Daniel A. Haber

Department of Medicine
Massachusetts General Hospital East
Cancer Center
Building 149, 13th Street
Charlestown, MA 02129
Tel: (617) 726-7805
Fax: (617) 724-6919
Email: haber@helix.mgh.harvard.edu
Web Page: The Haber Lab Page
9 postdoctoral fellows

Our laboratory is interested in the genetics of cancer, with primary emphasis on the characterization of tumor suppressor genes and the identification of genetic targets for molecular-directed therapy.

Wilms tumor is a pediatric kidney cancer that has been linked to inactivation of the WT1 gene, encoding a zinc finger transcritpion factor. Expression of WT1 is requried for development of the kidney, gonads, and mesothelial tissues. Germline mutations in WT1 result in genetic predisposition to Wilms tumor; somatic mutations and a chimeric fusion with the EWS gene contribute to the development of Wilms and mesothelial tumors, respectively. We have made use of cells with inducible expression of distinct WT1 isoforms, combined with microarray expression profiling and chromatin immnoprecipitation libraries, to search for transcriptional targets of WT1 that underlie its effect on cellular differentiation and tumor suppression. Additional candidate Wilms tumor genes are being sought.

In searching for somatic genetic events that underlie cancer progression, we observed that non-small cell lung cancers with dramatic responses to the tyrosine kinase inhibitor gefitinib harbor mutations in the drug's target, the epidermal growth factor receptor (EGFR). We have shown that these mutations alter the function of the EGFR kinase domain, selectively enhancing ligand-dependent activation of anti-apoptotic pathways. Suppression of these survival signals, either by specific tyrosine kinase inhibitors or by siRNA targeting the mutant EGFR, trigger apoptosis in cells harboring these mutations. These observations support the model of "oncogene addiction" and suggest that identification of critical genetic lesions in epithelial cancers may be effective in selecting optimal targets for molecular agents in the treatment of cancer. We are using both human and model systems to search for such additional theapeutic targets.

References:

• Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, and Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib New Engl. J. Med. 350: 2129-2139, 2004
• Sordella R, Bell DW, Haber DA, and Settleman J. Activation of anti-apoptotic pathways by gefitinib-sensitizing EGFR mutations in human lung cancer. Science 305: 1163-1167, 2004
• Kwak E, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch T, Sharma SV, Isselbacher K, Settleman J, and Haber, DA. An irreversible inhibitor of the epidermal growth factor receptor may circumvent acquried resistance to gefitinib. Proc. Natl. Acad. Sci. USA, 102: 7665-70, 2005
• Rivera MN and Haber DA. Wilms tumour: connecting tumorigenesis and organ development in the kidney. Nature Reviews Cancer, 5: 699-712, 2005