David Weinstock, MD
Instructor, Infectious Disease Service and Bone Marrow Transplant Service
Phone
212-639-2278
Education
MD, George Washington University School of Medicine
Residencies
Internal Medicine, New York Presbyterian Hospital/Cornell
Fellowship
Medical Oncology and Infectious Diseases, Memorial Sloan-Kettering Cancer Center
Board Certification
Internal Medicine; Infectious Diseases; Medical Oncology
Academic Appointments
Weill Medical College of Cornell University
Hospital Appointments
Memorial Hospital for Cancer and Allied Diseases
Research Interests
Dr. Weinstock's research interests are divided into two areas: 1) infectious complications associated with immunodeficiency after stem cell transplantation and 2) the relationship between DNA repair and the predisposition to hematologic malignancies.
Infectious Complications of Stem Cell Transplantation
Hematopoietic stem cell transplant recipients undergo a prolonged recovery of immune competence. During this period, they are susceptible to infection by a broad range of bacterial, fungal, viral and parasitic pathogens. Physicians at MSKCC have pioneered the use of transplant allografts depleted of T-cells in vitro. This approach markedly reduces the risk for developing graft-versus-host disease, a potentially fatal complication of transplantation, but induces marked lymphopenia for up to 1-2 years after transplant.
We have performed a series of prospective and retrospective (using comprehensive databases maintained by the Infectious Disease and Bone Marrow Transplant Services) studies to assess the risk for infection by distinct pathogens among the stem cell transplant recipients at MSKCC. My particular interest is in prophylactic strategies that target frequent pathogens (e.g. vancomycin-resistant Enterococcus, Aspergillus) to prevent infection after allogeneic stem cell transplantation.
DNA Repair and Leukemia Predisposition
Illegitimate DNA repair events, such as reciprocal chromosomal translocations, are early and essential steps in the malignant transformation of many human leukemias, lymphomas and sarcomas. In our laboratory, we established a series of transgenic murine embryonic stem cell lines capable of undergoing inducible translocation formation. We have demonstrated that the translocation junctions recovered from these cells recapitulate the repair characteristics from human cancer cells. Translocations can be induced either using a restriction endonuclease or the V(D)J recombinase. The latter events are a model for translocations observed in follicular and mantle cell lymphomas. Recent studies from our laboratory indicate that translocations are suppressed, rather than facilitated, by the Ku70 protein, an integral component of the DNA double-strand break (DSB) repair pathway known as nonhomologous end-joining. These studies definitively demonstrated that alternate, back-up DNA repair pathways are highly capable of mediating translocation formation, supporting a role for these pathways in cancer-associated rearrangements.
Future Research Plans
We are currently developing a translational system to identify the genetic and epigenetic effectors of imprecise DSB repair and their contributions to tissue-specific oncogenesis, using the novel technology of zinc finger nucleases (ZFNs). These nucleases can precisely introduce DSBs in vivo without the need for prior genomic manipulation to introduce a target sequence. We will utilize the ZFNs to test the hypothesis that deficiencies in specific components of the DSB response will correlate with the precision of DSB repair.
The initial studies will determine whether a subset of patients who developed secondary malignancies after treatment with therapeutic clastogens (i.e., ionizing radiation, chemotherapy) have defects in DSB repair. A second line of investigation will assess the risk for primary epithelial cancers, including breast and lung cancer. This system has broad utility in the study of cancer pathogenesis and the molecular epidemiology of cancer risk. In addition, the ZFNs could be developed as a clinical tool to predict the severity of treatment-related toxicity from therapeutic clastogens or assess the treatment response of a specific tumor.
References
1. Weinstock DM, Elliott B and Jasin M. A model of oncogenic rearrangements: differences between chromosomal translocation mechanisms and simple double-strand break repair. Blood 2006;107:777-80. [PubMedAbstract]
2. Weinstock DM, Richardson CA, Elliott B and Jasin M. Modeling oncogenic translocations: Distinct roles for double-strand break repair pathways in translocation formation in mammalian cells. DNA Repair 2006 (in press)[PubMedAbstract]
3. Weinstock DM, Jasin M. Alternative pathways for the repair of RAG-induced DNA breaks. Mol Cell Biol 2006;26:131-9[PubMedAbstract]
4. Weinstock DM, Nakanishi K, Helgadottir HR, Jasin M. Assaying double-strand break repair pathway choice in mammalian cells using a targeted endonuclease or the RAG recombinase. Methods Enzymol 2006;409;524-40[PubMedAbstract]
5. Weinstock DM, Zuccotti G. Adamantane resistance in Influenza A. JAMA 2006;295:934-6[PubMedAbstract]
6. Strasfeld L, Weinstock DM. Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents. Expert Rev Anti Infect Ther 2006;4:457-68[PubMedAbstract]
7. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE and Jakubowski A. Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant 2006;37:539-46[PubMedAbstract]
8. Weinstock DM, Boeckh M, Sepkowitz KA. Post-exposure prophylaxis against VZV infection among hematopoietic stem cell transplant recipients [letter]. Biol Blood Marrow Transplant 2006 (in press).
9. Garces Ambrossi G, Jakubowski A, Feinstein MB and Weinstock DM. Active tuberculosis limited to foreign-born patients after allogeneic hematopoietic stem cell transplant. Bone Marrow Transplant 2005;36:741-3 [PubMedAbstract]
10. Zuccotti G, Strasfeld L and Weinstock DM. New agents for the prevention of opportunistic infections in haematopoietic stem cell transplant recipients. Expert Opin Pharmacother 2005;6:1669-79[PubMedAbstract]
11. Weinstock DM, Boeckh M, Boulad F, et al. Postexposure prophylaxis against varicella-zoster virus infection among recipients of hematopoietic stem cell transplant: unresolved issues. Infect Control Hosp Epidemiol 2004;25:603-8[PubMedAbstract]
12. Weinstock DM, Gubareva LV and Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med 2003;348:867-8[PubMedAbstract]
13. Weinstock DM, Feinstein MB, Sepkowitz KA and Jakubowski A. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;31:1015-21[PubMedAbstract]
14. Rogers M, Weinstock DM, Eagan J, Kiehn T, Armstrong D and Sepkowitz KA. Rotavirus outbreak on a pediatric oncology floor: possible association with toys. Am J Infect Control 2000;28:378-80[PubMedAbstract]
15. Weinstock DM, Eagan J, Malak SA, et al. Control of influenza A on a bone marrow transplant unit. Infect Control Hosp Epidemiol 2000;21:730-2[PubMedAbstract]
