Ewing sarcoma– a bone/tissue sarcoma
Ewing sarcoma usually displays exquisite sensitivity to a variety of damaging agents (chemotherapies), but the reason for this damage response defect is not known. Our work identified that these sarcomas lack most of the normal damage responses because of an RNA metabolism issue that traps the BRCA1 protein, the gene usually associated with breast cancer. The unavailability of BRCA1 leads to a DNA repair defect that can be specifically targeted in the treatment of these cancers.
Ataxia-telangiectasia (AT) is caused by a mutation in ATM, a key damage response gene. AT patients suffer from immune dysfunction, neurological defects, as well as a cancer and diabetes predisposition. Aside from understanding that AT cells are sensitive to irradiation, little is understood about the clinical manifestation of the disease. To develop new insights we have examined the diabetes development associated with this disease and discovered that ß-cells have a metabolic problem resulting from a defect in importing cysteine; this defect results in an accumulation of glutamate and a defect in respiration. These observations provide new insight into disease development. Further, we have been able to demonstrate that we can rescue the diabetes phenotype by circumventing the cysteine import defect. We are now exploring the impact of this defect and intervention on the neurological defect and cancer development in AT.
Homologous recombination defective diseases
Homologous recombination defective diseases combination is associated with BRCA1 and BRCA2, the breast, and ovarian cancer-predisposing genes. We are particularly interested in mechanisms that control homologous recombination. Towards this, we study proteins such as BLM, p53, 53BP1, ATR, and CREBBP. When the genes of these proteins are inherited in a mutated for they lead to diseases usually associated with early-onset cancer; Bloom syndrome, Li Fraumeni, Seckel syndrome, and Myelodysplastic syndrome. Using mouse and cell models we work to examine these diseases, their impact on homologous recombination, and the molecular basis of these interactions. We have already discovered new roles for some of these proteins. For example, 53BP1 mutation occurs in chemorefractory BRCA1 breast cancers and Ewing’s sarcoma. However, we have found that loss of 53BP1 also results in DNA replication stress and this provides a new avenue for treating those cancers that have acquired these mutations. It is exactly this type of novel insight that expects will lead to better, more targeted therapies and preventative measures. Because of the interactions with homologous recombination and BRCA1/BRCA2 proteins, our work also impacts adult cancers, particularly breast and ovarian cancers. More importantly, because of these relationships, we hope to take advantage of the discoveries for targeted therapies developed in adult cancers to apply to childhood cancers.