Hasmeena Kathuria, MD, an assistant professor in the department of medicine at Boston University School of Medicine (BUSM), has received the Department of Defense Lung Cancer Promising Clinician Research Award (LCPCRA) to study the role of Ets transcription factors in the progression of lung cancer. It is hoped this research will provide important new information about the molecular progression of lung tumors and help identify new therapeutic targets to block tumor growth and metastasis. The LCPCRA supports research projects performed by promising physician-researchers.
Lung cancer is the leading cancer death in both men and women in the United States. Only about 15 percent of all lung cancer patients are alive five years after the initial diagnosis and subsequent treatments. At diagnosis, tumor cells have already left the original tumor and entered other tissue sites such as lymph nodes in about 75 percent of patients. Little is known about the factors that allow cancer cells to leave their original site of formation and move to other tissues and organs. Epithelial-mesenchymal transition (EMT), a process that involves loss of cell-cell contact and increase in cell movement, is a fundamental event in cancer spread. There is evidence suggesting that the genes and proteins to be studied in this application may be involved in several cancer-related processes but particularly those related to exit from the lung and seeding of cells into other sites.
Lkb1 kinase is a gene that is thought to protect cells from steps that cause progression to cancer cells. In lung cancer, 34 percent of human lung cancers have mutations in Lkb1 causing a loss or reduction in this function. Recently, research from the laboratory of co-investigator, Kwok-kin Wong, MD, (Dana Farber Cancer Institute) has led to the development of a mouse model of lung cancer that harbors the Lkb1 mutation and aggressively spreads to sites outside the lung. "We have identified a factor termed Ets1, along with several Ets1 target genes known to be involved in EMT such as Twist1, that are greatly increased in the mouse model compared to a mouse lung cancer model that does not harbor this mutation," explained Kathuria.
According to the researchers there is clear evidence that Ets1 is altered in lung cancer. This protein factor is a member of a family of proteins associated with other cancers. "When compared to levels of several thousand human genes in human cancers, Ets1 levels are greatly increased. This suggests that Ets1 may participate in detachment of cells, their movement out of the lung, and/or entry and growth in new sites," added Kathuria.
Therapeutic targeting of EMT activators and /or their regulators could be useful to impair EMT, and thus tumor spread. Identification of downstream pathways that are activated during EMT may reveal new diagnostic markers of early stages of lung cancer and possible novel targets for anti-metastatic therapeutics.