While new therapies for chronic myelogenous leukemia (CML) have been introduced over the past few years, these therapies are generally aimed at the activity of a protein called BCR-ABL that is the cause of CML. These drugs are inhibitors of the enzymatic activity of BCR-ABL, but the problem associated with this type of treatment is that the patient usually develops cells that are resistant to this class of drugs. Thus, new therapies aimed at different targets are needed. Our laboratories have focused on the development of drugs aimed at genes involved in cancer cell growth.

We have identified a small molecule that binds to genes and prevents the growth of human cancer cells in the laboratory and in a mouse model for cancer. This potentially therapeutic molecule works by targeting a gene that encodes one of the major proteins involved in packaging a cell's DNA into chromosomes, histone H4. Chromosome packaging is necessary in cell division and tumor growth. By binding to and silencing expression of the histone H4 gene, the small molecule prevents DNA packaging, blocks cells from dividing, and thwarts tumor growth. Although the human genome, the DNA in human cells, contains 14 copies of the gene for this histone protein, we found that only one of these genes is affected by our small molecule, and this gene is highly expressed in various cancers, making this gene and protein a new target for cancer therapy.

Based on these observations and the finding that this molecule is effective in blocking the growth of cancer cells derived from patients with chronic myelogenous leukemia, we now propose to test the effectiveness of this class of molecules in preventing CML cell growth, both in laboratory cell culture experiments and in mouse models for CML. We will synthesize additional molecules and test their efficacy in both cell culture and animal experiments. We will identify the mode of action of the effective molecules by studying the patterns of gene expression in CML cells treated with this molecule, and we will test the availability and potential toxic effects of the molecules in small animal models for CML disease. Based on the outcomes of these studies, we may identify candidate molecules for use in clinical trials for patients with recurrent CML.