Biomedical Graduate Studies

Description of Research Expertise

During the last two decades, my research laboratory has focused on studies to unravel the fundamental events responsible for the aggressive pediatric soft tissue cancer alveolar rhabdomyosarcoma (ARMS). After chromosome studies of this cancer identified translocations (exchanges of genetic material) between chromosome 13 and either chromosome 2 or chromosome 1, my laboratory identified that these translocations break within the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1, and join part of these genes with part of the FOXO1 gene on chromosome 13. This process results in the formation of a PAX3-FOXO1 or PAX7-FOXO1 fusion protein. Numerous studies have shown that this fusion protein is essential for the development of ARMS. My laboratory’s more recent studies are investigating how these fusion proteins are made and function in the cancer cells, and are exploring how to manipulate fusion protein expression and function in ARMS cells with the ultimate goal of developing novel strategies for targeting these fusion proteins and thereby treating this cancer.

To complement these studies of the fusion protein, my research laboratory is also investigating additional changes that occur during the development of ARMS. Our functional studies indicated that the PAX3-FOXO1 fusion protein must cooperate with other changes to cause normal cells to become tumorigenic. To search for such events in ARMS, my laboratory performed a large screen of DNA copy number changes on all chromosomes in the cancer cells, and participated in a large multi-laboratory next generation sequencing project that searched for small DNA changes throughout the ARMS genome. These studies revealed that, though there are few if any recurrent small DNA changes in ARMS, there are frequent changes in which chromosome regions increase in copy number in a process known as amplification. These amplification events will increase the production of cellular proteins that contribute to cancer formation. Current studies are identifying the proteins encoded by these amplified regions and the specific function of these proteins in ARMS. Finally, my research laboratory is now performing another genome-wide screen to investigate an additional set of DNA changes that occur at the level of methylation, a type of DNA modification. These methylation changes will affect whether a gene is expressed in cells by altering how the DNA packages with nuclear proteins to form the complex known as chromatin.

To investigate the clinical utility of translocations, amplification and other DNA changes, I have also established a translational research program exploring the role of these molecular markers in the diagnosis, prognosis, and management of pediatric sarcomas. These studies are addressing both molecular approaches for detection of these changes in tumors and the correlation of these molecular findings with clinical characteristics, including patient outcome. Many of these studies are performed as part of the larger research program of the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. The findings of these clinical research studies are now being incorporated into the next set of clinical trials conducted by the Soft Tissue Sarcoma Committee.

Description of Clinical Expertise

molecular diagnosis of cancer