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训练开始于查佩尔山的北卡罗来纳州大学（北卡罗来纳州），首先是在钱宁J. Der博士实验室的本科生，在我的卡罗莱纳夏季研究奖学金期间，以及后来在艾德丽安D.考克斯博士目前，我是克里斯托弗M。计数器，博士，在杜克大学。这些研究经验培养了我在一系列广泛的分子和细胞生物学技术，研究肿瘤发生，生化策略，以获取蛋白质功能，以及体内癌症模型，更重要的是，坚定了我的愿望，追求在未来的学术教师的位置。然而，通过K 01奖励机制提供的额外指导阶段将为我提供受保护的时间，与同事和合作者一起开发我自己的独立研究计划，提高我的演讲和管理技能，并沿着“教授之路”取得进展。具体而言，我正在积极追求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增加我的研究技能，让我有机会在杜克大学和国家科学会议上展示我的研究，并促进新的研究途径的发展，一旦我成为一名独立研究人员，就可以在校外资助的支持下进行探索。工作环境：药理学和癌症生物学系和杜克癌症研究所（DCI）的科学界，DCI和医学院（SOM）提供的资源和设施，杜克大学博士后服务办公室（OPS）提供的支持和资源，以及我的导师Christopher M.计数器，博士，在我的癌症生物学职业生涯的指导阶段，以及我从一名指导者向独立研究者过渡的过程中，将是宝贵的财富。简而言之，关于我的职业发展和教授之路，Counter博士的实验室为我从事我的研究兴趣做好了充分的准备，不断得到R 01赠款的资助，导致在2010年发表了高知名度的论文。 高影响力的期刊，并为我提供了定期展示我的研究和论文的机会。此外，Counter博士和我的导师委员会成员Pendergast博士、Thiele博士和Wang博士在博士后研究员的培训方面拥有丰富的经验，他们会对我的研究和科学手稿给予建设性的反馈，沿着帮助我铺平职业道路，特别是在向独立研究者过渡的那一年。OPS将有助于我继续接受负责任的研究行为（RCR）培训，并提供广泛的服务，包括模拟面试，实践学术工作会谈和研讨会，如学术求职的有效策略，管理实验室和财务管理。此外，Counter博士还担任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黑色素瘤疾病网站小组的成员，该小组旨在将基础研究发现转化为药物启动的I期试验。我有很多机会在他们每周或每月的工作进展会议上展示我的研究。综上所述，存在于杜克大学的研究环境，特别是在药理学和癌症生物学和DCI的部门，是理想的开展我的研究项目和职业发展。研究项目：如上所述，我的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，并使我对看到基础研究发现向前发展感兴趣。为此，我提出的研究项目是从我们以前的观察中发展而来的，即铜（Cu）的流入通过Cu-MEK 1相互作用增强了MEK 1对其底物ERK 1/2的磷酸化。黑色素瘤和广泛的其他癌症，如甲状腺癌和结肠癌，其在丝氨酸/苏氨酸激酶BRAF中具有激活突变，通常对针对突变BRAF的小分子激酶抑制剂有显著响应。然而，它们迅速产生耐药性，仅产生短期临床反应。因此，多种抑制MAPK信号传导的方法的组合对于更有效地治疗BRAF突变阳性癌症具有很大的希望。我们目前在《自然》杂志上进行的研究表明，高亲和力铜转运蛋白Ctr 1的遗传丢失减少了BRAFV 600 E转化细胞的肿瘤生长，并且用于治疗威尔逊病的铜螯合剂不仅在BRAFV 600 E转化细胞上产生了类似的结果，而且在对BRAF抑制剂vemurafenib耐药的细胞上也产生了类似的结果。总之，这些结果表明Cu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的一个新的和重要的研究问题，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在单独或与BRAF抑制剂维罗非尼联合使用Cu的药理学螯合作用，在由组成性活性BrafV 600 E和Pten损失驱动的黑色素瘤GEMM中。此外，我将研究Ctr 1基因消融和铜螯合在BRAF突变的甲状腺癌和结肠癌，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职位的基础。