NCI Renewal Grant to Develop New Cancer Therapies

By Sathya Achia Abraham

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 'epigenetic 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.

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.