Youcef M Rustum
State University of New York, USA
Biography
Youcef M. Rustum was born June 6, 1938, in DowertahaTartous, Syria. Following graduation from high school, Dr Rustum came to the United States at age 19. Following completion of an English course and two-years in the Department of Biological Chemistry at Columbia University College, Washington, DC, Dr Rustum came to the University of Buffalo to finish his BA in the Department of Chemistry in 1965. Dr Rustum continued with his graduate education at the State University of New York at Buffalo where he obtained a PhD in the Department of Biochemical Pharmacology in 1970. Since September 1970 Dr Rustum has been at Roswell Park Cancer Institute in Buffalo where he headed a Molecular Pharmacology laboratory with major emphasis on translational research aimed at the development of new drugs and therapy of cancer. From 1988 to 1995 Dr Rustum was the Deputy Director of the Grace Cancer Drug Center at Roswell Park Cancer Institute. In addition, since 1995, Dr Rustum has been in the position of Senior Vice President for Science Administration at Roswell Park. Dr Rustum has served in various senior administrative capacities to promote interaction and collaboration between RPCI, the State University of New York at Buffalo, Hauptman Woodward Institute and other national and international Institutions. Dr Rustum also Chair's the Institute Department of Cancer Biology
Abstract
Durable response, inherent or acquired resistance, and dose-limiting toxicities continue to represent major barriers in the treatment of patients with advanced clear-cell renal cell carcinoma (ccRCC). The majority of ccRCC tumours are characterized by the loss of Von Hippel–Lindau tumor suppressor gene function, a stable expression of hypoxia-inducible factors 1α and 2α (HIFs), an altered expression of tumour-specific oncogenic microRNAs (miRNAs), a clear cytoplasm with dense lipid content, and overexpression of thymidine phosphorylase. The aim of this manuscript was to confirm that the downregulation of specific drug-resistant biomarkers deregulated in tumour cells by a defined dose and schedule of methylselenocysteine (MSC) or seleno-L-methionine (SLM) sensitizes tumour cells to mechanism-based drug combination. The inhibition of HIFs by selenium was necessary for optimal therapeutic benefit. Durable responses were achieved only when MSC was combined with sunitinib (a vascular endothelial growth factor receptor (VEGFR)-targeted biologic), topotecan (a topoisomerase 1 poison and HIF synthesis inhibitor), and S-1 (a 5-fluorouracil prodrug). The documented synergy was selenium dose- and schedule-dependent and associated with enhanced prolyl hydroxylase-dependent HIF degradation, stabilization of tumour vasculature, downregulation of 28 oncogenic miRNAs, as well as the upregulation of 12 tumour suppressor miRNAs. The preclinical results generated provided the rationale for the development of phase 1/2 clinical trials of SLM in sequential combination with anti angiogenic therapeutics in ccRCC patients refractory to standard therapies. The presentation will discuss the potential role of specific types of oncogenic, namely miRNA-155 and miRNA-210, and HIFs as critical therapeutic targets for the development of mechanism-based therapy for cancer.