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.

Public Health Relevance

Melanomas, cancer of the skin in which ~70,000 new cases will be diagnosed this year, and a wide spectrum of other cancers are initiated by a mutation in the BRAF gene causing a BRAF protein to be made that is stuck in the on position;constantly telling the cells to multiply, which is a hallmark of cancer. Thus, the proposed study to evaluate whether drugs used to reduce copper levels, alone or in combination with other drugs, provide a survival advantage in preclinical models of metastatic melanoma and other BRAF-mutant cancers has direct significance to human health, especially as results from these studies could be immediately implemented in a clinical setting for the treatment of these cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Subcommittee B - Comprehensiveness (NCI)
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Davani, Behrous
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Duke University
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Brady, Donita C; Crowe, Matthew S; Greenberg, Danielle N et al. (2017) Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors. Cancer Res 77:6240-6252
Chen, Hsin-Yi; Brady, Donita C; Villanueva, Jessie (2016) Double Trouble: Kinase domain duplication as a new path to drug resistance. Pigment Cell Melanoma Res 29:493-5
Brady, Donita C; Crowe, Matthew S; Turski, Michelle L et al. (2014) Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492-6