Most chemotherapy for leukemia (blood cancer) and other cancers is toxic to both malignant and normal tissue, limiting its effectiveness and increasing patient-burden. Therefore, a major effort in leukemia and cancer research is to identify molecular targets in cancer cells that are essential for the cancer cell but not for normal stem cells. We demonstrate that a protein or molecule called DNA methyl-transferase enzyme 1 (DNMT1) is such an ideal molecular target; depletion of DNMT1 in hematopoietic stem cells increases their growth whereas depletion of DNMT1 in leukemia stem cells causes them to mature into more functional cells and stop dividing. Most encouragingly, we provide strategies for translating this observation into the clinic through novel formulation and modification of an existing nucleoside analogue drug called 5-aza-2'-deoxycytidine (decitabine). Because we believe these modifications will help realize the goal of a treatment that is nontoxic for normal cells, it could be given weekly, instead of only for a few days a month (cancer cells can continue to grow during the weeks without treatment, which are necessary for patient recovery with standard toxic treatment). Therefore, the novel compound could shift the cancer treatment paradigm further toward safe, well-tolerated, chronic, oral treatment that is more effective, could be readily used in young and old patients, and could also potentially be used to prevent new or recurrent cancer in high-risk situations.

Many oncology drugs seem promising in preclinical, phase I or II studies only to fail in extending the lifespan of patients. Increasingly, a recognized basis for this discrepancy is that treatment may destroy the bulk of cancer cells but not the critical subset of cancer cells called cancer stem cells, which are responsible for initiating cancer growth and are responsible for relapse of disease. Therefore, a pressing need exists for better models for testing drugs to determine if they are able to destroy the cancer stem cell population. In this proposal, we use just such a model, one that has been recently developed and is the only one in the country that uses human blood cells as the starting material. Therefore, results from our studies can be rapidly translated into information relevant to clinical trials and disease in humans.

In brief, we use a detailed understanding of the metabolism and mechanisms of action of an existing drug called decitabine to modify and improve it for the purpose of targeting a molecule called DNMT1, to produce a specific detrimental effect on cancer cells but not normal cells. The model system we use to assess the developed compounds is directly relevant to human disease and clinical translation. This model allows us to evaluate differential activity of the compounds on normal stem cells and the important sub set of the overall blood cancer cell population, blood cancer stem-cells, which most likely must be eradicated to cure cancer.