Molecular pathogenesis and therapy innovation for Merkel cell carcinoma

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

To identify molecular drivers of Merkel cell carcinoma, we have conducted analyses of human tumors and cancer cell lines across multiple genome-wide platforms to assay gene expression, identify gene mutations, and characterize chromosomal alterations. These data are being analyzed to identify key driver alterations for this tumor. We are also generating mice where oncogenic modifications are carried out in specific skin lineages to study Merkel cell carcinoma transformation and progression in vivo. In addition, we are developing and characterizing cancer cell lines of Merkel cell carcinoma for in vitro and xenograft studies. We are also developing clinical biomarkers for Merkel cell carcinoma. Our work investigating the epigenetic alterations in Merkel cell carcinoma have led to interesting discoveries about the relationship between Merkel cell polyomavirus and the host cell that forms Merkel cell carcinoma. In other studies we developed a protocol for the clinical expansion of T lymphocytes that recognize Merkel cell polyomavirus tumor antigens as a potential cellular therapy for virus positive Merkel cell carcinoma. In addition, we are conducting high throughput small molecule and genetic knockdown screens to identify pathways important for tumor survival and identify novel treatments for Merkel cell carcinoma. Through these studies we have identified several classes of small molecule compounds that effectively reduce the viability of Merkel cell carcinoma as single agents or in combination. Mechanistic validation and preclinical development of top screen hits is ongoing. Working with samples from patients with Merkel cell carcinoma, we have identified genetic risk factors for this disease and infection with the polyomavirus that can cause the cancer. Finally, analyzing cancer registry data has allowed us to identify patient factors that influence the risks and outcomes for Merkel cell carcinoma, including discovering populations with higher risks for cancer formation.