David E. Fisher
Our group studies cell death/proliferation signals in relation to development and disease, particularly in skin cancer. We attempt to understand critical modes of cell homeostasis with a goal of molecular targeted therapy as well as prevention of melanoma and other human cancers.
1) Lessons for malignancy from normal development. We study biology of melanocytes as a means of identifying pathways which drive melanoma in man. This includes examination of mechanisms underlying growth/survival of benign moles, most of which contain mutations in either BRAF or N-Ras oncogenes. We also study melanocyte death in hair follicles, a process associated with hair graying. Pathways were identified which link graying to melanocyte and melanoma survival, offering potential leads for novel therapies. Other studies focus on pathways modulating melanocytic responses to environmental cues and employ oncogene-transformed melanocytic lines which exhibit growth factor independence, mimicking human melanoma in a genetically controlled manner.
2) Control of life and death in melanoma. Malignant transformation of melanocytes produces one of the most treatment resistant malignancies in man. We have identified a transcriptional network which regulates melanoma cell survival and proliferation as well as melanocyte differentiation during development. Using diverse methods including mouse models, human tumor expression arrays, and cellular assays, we examine mechanisms through which melanoma cells evade death, with the goal of improving therapy. Studies include preclinical and clinical analyses of novel melanoma treatments. We also study the role of UV in pigmentation responses and carcinogenesis.
3) MITF transcription factor family in development & cancer. Mitf is a helix-loop- helix factor homologous to Myc, whose mutation in man produces absence of melanocytes. Mitf acts as a master regulator of melanocyte development and is targeted by several critical signaling pathways. Recently, members of the Mitf family have been discovered as oncogenes in a variety of human malignancies, particularly sarcomas of childhood. Their roles in cancer as well as strategies to target them therapeutically are under active investigation. Detailed mechanistic studies focus on transcription factor interactions with chromatin, particularly positioned nucleosomes.
4) Small molecule drug screens for therapeutic or preventative treatments. We carry out high throughput robotics based screens of lipophilic drugs capable of skin penetration, in order to identify new skin targeted therapies as well as agents capable of modifying skin pigmentation and cancer risk. We also utilize novel model systems.
55 Fruit Street
Bartlett Hall 622
Boston, MA 02114