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Research at Mass General
Henning Willers, MD Radiation Oncologist Massachusetts General Hospital
Assistant Professor of Radiation Oncology Harvard Medical School
As part of the Cellular & Molecular Radiation Oncology Laboratory, the Willers Laboratory studies DNA repair and recombination. The goal of cancer therapy using ionizing radiation and/or chemotherapeutic agents is to selectively kill tumor cells while sparing surrounding normal tissues. In order to achieve such therapeutic gain, pre-existing genetic differences between tumors and normal tissues have to be exploited. To this end, in the Laboratory of Cellular & Molecular Radiation Oncology, we have two main research interests:
The Role of the Tumor Suppressor Gene p53 in DNA Double-Strand Break (DSB) Repair
DSBs represent the most important type of DNA damage inflicted by radiation or various chemotherapeutic agents. If DSBs are not properly repaired, they can either lead to cell death or produce genetic changes in the surviving cells, which may promote cancer development. Over the past few years, it has become clear that perturbations of DSB repair are a frequent cause of genomic instability in cancer cells. Conversely, these cells may also be more sensitive to DNA damaging agents. Thus, the DSB repair defects that promote carcinogenesis by causing genetic instability may also be the weakness of the tumors that arise in this setting. This concept has been referred to as the "Achilles' Heel of Cancers" and holds great promise for the advancement of cancer treatment in the not-too-distant future. The p53 tumor suppressor is inactivated in the majority of human cancers. In normal cells, p53 suppresses malignant cell transformation through several mechanisms. We recently established a novel role of p53 in the downregulation of homologous recombination (HR), which is a major DSB repair pathway.
A major goal of our current work is to determine how upregulated HR in cells with non-functional p53 contributes to tumor formation and affects cellular sensitivity to DNA damaging agents. We are particularly interested in identifying the upstream proteins that control this effect of p53, including ATR (in collaboration with Lee Zou, Center for Cancer Research). In addition, more recently we described a role of p53 in the control of non-homologous end-joining (NHEJ), which represents another major DSB repair pathway. In the context of these projects, our laboratory has developed a special expertise in the design and application of plasmid substrates that integrate into the genome and allow the study of HR and NHEJ in living cells.
Functional Biomarkers of Radio- and Chemosensitivity
Many proteins involved in the response to damaged DNA form subnuclear foci that can be detected by immunofluorescence microscopy. These foci represent potentially powerful biomarkers for the activity of a particular repair pathway. We are particularly interested in detecting disruptions of the Fanconi Anemia/BRCA pathway in breast, lung, and other cancer types, which may render the affected tumors hypersensitive to various DNA damaging agents. Ultimately, genotyping and phenotyping of cancers for the integrity of DNA repair pathways will lead to a better prediction of how a given tumor will respond to treatment, and this will allow us to tailor therapy to the individual cancer and patient. We are conducting this research in collaboration with Lisa Kachnic and Carol Rosenberg, Boston University.
Molecularly Targeted Radiation Therapy
Ionizing radiation not only causes damage to DNA but also affects intra- and inter-cellular signaling pathways in a complex manner. Many of these alterations constitute cytoprotective responses that help cells to survive radiation exposure. In collaboration with Jeff Settleman, Center for Molecular Therapeutics in the Center for Cancer Research, we are seeking to identify signaling alterations in lung cancers that can be targeted in order to overcome the resistance of these tumors to radiation.
Henning Willers, MD Principal InvestigatorGroup Members
View a list of publications by researchers at the Willers Laboratory
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