Peter M. Glazer, MD, PhD
Professor and Chairman, Department of Therapeutic Radiology
Professor of Genetics
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peter.glazer@yale.edu |
Degrees/Education :
B.A., Harvard Universtiy (1979)
M.Sc., University of Oxford (1981)
M.D., Yale University (1987)
Ph.D., Yale University (1987)
Resident, Therapeutic Radiology, Yale New-Haven Medical Center (1988-91)
Faculty Appointments :
Assistant Professor, Yale University School of Medicine, Department of Therapeutic Radiology (1991-95)
Associate Professor, Yale University School of Medicine, Department of Therapeutic Radiology, Genetics (1995-99)
Medical Director, Phelps Radiation Center, Uncas on Thames Hospital (1997-98)
Medical Director, Radiation Therapy, William W. Backus Hospital (1998-2002)
Professor, Yale University School of Medicine, Therapeutic Radiology, Genetics (1999-2002)
Professor and Chairman, Yale University School of Medicine, Department of Therapeutic Radiology (2002-present)
Certifications/Honors :
Charles E. Culpepper Scholar in Medical Science (1991-95)
American Society for Photobiology, 1997 New Investigator Award
Michael Fry Research Award 1998, Radiation Research Society
Leukemia Society of America Scholar (1996-2001)
Stohlman Scholar 2001, Leukemia and Lymphoma Society
Clinical Interests : General radiation therapy; breast cancer; prostate cancer; lung cancer
Research Interests:
Gene targeting and gene therapy; Genetic instability in cancer; Mutagenesis;
DNA repair; Radiation resistance; Cellular responses to radiation and chemotherapy.
Gene targeting via triple helix formation. From an interest in studying cellular DNA repair and recombination pathways, we recognized the utility of DNA triple helix formation as a mechanism for the site-specific introduction of DNA damage in mammalian cells. Using psoralen-conjugated triplex-forming oligonucleotides, we initially demonstrated the feasibility of triplex-targeted mutagenesis in several model systems. We were able to determine conditions under which triplex oligonucleotides can enter cells and efficiently bind to and modify a target site within cells, leading to base pair specific mutations. Experiments with oligonucleotides not tethered to a reactive agent but capable of high affinity third strand binding revealed that triple helix formation can induce DNA repair and recombination in mammalian cells. This work has raised the possibility of using triplex formation as both a gene knock out and a gene correction modality. It has also suggested that unusual DNA structures may provoke repair activity and may contribute to genomic instability. We are currently studying the feasibility of targeting chromosomal genes using this approach, either by directly inducing mutations in the target gene or by stimulating recombination in a site-directed manner.
Tumor hypoxia, genetic instability, and tumor progression. We hypothesized that that acquired genetic instability in cancer cells may arise from the dysregulation of critical DNA repair pathways due to cell stresses within the tumor microenvironment such as hypoxia. We initially confirmed this hypothesis by measuring mutation frequencies in experimental tumors using a lambda-based chromosomal shuttle vector reporter system. To elucidate the mechanism underlying this phenomenon we used a microarray-based approach to screen for hypoxia-regulated DNA repair pathways. We found that hypoxia specifically down-regulates the expression of Mlh1 and Rad51, key mediators of DNA mismatch repair and of homologous recombination in mammalian cells, respectively. Down-regulation of Mlh1 and Rad51 expression by hypoxia was observed in numerous cell lines from a wide range of tissues, and was not correlated with cell cycle profile or hypoxia-inducible factor expression. Rad51 down-regulation was also detected in vivo in the tumor microenvironment, as we observed consistent inverse correlations between hypoxia-marker staining and Rad51 expression by immunofluorescence in cervical and prostate cancer xenograft models. We propose the existence of a hypoxic phenotype in solid tumors, characterized by decreased expression of the critical DNA repair genes, Mlh1 and Rad51, representing a novel mechanism of acquired genetic instability in the tumor microenvironment and dysregulated DNA damage response in cancer cells.
Mechanism of cancer cell killing by cisplatin. Cisplatin is one of the most widely used cancer chemotherapy agents, but its mechanism of action is not fully understood. Current models suggest that cell killing by cisplatin occurs in a cell-autonomous manner via formation of platinum-DNA adducts that, if not removed by DNA repair, block transcription and replication. We have found that there is a separate cell-interdependent pathway of cisplatin killing in which damaged cells can transmit a death signal to neighboring cells. This signal is produced within the damaged cell by the kinase function of the Ku70, Ku80, and DNA-PK complex and is conveyed to the recipient cell by direct cell-to-cell communication through gap junctions. Our findings suggest that DNA-PK activity and gap junction expression in human cancers may influence the clinical response to cisplatin. In addition, strategies to manipulate these cellular components in conjunction with cisplatin treatment may provide new approaches to cancer therapy.
Training :
Post Doctoral: Yale University, Ph.D., Genetics (1987)
Residency: Yale-New Haven Hospital, Radiation Therapy (1988-91)
Fellowship: Yale-New Haven Hospital, Radiation Therapy
Board Certification: Radiation Oncology, Board Certified (1992)
