NCI renewal grant to develop new cancer therapies

December 04, 2007

Richmond, Va. (Dec. 4, 2007) â€" A Virginia Commonwealth University Massey Cancer Center research team has received a renewal grant totaling nearly $1.3 million from the National Cancer Institute to improve the activity of a novel class of agents, known as histone deacetylase inhibitors, in the treatment of leukemia and other blood malignancies.

Through the five-year grant, Steven Grant, M.D., Massey's associate director for translational research and co-leader of the cancer center's cancer cell biology program, and his research team will focus efforts to support ongoing basic and clinical research.

Histone deacetylase inhibitors represent a diverse group of agents that modify the structure of chromatin, and by extension, genes involved in the control of death and differentiation in cancer cells. Chromatin houses the genome and is composed of DNA and scaffolding proteins, notably histones.

However, histone deacetylase inhibitors acetylate other proteins and exert multiple other effects which trigger apoptosis, or programmed cell death, in tumor cells. Acetylation is a chemical reaction that can change the molecular properties of certain proteins.

"Histone deacetylase inhibitors are currently the focus of intense interest as so-called â€Ëœepigenetic agents,' that is, agents that act by modulating gene expression," said Grant, who is also the primary investigator for the project.

"Our goal is to exploit recent insights into the mode of action of these agents to make them even more effective in various hematologic malignancies by rationally combining them with other molecularly targeted agents," he said.

Recently, histone deacetylase inhibitors have been approved for the treatment of patients with cutaneous T cell lymphoma, a type of cancer of the immune system. In previous work, Grant's team has shown that histone deacetylase inhibitors induce acetylation and activation of a transcription factor, NF-kappaB, which regulates the expression of genes implicated in antioxidant defenses and cell survival.

According to Grant, the team has also identified agents that antagonize acetylation and activation of NF-kappa B by histone deacetylase inhibitors, resulting in a dramatic increase in oxidative injury and lethality. Such agents include inhibitors of IKK-beta and a class of agents known as proteasome inhibitors. Further, proteasome inhibitors have already proven very active in multiple myeloma and certain types of lymphoma, said Grant.

"Our goal is to elucidate the mechanisms by which such agents increase histone deacetylase inhibitor activity against leukemia and related malignancies," Grant said.

"We can then utilize this information as a platform to develop novel combination regimens incorporating histone deacetylase inhibitors and NF-kappa B antagonists such as proteasome and IKK beta inhibitors in the treatment of acute leukemia and other hematologic malignancies."

Grant and his team are already leading a multi-institutional trial of vorinostat, a histone deacetylase inhibitor, in combination with flavopiridol, a cell cycle inhibitor, in patients with refractory acute leukemia or myelodysplastic syndrome.

Additionally, the team has recently received approval to lead a multi-institutional trial of vorinostat and bortezomib, a proteasome inhibitor, in patients with refractory diffuse lymphocytic B-cell lymphoma or mantle cell lymphoma.
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Investigators from the VCU School of Medicine, Paul Dent, Ph.D.; Mohamed Rahmani, Ph.D.; Yun Dai, Ph.D.; Roberto Rosato, Ph.D.; and Viswanathan Ramakrishnan, Ph.D., collaborate with Grant on this work.

About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls nearly 32,000 students in 205 certificate and degree programs in the arts, sciences and humanities. Sixty-five of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.

About the VCU Massey Cancer Center: The VCU Massey Cancer Center is one of 61 National Cancer Institute-designated institutions that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers more clinical trials than any other institution in Virginia, serving patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 1-877-4-MASSEY.

Virginia Commonwealth University

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