BBS Faculty Member - David Weinstock

David Weinstock

Department of Medical Oncology

Dana Farber Cancer Institute
Dana Farber Building, Room 510B
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-4245
Fax: 617-632-6380
Email: DavidM_Weinstock@dfci.harvard.edu
Visit my lab page here.



The Weinstock laboratory uses a variety of in vitro and in vivo techniques to identify and target novel oncogene alterations directly from hematologic malignancies and elucidate mechanisms of aberrant DNA repair within malignant and nonmalignant stem cells.

Identifying and targeting vulnerabilities in lymphoid neoplasms. The Weinstock laboratory, which currently includes ~25 students, fellows and professional scientists, established a functional screen to identify mutated genes directly from tumors that can promote proliferation and survival in cells.  Among our discoveries with that approach was that the cytokine receptor CRLF2 is altered in about 5-10% of acute lymphoblastic leukemia (ALL) cases.  We went on to show that CRLF2 alterations confer a poor prognosis, that they results from a specific mechanism of DNA breakage and repair, and that they activate multiple pathway of signaling in the cancer cell.   We subsequently identified mutations of G-protein beta subunits across a range of different cancers that drive transformation and resistance to kinase inhibitors.  Recently, we defined the biology of a rare subtype of follicular lymphoma, established a clinicogenetic prognostic model for follicular lymphoma, co-developed a strategy to define therapeutic sensitivity of single leukemia cells, and demonstrated the potential for next-generation lymphoma diagnostics in sub-Saharan Africa.  Work from our lab has led to 5 clinical trials that are currently open or under review by the SRC/IRB.  I lead a Specialized Center for Research (SCOR) that includes DFCI, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical College, along with additional affiliated centers (City of Hope, Nebraska, Stanford, University of Miami, Fred Hutchinson Cancer Research Center, Washington University) that is focused on developing new strategies to target T-cell lymphomas.

(b)
Applying patient-derived models of hematologic neoplasms to define biology and therapeutic vulnerabilities. We utilize a system that allows for the growth of human leukemias in mice, which affords the opportunity to test targeted therapeutics against these leukemias within a living animal.  We have established a panel of >300 human leukemias and lymphomas that grow in mice.  We have utilized these models to orchestrate phase II-like pre-clinical trials completely in mice. Ongoing studies are defining biomarkers of response and mechanisms of resistance to a range of therapies.  We have made the models available through an open source web portal (www.PRoXe.org), which has been accessed by researchers from >200 institutions around the world, and developed a core laboratory that I lead to distribute the xenografts.

(c)
Defining mechanisms, clinical implications, and timing of mutation acquisition in hematologic neoplasms.  Using newer forms of DNA sequencing, we have mapped out the ontogeny of mutations acquisition that leads to lymphoma in a small cohort of patients.  We have now extended this analysis into a much larger set to define which cells acquire mutations that lead to lymphoma and in what order.  In addition, we are analyzing the genotypes of a large number of well-annotated lymphomas to develop improved prognostic algorithms that integrate genetic and clinical biomarkers.



Last Update: 8/1/2017



Publications

For a complete listing of publications click here.

 


 



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