Michael E. Williams, MD
Molecularly-targeted clinical trials for hematologic malignancies
Laboratory research: Their focus is on mechanisms of cell cycle dysregulation in the pathogenesis of lymphoma. They have shown that mantle cell lymphoma almost uniformly overexpresses cyclin D1, and that many MCL also have deletion or loss of function mutations in negative cell cycle regulators such as p53 or the cyclin dependent kinase inhibitors p16 and p18. A subset of human multiple myelomas share similar mutations. They demonstrated in vitro and in vivo (SCID mouse model) that an expression vector which replaces p18 function inhibits proliferation of a p18-null myeloma cell line (Leukemia 2002; 16:127-34; in collaboration with Dr Tim Bender, Microbiology). During a research sabbatical year with the Lymphoma Tumor Group and the Developmental Therapeutics Program at the BC Cancer Agency in Vancouver, Dr. Williams collaborated in the development of a preclinical model for MCL utilizing 5 human cell lines. A Rag2M/SCID murine model has demonstrated antitumor activity of the anti-CD20 monoclonal rituximab, BCL2 antisense oligonucleotides, and a dose-response to cyclophosphamide. The testing of combinations of these therapies as well as cyclin D1 inhibitors (antisense, flavopiridol and other small molecules) is in progress, with the aim of bringing active agents or combinations into phase I clinical trials in Vancouver and Charlottesville. This work is conducted in collaboration with Dr Ronald Taylor, Biochemistry and Molecular Genetics, with support from the Animal Facility for murine work. Other collaborators include Dr John Densmore (Hematology/Oncology) and Dr John Cousar (Hematopathology).
The MCL research is supported by a grant from the Lymphoma Research Fdtn. Dr. Williams was elected in January, 2005 as Chair of the LRF Mantle Cell Research Consortium, an international effort aimed at improving communication and promoting basic and clinical research relevant to this aggressive lymphoma.
Clinical research: Clinical research protocols are focused in non-Hodgkin lymphoma and CLL. These trials are conducted in collaboration with Dr John Densmore and colleagues in the Cancer Center Hematologic Malignancy Program, and with Dr Ronald Taylor in Biochemistry and Molecular Genetics, with support from the Cancer Center Clinical Trials Office and the Biostatistics Core. A weekly Hematologic Malignancy Tumor Board has been established with Dr John Cousar (Hematopathology) and Dr Wendy Golden (Cytogenetics), and they are developing a clinical research database. Their NHL trials include the ECOG 4402 indolent lymphoma study of front-line rituximab followed by maintenance rituximab vs observation, for which Dr. Williams serves as co-chair (Dr Brad Kahl, University of Wisconsin, is study chair). Dr. Williams serves on the ECOG lymphoma core committee. They participate in several vaccine trials (Favid autologous vaccine; Favrille), and have just completed two multicenter studies of bendamustine for relapsed NHL. Investigator-initiated trials of radioimmunotherapy with maintenance rituximab for relapsed large cell lymphoma, and bortezomib plus rituximab for relapsed indolent lymphoma, are in final stages of approval and opening for accrual.
They have developed a major effort in CLL, investigating mechanisms of response and resistance to rituximab, in collaboration with Dr Ronald Taylor. The pilot study has been completed, and will be presented at the International Lymphoma Conference in Lugano, Switzerland in June 2005. The follow-up study using optimized thrice-weekly rituximab is now in development, with anticipated opening in 4th quarter 2005. This work has revealed important insights regarding modulation and loss of CD20 from CLL cells after very low dose rituximab (60 mg/m2), suggesting that more frequent, low-dose (eg, 20 mg/m2), may be more efficacious in clearing circulating CLL cells and may be administered with fewer infusion reactions.