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PrintYardena Samuels, Ph.D.
B.Sc. Cambridge University, United Kingdom, 1993
M.Sc. Hebrew University of Jerusalem, Israel, 1997
Ph.D. Ludwig Institute for Cancer Research, United Kingdom, 2002
(301) 451-2628
(301) 594-0023 
50 South Dr, MSC 8000
Bethesda, MD 20892-8000
Dr. Samuels uses a variety of genomic approaches to identify novel somatic mutations in late-stage cutaneous melanoma. Genetic alterations, including point mutations, deletions and amplifications, occur in every cancer cell. These changes are known to occur in oncogenes, tumor suppressor genes, and stability genes. Although many of these genes have been identified for certain types of tumors, most still remain to be discovered.
Melanoma arises as a result of the malignant transformation of melanocytes, the pigment-producing cells located in the bottom layer of human skin. It is the most common fatal skin cancer, and its incidence has increased 15-fold in the United States over the last 40 years — faster than any other malignancy. Each year in the United States, over 60,000 people are diagnosed with malignant melanomas and more than 8,000 die of the disease.
In early stage disease, in its radial growth phase (RGP), the melanoma tumor stays on the skin's surface; however, once the malignancy advances to the vertical growth phase (VGP), it penetrates through the skin and is able to metastasize. As melanomas penetrate farther into the skin, treatment options as well as cure and survival rates decrease. In fact, five-year survival rates for VGP melanoma range from 13 to 69 percent, and no treatment has yet been found to be universally effective.
Melanoma disease progression is assumed to be associated with the accumulation of genetic mutations over time. Genes that have been implicated in the development of melanomas include CDKN2A, NRAS, and BRAF. Comprehensive cancer genome sequencing may identify recurring genetic alterations that will ultimately lead to targeted approaches for the diagnosis and treatment of melanoma, enabling personalized treatment.
Dr. Samuels' group aims to discover recurrent tumor-specific mutations in gene families within melanoma tumors. Once these mutations are identified, her group focuses on characterizing the biochemical, functional, and clinical aspects of the most highly mutated genes. To facilitate this search, the Samuels laboratory has established a library of metastatic melanoma tumors and matched normal tissues in collaboration with the National Cancer Institute. Dr. Samuels uses candidate approaches as well as whole exome and whole genome sequencing to identify novel somatic mutations.
The Samuels laboratory has recently examined the genes encoding matrix metalloproteinases and tyrosine kinases, both of which play important roles in regulating the cellular events that lead to tumor formation. Importantly, the Samuels laboratory's research on tyrosine kinases has revealed that ERBB4 is somatically mutated in 19 percent of melanoma cases. Studies of seven missense mutations in ERBB4 showed that all mutants exhibited increased kinase activity. Exposure of melanoma cells to the FDA-approved ERBB inhibitor lapatinib resulted in a greater reduction in cell proliferation in cells containing endogenous ERBB4 mutations than in cells containing endogenous wild-type ERBB4. Based on these results, and in collaboration with Dr. Rosenberg, a phase II clinical study will be conducted in which melanoma patients harboring ERBB4 mutations will be treated with lapatinib.
Since solid tumors can result from genetic alterations in a large number of genes that function through a relatively small number of pathways, therapeutic development may lie in the discovery of agents that target the physiologic effects of these altered pathways. Thus, inhibitors that broadly target downstream mediators or nodal points may be the most effective. The Samuels group's whole exome and whole genome research may not only lead to the discovery of novel highly mutated genes, but may also help determine which pathways are altered in melanoma, and how these genes and pathways interact. Ultimately, Dr. Samuels aims to decipher the genetic landscape of melanoma in order to enhance biological insight into the disease, and to point to novel strategies for better patient care.
Dr. Samuels' earlier work has provided her strong expertise for these studies. Specifically, she previously used high-throughput DNA sequencing to analyze the phosphatidylinositol-3-kinase (PI3K) gene family, and discovered a large number of mutations associated with human cancer in the lipid kinase-encoding gene PIK3CA. This gene is now known to be one of the most highly mutated oncogenes in human malignancies and is the focus of several targeted therapy trials.
Last Updated: September 20, 2011
