The goals of Dr. Bell's laboratory are to understand the genetic alterations that lead to clinically aggressive subtypes of endometrial cancer and to apply this knowledge to improve the clinical management of women with endometrial cancer.
Endometrial cancer, which affects the endometrium (the lining of the uterus), is the most commonly diagnosed gynecological malignancy in the United States and is the 8th leading cause of cancer death among American women. In the United States, there are about 42,000 new cases of endometrial cancer diagnosed each year, along with about 7,700 deaths attributable to this disease. Worldwide, approximately 50,000 women die of endometrial cancer each year. Most patients present with "type I" tumors with endometrioid histology and have a good prognosis, but around one in every seven patients is diagnosed with a "type II" serous or clear cell tumor. Type II tumors are the most clinically aggressive form of endometrial cancer. As a result, these tumors contribute disproportionately to mortality and cause about 40 percent of all endometrial cancer deaths even though they represent only a small fraction of diagnosed cases.
Most human tumors are caused by the accumulation of genetic and epigenetic alterations in so-called cancer genes. Over the past few years, it has become evident that some genetic alterations may be exploited as therapeutic targets in cancer treatment. For example, the drug imatinib is highly effective in the treatment of chronic myelogenous leukemias with an underlying BCR-ABL chromosome translocation. Similarly, a subset of non-small cell lung cancers with specific mutations that affect the catalytic domain of the epidermal growth factor receptor (EGFR) responds to the drugs gefitinib and erlotinib. Therefore, uncovering the genetic basis of human tumors is the first step towards personalized medicine using molecularly-targeted therapeutics.
Dr. Bell aims to identify the genetic alterations that cause serous and clear cell tumors of the endometrium en route to developing new therapies for type II endometrial cancers.
Towards that end, her research group is taking an integrated approach to catalogue the genomic alterations in type II tumors. This includes systematic searches for changes in gene copy number, expression and sequence. They are using high-density, single-nucleotide polymorphism (SNP) genotyping to identify genome-wide copy-number changes in type II endometrial tumors. In complementary studies, they are searching for changes in gene expression in these tumors. Parallel studies include extensive collaborations with the NIH Intramural Sequencing Center for performing high-throughput mutational screens to search for changes in gene sequence. Two strategies are used for the mutational analyses. The first involves a candidate gene approach in which genes that make potentially "druggable" proteins are interrogated using high-throughput Sanger sequencing. The second strategy employs next generation sequencing to systematically interrogate type II tumors for somatic mutations in the exons of more than 18,000 protein-coding genes. The copy number, expression and mutation data are integrated to identify genes or functional pathways that are recurrently altered in type II EC. Once specific genetic alterations are found, follow-up studies are performed to determine whether, and how, they affect the function of the encoded proteins. Individual genes or functional pathways are prioritized for analysis based on their potential therapeutic relevance.
Dr. Bell brings valuable expertise to her studies of endometrial cancer. Previously, she discovered a cancer-susceptibility gene (CHEK2) that has been implicated in the development of breast and prostate cancer. She also defined the genetic alterations responsible for clinical sensitivity and resistance of lung cancer patients to the tyrosine kinase inhibitor gefitinib (Iressa); her group plans similar evaluations of the usefulness of potential therapies for type II endometrial cancer.
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Last Updated: May 18, 2014