ph.D., during my Carolina Summer Research Fellowship, and later as a graduate student in the lab of Adrienne D. Cox, Ph.D. Currently I am a post-doctoral fellow in the lab of Christopher M. Counter, Ph.D., at Duke University. These research experiences have trained me in a wide array of molecular and cellular biology techniques to study tumorigenesis, biochemical strategies to access protein function, and in vivo models of cancer, and more importantly, firmly solidified my desire to pursue an academic faculty position in the future. However, the additional mentored phase provided through the K01 award mechanism of funding will provide me with the protected time to develop my own independent research program with a network of colleagues and collaborators, improve my presentation and management skills, and progress along the "path to professorship". Specifically, I am actively pursuing an innovative research project proposed in this application that will add to my research skills by expanding my research to preclinical trials in in vivo models of tumorigenesis, give me the opportunity to present my research within Duke University and at national scientific conferences, and foster the development of novel research avenues that can be explored with extramural grant support once I've become an independent researcher. Environment: The scientific community within the Department of Pharmacology and Cancer Biology and Duke Cancer Institute (DCI), the resources and facilities provided by the DCI and School of Medicine (SOM), the support and resources provided by the Office of Postdoctoral Services (OPS) at Duke University, and the experience, commitment and support from my mentor, Christopher M. Counter, Ph.D., will be valuable assets during this mentored phase of my career in cancer biology and as I transition from a mentored to independent researcher. Briefly, in regards to my career development and path to professorship, Dr. Counter's lab is well equipped for me to undertake my research interests, is continually funded by R01 grants that result in publication of high profile papers in high impact journals, and provides me with opportunities to regularly present my research and papers. In addition, Dr. Counter and the members of my mentorship committee, Drs. Pendergast, Thiele, and Wang, have vast experience in the training of postdoctoral fellows and will give me constructive feedback on my research and scientific manuscripts, along with helping pave my career path, especially in the transition year to an independent investigator. The OPS will be instrumental in my continued training in the Responsible Conduct of Research (RCR) and in providing a wide spectrum of services, including mock interviews, practice academic job talks, and workshops such as effective strategies for the academic job search, managing a lab, and financial stewardship. Additionally, Dr. Counter serves as co-leader of the NCI- designated DCI Tumor Biology Program, comprised of 30 labs from a broad spectrum of basic and clinical departments focusing on cancer research, and is a member of the DCI Melanoma Disease-Site Group, which aims to translate basic research discoveries to investigator-initiated phase I trials. I have many opportunities to present my research at their weekly or monthly work-in-progress meetings. Taken together, the research environment that exists at Duke University, specifically within the Department of Pharmacology and Cancer Biology and DCI, is ideal to carry out my research project and career development. Research Project: As mentioned above, two major goals of my post-doctoral training are to increase my exposure to in vivo models of tumorigenesis and to engage my interest in seeing basic research discoveries move forward. To that end, my proposed research project evolved from our previous observations that copper (Cu) influx enhances MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction. Melanomas and a wide spectrum of other cancers, like thyroid and colon cancer, that harbor activating mutations in the serine/threonine kinase BRAF, often respond dramatically to small molecule kinase inhibitors against mutant BRAF. However, they rapidly develop resistance, yielding only short-term clinical responses. Thus, combinations of multiple approaches to inhibit MAPK signaling hold great promise for more effective treatment of BRAF mutation-positive cancers. Our current work under review at the journal Nature shows that genetic loss of the high affinity Cu transporter Ctr1 reduced the tumor growth of BRAFV600E-transformed cells, and that a Cu chelator used in the treatment of Wilson's disease yielded a similar result not only on BRAFV600E-transformed cells, but also on cells resistant to a BRAF inhibitor, vemurafenib. Taken together, these results suggest that Cu-chelation therapy could be repurposed for the treatment of BRAF mutation- positive cancers. Thus in order to address a novel and significant research question in cancer biology that is relevant to my research interests and to continue to develop my skills in cancer biology, I am proposing scientific aims focused on the use of pharmacological chelation of Cu either alone or in combination with the BRAF inhibitor, vemurafenib, in a GEMM of melanoma driven by constitutively active BrafV600E and loss of Pten. In addition, I will investigate Ctr1 genetic ablation and Cu chelation in BRAF-mutant thyroid and colon cancers that are also reliant on sustained MAPK pathway activation. These research endeavors will solidify my training as a cancer biologist and spark novel research questions that will become the foundation for my pursuit of an academic faculty position in cancer biology.

描述（由申请人提供）：我作为一名癌症生物学家的培训开始于北卡罗来纳大学教堂山分校 (UNC-CH)，首先是在卡罗莱纳州期间，在 Channing J. Der 博士的实验室里读本科生。暑期研究奖学金，后来成为 Adrienne D. Cox 博士实验室的研究生。目前我是杜克大学 Christopher M. Counter 博士实验室的博士后研究员。这些研究经验使我掌握了广泛的分子和细胞生物学技术，以研究肿瘤发生、获取蛋白质功能的生化策略以及癌症的体内模型，更重要的是，坚定了我在该领域追求学术教职的愿望。未来。然而，通过 K01 奖励机制提供的额外指导阶段将为我提供受保护的时间，与同事和合作者网络一起开发自己的独立研究计划，提高我的演讲和管理技能，并沿着“通往教授职位”。具体来说，我正在积极开展本申请中提出的创新研究项目，该项目将通过将我的研究扩展到肿瘤发生体内模型的临床前试验来提高我的研究技能，让我有机会在杜克大学和国家科学会议上展示我的研究成果会议，并促进新颖的研究途径的发展，一旦我成为一名独立研究员，就可以在校外资助的支持下探索这些途径。环境：药理学和癌症生物学系和杜克癌症研究所 (DCI) 内的科学界、DCI 和医学院 (SOM) 提供的资源和设施、博士后服务办公室 (OPS) 提供的支持和资源）在杜克大学，我的导师 Christopher M. Counter 博士的经验、承诺和支持将在我癌症生物学职业生涯的指导阶段以及我从指导研究员向独立研究员的转变过程中成为宝贵的资产。简而言之，就我的职业发展和成为教授的道路而言，Counter 博士的实验室装备精良，足以让我从事我的研究兴趣，并持续得到 R01 资助的资助，从而在 高影响力期刊，并为我提供了定期展示我的研究和论文的机会。此外，Counter 博士和我的指导委员会成员 Drs. Pendergast、Thiele 和 Wang 在博士后培训方面拥有丰富的经验，他们将为我的研究和科学手稿提供建设性的反馈，并帮助铺平我的职业道路，特别是在向独立研究者过​​渡的那一年。 OPS 将有助于我继续进行负责任的研究行为 (RCR) 培训，并提供广泛的服务，包括模拟面试、学术工作演讲练习和研讨会，例如学术工作搜索的有效策略、管理实验室和财务管理。此外，Counter 博士还是 NCI 指定的 DCI 肿瘤生物学项目的联合负责人，该项目由来自广泛的基础和临床部门的 30 个实验室组成，专注于癌症研究，并且是 DCI 黑色素瘤疾病现场组的成员，旨在将基础研究发现转化为研究者发起的第一阶段试验。我有很多机会在他们的每周或每月的正在进行的会议上展示我的研究。总而言之，杜克大学的研究环境，特别是药理学和癌症生物学系以及 DCI 内的研究环境，非常适合我开展研究项目和职业发展。研究项目：如上所述，我博士后培训的两个主要目标是增加我对肿瘤发生的体内模型的接触，并激发我对基础研究发现进展的兴趣。为此，我提出的研究项目是从我们之前的观察演变而来的，即铜 (Cu) 流入通过 Cu-MEK1 相互作用增强其底物 ERK1/2 的 MEK1 磷酸化。黑色素瘤和多种其他癌症，如甲状腺癌和结肠癌，在丝氨酸/苏氨酸激酶 BRAF 中存在激活突变，通常对针对突变 BRAF 的小分子激酶抑制剂产生显着反应。然而，它们会迅速产生耐药性，仅产生短期临床反应。因此，抑制 MAPK 信号传导的多种方法的组合为更有效地治疗 BRAF 突变阳性癌症带来了巨大希望。我们目前正在《自然》杂志上审查的工作表明，高亲和力铜转运蛋白 Ctr1 的遗传缺失减少了 BRAFV600E 转化细胞的肿瘤生长，并且用于治疗威尔逊氏病的铜螯合剂不仅在 BRAFV600E 上产生了类似的结果-转化细胞，而且还针对对 BRAF 抑制剂维莫非尼 (vemurafenib) 具有抗性的细胞。总而言之，这些结果表明铜螯合疗法可以重新用于治疗 BRAF 突变阳性癌症。因此，为了解决与我的研究兴趣相关的癌症生物学中一个新颖且重要的研究问题，并继续发展我在癌症生物学方面的技能，我提出的科学目标集中于单独或联合使用铜的药理螯合。与 BRAF 抑制剂维莫非尼 (vemurafenib) 联合治疗由持续活跃的 BrafV600E 和 Pten 缺失驱动的黑色素瘤 GEMM。此外，我还将研究 BRAF 突变型甲状腺癌和结肠癌中的 Ctr1 基因消融和 Cu 螯合，这些癌症也依赖于持续的 MAPK 通路激活。这些研究工作将巩固我作为癌症生物学家的训练，并引发新的研究问题，这些问题将成为我追求癌症生物学学术教职的基础。