A metaphor for cancer is normal development gone awry. All tissues in the body arise from embryonic stem cells that gradually give rise to specialized cells. Cancer resembles a case of arrested development because less differentiated tumors are almost always the most aggressive. So it’s no surprise that genes regulating normal fetal and childhood development have been implicated in adult cancer. The question now: If a gene regulating development can cause cancer, can blocking that gene eradicate the tumor? One such gene is Notch. First described almost a century ago, Notch has become the object of intense study in cancer. Evidence is growing that Notch signaling can drive the growth of a wide range of tumors, from leukemia to breast cancer. At least two cancer clinical trials are under way using Notch inhibitors, and several others are pending.“This is an exploding field,” says Lucio Miele, MD, Ph. D., a cancer researcher at Loyola University Medical Center in Maywood, Ill. Notch was first identified in 1919 by geneticist Thomas Hunt Morgan, Ph. D., of Columbia University in New York.(Morgan named the gene after the notches that appeared in the wings of fruit flies lacking a gene copy.) In 1937, Donald Poulson, Ph. D., of the Carnegie Institution in Baltimore showed that defects in Notch caused cells originally destined to be skin to instead become neural tissue. This innovation established Notch’s role in determining a cell’s fate. Notch signaling usually blocks differentiation, thus allowing orderly deployment of diverse cell types in tissues and organs. For example, Notch signaling from developing neurons in chicks keeps adjacent cells from also turning into neurons and allows them to become glia, the brain’s support cells. Notch is a relative newcomer to the cancer field. In 1991, Notch1 (one of four Notch receptors in humans) was identified at a translocation breakpoint in rare cases of T-acute lymphoblastic leukemia/lymphoma (T-ALL). The following year, Notch4 was found at the site of a retroviral gene insertion that leads to breast cancer in mice. The 1999 discovery that gamma secretase cleaves Notch receptors, triggering Notch signaling, has led to an explosion of cancer research using gamma secretase inhibitors originally developed in the late 1990s to treat Alzheimer disease.(Gamma secretase enables amyloid plaques to build up in the brain in Alzheimer disease.) Many groups have now shown that these drugs can block tumor growth in cell culture.