Our Science – Hassan Website
Raffit Hassan, M.D.
As a medical oncologist my scientific interest is the preclinical and clinical evaluation of novel therapeutic agents for cancer treatment. Over the last several years our work has focused on the development and clinical evaluation of immunotoxins targeting mesothelin-expressing tumors. Mesothelin is a 40-kDa glycosylphosphatidylinositol (GPI)- linked cell surface glycoprotein that is present on normal mesothelial cells and overexpressed in several tumors especially ovarian cancers, mesotheliomas and pancreatic cancer. Our laboratory studies have shown it to be a promising target for cancer therapy. Since the murine anti-mesothelin monoclonal antibody K1 by itself is not cytotoxic towards mesothelin positive cells, we have developed immunotoxins targeting mesothelin using the potent bacterial toxin, Pseudomonas exotoxin (PE). This toxin consists of three functional domains: the cell binding domain that allows binding to a cell surface protein, the translocation domain that brings an active fragment of the toxin to the cytosol and the ADP-ribosylation domain that inhibits protein synthesis leading to cell death. For making immunotoxins we use a mutated 38 kDa fragment of PE termed PE38, lacking the cell binding domain that can be replaced by a targeting moiety such as the Fv portion of an antibody. SS1(dsFv)PE38 (SS1P), is a recombinant immunotoxin consisting of the anti-mesothelin Fv (obtained by phage display) linked to PE38.
Based on the in vitro and in vivo activity of SS1P and toxicological studies in cynomolgus monkeys, SS1P was approved by the FDA for clinical evaluation in patients. Currently, we are conducting a Phase I clinical trial of SS1P in mesothelin positive tumors at the NCI and 23 patients have been treated thus far. Completion of this Phase I clinical trial will provide valuable information regarding the maximum tolerated dose, dose limiting toxicities, immunogenicity, pharmacokinetics as well as anti-tumor activity of SS1P. Following completion of the Phase I study, we plan to conduct Phase II studies, to evaluate the anti-tumor activity of SS1P in specific tumor types expressing mesothelin. Since greater than 90% of mesotheliomas and pancreatic tumors express mesothelin, and there are no effective treatments for these diseases, conduct of phase II studies of SS1P in these tumor types will be a priority.
Another clinical focus of my research is to develop a program for the treatment and diagnosis of mesotheliomas. Novel approaches for the treatment of this disease including tumor vaccines and drug combinations will be studied. In addition, related laboratory work will include identification of biomarkers for diagnosis and follow up of mesotheliomas. Latter this year we will be organizing the 1st international meeting on peritoneal mesotheliomas at the NIH, to address some of these issues.
This page was last updated on 2/7/2013.