INTERESTS
cancer, pharmacology, childhood cancers, acute leukemia, apoptotic pathways in cancer cells, genomic and epigenomic analysis of childhood cancer, relapsed/resistant leukemia

RESEARCH SUMMARY
In our laboratory we focus on two major challenges facing children with acute lymphoblastic leukemia (ALL). First, in spite of dramatic improvements in outcome, one in five children will suffer a relapse and then have a poor prognosis. Second, the physical and emotional costs of therapy for those who are cured are high, with short- and long-term side effects.

Therefore, we seek to understand mechanisms of drug resistance and to identify pathways unique to the cancer cell that can serve as targets for more effective, less toxic therapeutic approaches.

We use modern genomic and epigenomic methods to understand the genesis and evolution of ALL that leads to treatment failure. We have shown that resistant cancer cells acquire novel mutations that are responsible for drug resistance. In some cases, a small clone emerges through the selective effect of chemotherapy in a model reminiscent of Darwinian evolution. However, in other cases, such mutations may have been acquired during the course of treatment. Through years of effort we have created a “genetic fingerprint” of resistant cells and have used this information to pilot novel methods to prevent and treat relapse.

Most recently we have focused on the epigenome—molecular mechanisms that control gene activity that are not related to the DNA sequence itself. We have shown that DNA modifications, including methylation and histone changes, also allow the cancer cell to overcome therapy. The availability of new agents that target these epigenetic changes may allow for more effective treatment of relapsed disease and we are exploring this approach in laboratory models.

Our laboratory encompasses the full spectrum of investigation involving basic bench research, highly translational efforts using samples from patients, and clinical trials in children with ALL.