Research Abstract
Our long term interest is in 2 general areas:
1. Genomic instability: we have developed a model system with which to identify the emergence of DNA rearrangements that follow exposure to a specific stimulus, e.g., exposure to a viral oncoprotein such as the AdE1A, or polyoma middle T antigens. We have established that these oncoproteins are necessary but not sufficient for induction of DNA rearrangements. Recent work has focused on other factors that mediate the induction of genetic rearrangements. Differential display analyses demonstrated the presence of several unique cDNAs the expression of which is upregulated, which are homologues of known helicases and appear to have an important role in generating a rearrangement event.
2. Another interest is the basis of resistance and sensitivity to inhibitors of topoisomerase II. We have cloned the hamster cDNA for top II and demonstrated the point mutation associated with drug resistance, and have cloned the promoter of the human topII alpha gene. Using conditional mutants we have demonstrated that sensitivity and resistance to inhibitors of top II are correlated with expression of this enzyme, and that the latter is inversely correlated with resistance to alkylating agents.
3. A distinct focus of our research has been a longstanding series of clinical investigations that are evaluating the efficacy of high dose chemotherapy and autologous stem cell reinfusion as a novel therapy for patients with advance solid tumors, e.g., breast cancer, testis cancer, small cell carcinoma of the lung, recurrent malignant lymphoma (HD and NHL). The studies undertaken have been a product of a collaboration by investigators at the BIDMC and the DFCI, and have been performed by the Solid Tumor Autologous Program (STAMP). The thrust of the clinical studies being performed by this group is twofold: enhancing the efficacy of high dose therapy by identifying new agents to be incorporated into this experimental therapeutic context, and the studies designed to understand minimal residual disease (MRD) and develop novel approaches to its treatment -- specifically employing vaccine and other inmmunologic strategies.
