VCU Massey Cancer researcher receives $700,000 in research funding to target new cancer treatments

By Sathya Achia Abraham

A Virginia Commonwealth University Massey Cancer Center researcher has received two grants totaling $700,000 from the V Foundation for Cancer Research and the Multiple Myeloma Research Foundation to develop new antileukemic/anti-cancer strategies and to create novel treatment approaches for multiple myeloma and related blood cancers.

Through these grants, Steven Grant, M.D., Massey’s associate director for translational research and co-leader of the cancer center’s cancer cell biology program, will focus efforts to support basic and clinical research.

The VCU Massey Cancer Center is among just six National Cancer Institute-designated cancer centers to receive a competitive three-year grant totaling nearly $600,000 from the V Foundation for Cancer Research. Investigators from the VCU School of Medicine; Paul Dent, Ph.D., from the Department of Biochemistry; and John Roberts, M.D., and Mohamed Rahmani, Ph.D., both from the Department of Internal Medicine, will collaborate with Grant on this research.

“We hope to use the information generated with the support of this award to develop an entirely new antileukemic and anti-cancer strategy in which novel molecularly targeted agents are rationally combined,” said Grant, who is also the primary investigator for the project.

In previously published work, Grant’s team uncovered a new mechanism of action of the anti-cancer drug sorafenib. Sorafenib inhibits the oncogene Raf-1, but also induces a process known as ER stress in leukemia cells that leads to inhibition of protein translation. This results in the reduced expression of pro-survival factors, such as the anti-apoptotic protein Mcl-1. In previous research study, Grant’s team recently reported that the antileukemic activity of a novel Bcl-2 antagonist, which is now entering the clinical arena, depends critically upon expression levels of Mcl-1 in tumor cells.

“The purpose of the V Foundation research project is to develop a completely novel antileukemic strategy in which sorafenib is employed to down-regulate Mcl-1 and in so doing, to lower the apoptotic threshold of malignant cells that have been exposed to clinically relevant Bcl-2 antagonists,” said Grant.

According to Grant, the ultimate goal will be to use these findings as a foundation for initiating clinical trials combining sorafenib with Bcl-2 antagonists in patients with refractory leukemia and potentially other hematologic malignancies.

In other cancer-related research, through a one-year, $100,000 grant from the Multiple Myeloma Research Foundation, Grant and co-investigator, Yun Dai, Ph.D., assistant professor of medicine in the School of Medicine, will work toward developing a new approach to the treatment of multiple myeloma, an incurable, but treatable form of cancer. They will combine small molecule inhibitors of anti-apoptotic proteins, such as Bcl-2, that block the cell death process with the cell cycle inhibitor flavopiridol. Flavopiridol inhibits cancer-cell progression through the cell cycle.

“Multiple myeloma is a malignancy that has proven unusually susceptible to novel targeted agents. Our basic thesis is that it may be even more vulnerable to rational combinations of such agents,” said Grant, who is a professor of medicine, biochemistry and pharmacology.

Grant’s team has previously reported that, in addition to its cell cycle effects, flavopiridol blocks the expression of proteins that prevent myeloma cell apoptosis, or programmed cell death at the transcriptional level. This dramatically sensitizes these cells to the lethal effects of Bcl-2 antagonists.

In addition, a new schedule of flavopiridol has recently been developed that has shown encouraging activity in chronic lymphocytic leukemia, another B-cell malignancy.

Grant said that the aim of the planned studies supported by the MMRF award will be to demonstrate that flavopiridol can increase the activity of clinically relevant Bcl-2 antagonists in patient-derived multiple myeloma cells, and to test this strategy in an animal model of multiple myeloma. The ultimate goal of this project will be to translate these findings into a clinical trial for patients with advanced multiple myeloma and other related hematologic malignancies.