Despite advances in the treatment of ovarian cancer, the prognosis of patients with advanced ovarian cancer is still poor. Approaches which circumvent chemo-resistance associated with ovarian cancer are needed. Since working as an oncology fellow in the laboratory of Dr. Ira Pastan at the National Cancer Institute, I have been involved in developing immunotoxins targeting mesothelin. Mesothelin is a cell surface glycoprotein that is overexpressed in some patients with ovarian cancer, malignant mesotheliomas and certain squamous cell carcinomas. Mesothelin is an attractive candidate for targeted therapy since it is not expressed by normal tissues except mesothelial cells and is not shed in significant amounts into the bloodstream. SS 1 (dsFv)-PE38 is a recombinant immunotoxin developed by fusing the disulfide stabilized light and heavy chains of a murine anti-mesothelin variable region (Fv) with a mutant Pseudomonas exotoxin. It exhibits significant activity in vitro as well as causes regression of mesothelin expressing tumors in nude mice. Compared to prior immunotoxins, SS 1 (dsFv)-PE38 has several advantages including small size which should increase tumor penetration and decrease immunogenicity. The goal of this research project is to evaluate the safety and efficacy of SS 1 (dsFv)-PE38 in patients with mesothelin expressing ovarian cancer, and also to understand the prognostic significance of mesothelin expression in cancer of the ovary. This award provides me the opportunity to experience the full spectrum of drug development from my pre-clinical work on anti-mesothelin immunotoxins to their clinical evaluation in patients. This award will also allow me to pursue a structured research training program, an essential first step to become a productive clinical researcher. Training will include graduate courses in clinical research, tumor immunology, participation in clinical and laboratory meetings and presentation at scientific meetings. My mentor and co-mentors who are established clinical and basic researchers will provide oversight and scientific guidance. The proposed research and training will allow me to become an independent investigator involved in developing and evaluating new biologic agents in patients with cancer.
