VCU Massey Cancer Center researcher receives highly competitive National Cancer Institute funding to develop new leukemia treatment

By Andrea Butler
Massey Cancer Center

An internationally renown researcher at the Virginia Commonwealth University Massey Cancer Center, Steven Grant, M.D., received a $1.2 million grant from the National Cancer Institute to partially fund a phase I clinical trial for patients with acute forms of leukemia.

The study will use two novel, targeted agents, belinostat and bortezomib, in combination. The goal is to develop a new therapeutic approach for treating acute myeloid and lymphoid leukemias; blast crisis of chronic myelogenous leukemia; and myelodysplastic syndrome, or MDS.

The funding will also support correlative laboratory studies using leukemia cells obtained from the patients before and after treatment to gain insights into the molecular mechanisms responsible for synergistic actions between the two agents.

The trial will be led by Grant and will be carried out in collaboration with M.D. Anderson Cancer Center in Houston, Texas, and H. Lee Moffitt Cancer Center in Tampa, Fla., Investigators expect to open the study in January 2010.

Grand Opportunities, or “GO” grants, are funded by the American Recovery and Reinvestment Act and are intended for large, translational initiatives that involve multiple National Cancer Institute-designated cancer centers. They are among the most highly selective cancer research grants the National Cancer Institute is awarding as part of the federal stimulus funding program. The grants fund research that is ready to “go” from the laboratory to patients through early phase clinical trials.

“The National Cancer Institute sought high-impact ideas that lend themselves to short-term funding and that may lay the foundation for new fields of investigation,” said Gordon D. Ginder, M.D., director of the VCU Massey Cancer Center.

“Among hundreds of grant applications for extremely worthy projects, Dr. Grant’s rose to the top because of his proven scientific record, his ability to lead multi-institutional studies, and his pioneering, rational approach to developing new therapies,” he said.

About the two agents
 
Belinostat, from TopoTarget, a Danish biotech company, is a member of a class of agents known as histone deacetylase, or HDAC, inhibitors. These inhibitors act by modifying chromatin structure and the expression of genes involved in the regulation of cell differentiation and death. Other members of this class of agents have recently been approved for the treatment of cutaneous T-cell lymphoma.

The other agent is bortezomib, from Millennium Pharmaceuticals, a proteasome inhibitor that interferes with the cell’s ability to degrade unwanted proteins. Bortezomib has previously been approved for the treatment of patients with advanced multiple myeloma or mantle cell lymphoma.

Previous studies inform this new approach
 
The clinical trial is based on preclinical evidence developed by Yun Dai, M.D., Ph.D., and other members of Grant’s laboratory, which showed that very low concentrations of belinostat and bortezomib, when administered together, are highly lethal toward patient-derived leukemia cells. The trial is designed to determine what drug doses can be safely administered together in patients, and to make dose recommendations for future clinical trials.

Investigators at Massey and other cancer centers have published studies indicating that proteasome and HDAC inhibitors cooperate to induce a form of cell death known as apoptosis in cancer cells, particularly those of hematopoietic origin such as leukemia cells. Such interactions have been attributed to multiple mechanisms, including interruption of certain survival pathways, for example, those related to NF-?B, and/or interference with protein disposition in cancer cells.

Previous studies also have shown that proteasome inhibitors such as bortezomib are clearly active in patients with multiple myeloma and mantle cell lymphoma, and HDAC inhibitors are also showing initial activity in acute leukemia. Results of recent trials combining HDAC and proteasome inhibitors have shown very promising activity in multiple myeloma. However, very little information is available concerning the activity of such proteasome/HDAC inhibitor regimens in acute leukemia.

This trial is among the first to test the feasibility of simultaneously administering an HDAC such as belinostat and a proteasome inhibitor such as bortezomib to patients with acute leukemia or myelodysplastic syndrome.

Collaborators and contact information

Steven Grant, M.D., holds the Shirley Carter Olsson and Sture Gordon Olsson chair in oncology at the VCU Massey Cancer Center. He is also associate director of translational research and co-leader of Massey’s cancer cell biology research program. His collaborators from Massey include Beata Holkova, M.D., John Roberts, M.D., Yun Dai, M.D., Ph.D., Sarah Kolla, M.D., Martha Wellons, R.N., and Mary Beth Tombes, R.N. 

The other principal investigators are Guillermo Garcia-Manero, M.D., at M.D. Anderson Cancer Center, and Domenico Coppola, M.D., at H. Lee Moffitt Cancer Center.

Patients wanting more information on the study may contact Mary Beth Tombes at 804-628-1357 or mtombes@vcu.edu.