Massimo Loda, MD
Professor, Department of Pathology, Harvard Medical School
Senior Pathologist, Pathology, Brigham And Women's Hospital
Principal Investigator, Pathology, Dana-Farber Cancer Institute
DF/HCC Program AffiliationGastrointestinal Malignancies
Research AbstractWhile the selective and irreversible destruction of a given protein occurs through its ubiquitination, this enzymatic process can be reversed by de-ubiquitinating enzymes .
We have been interested for several years in this family of enzymes and recently discovered that one such enzyme, USP2a, is androgen responsive, is overexpressed in prostate tumors, and most importantly, regulates the stability of fatty acid synthase (FAS), essential for tumor cell survival. Since inhibition of this enzyme as well as of its substrate, fatty acid synthase, results in significant prostate cancer cell death, these are both important therapeutic targets in this disease. Dr. Loda's laboratory is focused on the role played by these proteins in prostate carcinogenesis and in the development of USP2a and FAS inhibitors that may be used in the clinic.
The regulation of replication in human cells is complex. Several genes are involved, either favoring or inhibiting progression of cellular division. Targeted protein degradation by the ubiquitin-proteasome pathway plays a vital role in monitoring the abundance of several proteins involved in cell cycle regulation. We have shown that loss of p27, a powerful inhibitor of cyclin-dependent kinases, has been associated with aggressive behavior in a variety of tumors, including prostate cancer. Our laboratory has also demonstrated, for the first time, that targeted destruction of p27 is a mechanism utilized by cancer cells to become more aggressive. Furthermore, we have shown that the ubiquitin ligase responsible for the degradation of p27, Skp2 is overexpressed in estrogen receptor-negative human breast cancers. We focus our research efforts on the dysregulation of p27 in cancer utilizing cell line and animal models as well as human tumors.