To learn more about the Initiative for Chemical Genetics, see our recent review in the September 15, 2006 issue of Cancer Research.

The National Cancer Institute's Initiative for Chemical Genetics aims to accelerate the development of new cancer strategies and therapies. By activating or inactivating targeted protein functions, molecular probes can promote anti-tumor activity and provide new therapeutic approaches for cancer.

One avenue of this work involves research with multiple myeloma. Multiple myeloma is an incurable cancer, named for the multiple lytic lesions in bones seen in patients as depicted here (top right). With a microscope, the toxic proteins secreted by these cells are visible as circular inclusions. For patients, these proteins circulating in the blood stream have severe symptomatic consequences for the immune system and frequently cause kidney failure. However, these same proteins also indicate that the myeloma cell might be particularly sensitive to therapies that result in misfolded proteins in the cell. A collection of misfolded proteins is shown in the third panel as a yellow aggregate next to the blue nucleus, here in lung cancer cells. The stress on the cell of harboring aggregates of these toxic proteins likely contributes to cancer cell death. Using powerful chemical and genetic techniques, we are exploring the mechanisms whereby cancer cells eliminate toxic proteins. Already, we have identified a family of molecules active against a critical target in this pathway, HDAC6. We have shown that HDAC6 inhibitors are active against myeloma cells and even more potent with additional inhibitors of protein degradation.

Building on these successes, we hope to assemble a small molecule tool set for selectively blocking protein folding and degradation. Importantly for patients with incurable or advanced cancers, these chemical tools will serve as leads for drug development.