Harold E. Varmus, M.D.
Cancer Genetics Branch
Building 50, Room 5146
50 South Drive
Bethesda, MD 20892
The Varmus laboratory uses a variety of experimental approaches to understand the molecular mechanisms of oncogenesis, with an emphasis on the use of mouse models of human cancer and human lung adenocarcinomas.
In its work on mouse models, the group has focused on the functions required to maintain the oncogenic state, the relationship between normal development lineages and oncogenic events, the molecular basis of tumor progression, and strategies for targeted therapeutics.
Dr. Varmus's group joined the NHGRI Intramural Research Program in 2010. Over the past decade at Memorial Sloan-Kettering Cancer Center, the laboratory Varmus group addressed these issues through the creation and study of models for cancers of the breast, pancreas, lung, ovary, mesenchymal tissues, and plasma cells and other hematopoietic lineages, using a variety of methods to generate oncogenic mutations that included conventional and regulated transgenes, non-conditional and conditional null mutations, and tissue-specific delivery of genes with retroviral vectors.
Dr. Varmus's group joined the NHGRI Intramural Research Program in 2010. Current work on these issues follows two approaches. In the context of a mouse model for acute myeloid leukemia, the laboratory conducts studies of the Bcl-2 family of proteins, with an emphasis on the novel factors that control their abundance and the contribution that the six anti-apoptotic Bcl-2 proteins make to oncogenesis. Using mice carrying stage-specific transgenes and retroviral vectors, the laboratory is making efforts to determine the stages in the development of B-cells - a well-characterized cell lineage - at which cells are susceptible to the oncogenic influences of known cancer genes c-Myc and p53.
For the past eight years, the laboratory has devoted special efforts to an understanding of human lung cancer, especially adenocarcinomas driven by mutations in the gene encoding the epidermal growth factor receptor (EGFR). This work was triggered by dramatic remissions observed in some patients with lung adenocarcinomas - especially non-smokers - after treatment with tyrosine kinase inhibitors, and led to the description of lung-specific somatic mutations of EGFR.
Various approaches to this important medical problem have since been pursued by Dr. Varmus's group. The laboratory recapitulated EGFR-induced cancers and K-Ras-induced lung cancers in mouse models in which the oncogene is temporally controlled by doxycycline-dependent regulatory elements. In a large collaboration that later became The Cancer Genome Atlas project, Dr. Varmus's group identified additional mutations in human lung adenocarcinomas; identification of those mutations in mouse models followed as part of a collaboration sponsored by the Starr Cancer Consortium. Resistance to tyrosine kinase inhibitors that occurs inevitably during cancer treatment was explained by the identification of a second mutation in the EGFR tyrosine kinase domain and recapitulating drug resistance in mouse models. The role of other members of the EGFR family in lung carcinogenesis has been examined as well.
Using high-throughput screening methods, the the Varmus group identified small molecules that inhibit the growth of human lung cancer cell lines and investigated molecular targets of those compounds. The laboratory has studied the inflammatory response that often accompanies lung adenocarcinomas in mice and human beings. They are harnessing mass spectroscopy and other proteomic methods to look for proteins (especially phosphoproteins) involved in oncogenic signaling pathways in EGFR- and K-Ras-driven lung tumor cells. Their efforts have extended to seeking plasma proteins that might serve as biomarkers for lungs cancers induced by mutant K-Ras or EGFR genes. The biomarker effort is a component of collaborative mouse model studies conducted with the Canary Foundation.
Politi K, Fan PD, Shen R, Zakowski M, Varmus H. Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. Dis Model Mech. 2010;3(1-2):111-9.
Somwar R, Shum D, Djaballah H, Varmus H. Identification and preliminary characterization of novel small molecules that inhibit growth of human lung adenocarcinoma cells. J Biomol Screen. 2009;14(10):1176-84.
Jechlinger M, Podsypanina K, Varmus H. Regulation of transgenes in three-dimensional cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction. Genes Dev. 2009;23(14):1677-88.
Asimakopoulos F, Varmus HE. Cell-specific transduction of Prdm1-expressing lineages mediated by a receptor for avian leukosis virus subgroup B. J Virol. 2009;83(10):4835-43.
Beverly LJ, Varmus HE. MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. Oncogene. 2009;28(9):1274-9.