June faculty and staff features

Steven Grant, M.D., Massey Cancer Center and School of Medicine

Grant, a professor of medicine and Massey’s associate director for translational research, and his research team have received a National Cancer Institute renewal grant totaling approximately $1.25 million to develop a more selective approach to the treatment of multiple myeloma, an incurable, malignant disorder of the bone marrow involving plasma cells.

The renewal award builds upon recent work from Grant’s laboratory demonstrating that exposure of human multiple myeloma and leukemia cells to agents known as Chk1 inhibitors disrupts the ability of these cells to arrest progression through the cell cycle and to repair DNA damage. This series of events leads to the dramatic activation of a compensatory survival signaling cascade known as the Ras/MEK/ERK pathway, which itself is frequently dysregulated in cancer.

Previously, Grant and his team showed that interruption of latter pathway by pharmacologic inhibitors dramatically induces programmed cell death in multiple myeloma cells exposed to Chk1 antagonists. They observed these results with farnesyltransferase inhibitors, which inhibit Ras activation, as well as with agents known as MEK inhibitors, which prevent activation of ERK. Grant said that this process appears to be restricted to cancer cells, such as myeloma or leukemia cells, but spares their normal, healthy counterparts. In addition, this strategy overcomes most forms of drug resistance and is active in animal models.

The team will now extend these findings to newer, clinically relevant Chk1 and MEK inhibitors, identify the mechanisms responsible for this interaction, focus on the induction of DNA damage. They will also determine how this strategy overcomes novel forms of drug resistance. According to Grant, the ultimate goal of this project is to develop a selective approach to multiple myeloma therapy combining clinically relevant Chk1 inhibitors with antagonists of the Ras/MEK/ERK pathway.

This ongoing research is the basis for a Phase II, multi-institutional clinical trial that is expected to open later this year, with Grant as the principal investigator. Co-investigators on the project include VCU School of Medicine researchers Yun Dai, M.D., Ph.D., Xinyen Pei, M.D., Shuang Chen, M.D., Ph.D., and Paul Dent Ph.D.