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

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北卡罗来纳大学教堂山分校（UNC- CH），首先作为Channing J. Der博士实验室的本科生，在我的Carolina暑期研究奖学金期间，后来作为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。这些研究经历训练了我广泛的分子和细胞生物学技术来研究肿瘤发生，生化策略来获取蛋白质功能，以及癌症的体内模型，更重要的是，坚定了我未来追求学术教师职位的愿望。然而，通过K01基金奖励机制提供的额外指导阶段将为我提供受保护的时间，让我与同事和合作者一起开发自己的独立研究项目，提高我的演讲和管理技能，并沿着“教授之路”前进。具体来说，我正在积极地追求这个申请中提出的一个创新的研究项目，它将通过扩大我的研究到肿瘤发生的体内模型的临床前试验来增加我的研究技能，给我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的研究人员，就可以在校外资助的支持下进行探索。环境: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. Counter博士的经验、承诺和支持，在我癌症生物学职业生涯的这一指导阶段，以及我从一名导师转变为独立研究人员的过程中，将是宝贵的资产。简而言之，就我的职业发展和教授之路而言，Counter博士的实验室为我从事我感兴趣的研究提供了良好的条件，并不断获得R01基金的资助，并在美国发表了高知名度的论文

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.