Advanced Research Scientist , Biochemistry and Molecular Biology
Southern Research Institute
200 Ninth Avenue South
Birmingham, AL 35205
Dr. Thottassery obtained a Ph.D. from the School of Biological Sciences at The University of Missouri-Kansas City in 1992 and received post-doctoral training at the University of Tennessee-Memphis and the St. Jude Children's Research Hospital in Memphis, TN. He joined Southern Research in 1998, where he is currently a Project Leader in the Biochemistry and Molecular Biology Department. Since 1994, Dr. Thottassery's research career has focused in various aspects of cancer biology and therapeutics, including: anticancer drug discovery; cell cycle regulatory pathways; signal transduction of growth factors; angiogenesis and antiestrogen resistance in breast cancer; pathways regulated by the tumor suppressor p53 and its homologue p73; and several other cancer-related areas.
His research has been funded by the Susan G. Komen Breast Cancer Foundation, a Career Development Grant from the NCI SPORE program, Department of Defense (DoD) grants, an NIH program project, and several commercial contracts. Dr. Thottassery has also served on several grant review panels in the DoD Breast Cancer and Prostate Cancer Research Programs. He currently serves as an adjunct graduate faculty member at the UAB School of Medicine Department of Pathology and is also a member of the UAB Comprehensive Cancer Center.
Antiestrogen Resistance in Breast Cancer. A primary focus of Dr. Thottassery's work at Southern Research is to elucidate mechanisms of antiestrogen resistance in breast cancer patients. In the two-thirds of breast cancer patients who have estrogen receptor positive (ER+) disease, estrogen plays a critical role in the growth of tumor cells. Tamoxifen, an ER agonist/antagonist, and aromatase inhibitors are used routinely in treatment in ER+ disease, although progression after an initial response remains a significant problem. ICI 182780 (Faslodex), a pure antiestrogen, inhibits the growth of tamoxifen-resistant lines and has also shown effectiveness in tamoxifen-resistant patients, although there were no complete responses. Dr. Thottassery's research seeks to understand the mechanisms of antiestrogen resistance, which could lead to strategies that might either restore or prolong sensitivity to such therapies. Studies conducted at Southern Research have demonstrated that Cks1, a small protein component of cyclin-cdk complexes, which is also a part of SCFSkp2 ubiquitin ligase, contributes to multiples essential roles during cell cycle progression in ER+ breast cancer cells (Westbrook et al Cancer Research 67:11393-401, 2007). These studies showed that Cks1 was essential for cycling induced by either estradiol or growth factors that stimulate antiestrogen-resistant growth like heregulin β1. Cks1-depleted cells not only exhibit slowed G1 progression, but also accumulate in G2/M due to blocked mitotic entry as a result of diminished cdk1 expression. This suggests that Cks1 plays certain non-redundant roles in these proliferative pathways in breast cancer cells and therefore can be a target for therapy in addition to adjuvant antiestrogens.
Molecular Mechanisms of Nucleoside Anticancer Agents. Dr. Thottassery is a member of a research team at Southern Research that investigates newer nucleosides and the mechanisms by which their effects are elicited in tumor cells. Southern Research has maintained a nucleoside drug discovery program for several years, and two FDA-approved drugs - Fludarabine and Clofarabine - have resulted from these efforts. Clofarabine was approved by the FDA in 2004 for the treatment of childhood acute lymphocytic leukemia. Another agent, 4'-thio-arabinofuranosyl cytosine, is currently being evaluated for antitumor activity in clinical trials. Southern Research investigates the role of cellular pathways in the effects mediate by these agents.