Dennis E. Hallahan, M.D.

Professor and Chairman
Radiation Oncology

Molecular Cell Biology Program

  • 314-362-9700

  • 8224

  • dhallahan@WUSTL.EDU

  • cancer, cell death, drug delivery, radiation, signal transduction

  • The mechanisms of cell death in normal tissues during cancer therapy

Research Abstract:

Cancer Biology and Molecular Biology
Unresectable malignant gliomas (MG) are universally fatal especially in children with brain stem and midbrain gliomas. Disease progression occurs despite wide margins of irradiation and high radiation doses. Swelling within the tumor, angiogenesis and invasion are hallmarks of malignant gliomas. We have studied the mechanisms by which MG develops resistance to radiation therapy. We have found that an enzyme lyso-PLD (also known as autotaxin) produces a substance, LPA, which can regulate radiation resistance, swelling and angiogenesis within tumors treated with radiation therapy. The over arching hypothesis of this research is that interruption of the signaling through lyso-PLD or the LPA receptors will improve malignant glioma response to therapy. Inhibitors of these molecular targets are presently in development at pharmaceutical companies. We study the efficacy of specific inhibitors of lyso-PLD and LPA receptors when combined with radiotherapy in mouse models of human malignant gliomas.

Neurobiologv and Signal Transduction
The Hallahan laboratory studies the mechanisms of cell death in normal tissues during cancer therapy. In particular, we have found that a signal transduction pathway required for radiation induced apoptosis in normal tissues involves glycogen synthase kinase 3beta. GSK-3beta regulates the apoptosis machinery within normal tissues. Cancer cells do not require GSK-3beta or apoptotic machinery to respond to cancer therapy. In contrast, injuries in normal tissues such as the brain and intestine require GSK-3 signaling. We have found that inhibitors of GSK-3beta prevent injury in normal tissues. These inhibitors prevent injury to the brain and improve neurocognitive function and reduce injury in the intestine of animal models. Presently, we are studying the mechanisms by which GSK-3 inhibition prevents program cell death in normal tissues. Studies involve the epigenetic response to GSK-3 inhibitors. We identify transcription factors and apoptotic machinery that are activated during cancer therapy but inhibited during GSK-3 blockade.

Developmental Therapeutics in Cancer
The Hallahan laboratory has identified several peptides and over a dozen monoclonal antibodies that bind to cancer following treatment with ionizing radiation. Using this strategy, drug delivery can be targeted specifically to cancer and guided by use of a beam of radiation therapy. These targeting ligands have been conjugated to the drug delivery systems, including liposomes and nanoparticles to improve he specificity of drug delivery of cancer.

The Hallahan laboratory collaborates extensively with pharmaceutical companies to identify radiation sensitizing and radiation protecting drugs. Pre-clinical efficacy studies were conducted in mouse models of human cancer.

The Hallahan laboratory also characterizes the immunological response of antibodies targeted by radiation. These monoclonal antibodies bind to radiation inducible neo-antigens. These antibodies can activate immune response. In addition, therapeutic agents are conjugated to the antibodies to provide cancer specific drug delivery. Identification of radiation inducible neo-antigens involves the co-precipitation of antigens from cancer by use of monoclonal antibodies. Antigens are then identified by use of proteomic technology. Humanization of these mouse monoclonal antibodies will be performed with the goal of bringing antibodies into clinical trials. Optimization and humanization strategies for antibodies is a primary goal of the laboratory.

Selected Publications:

Linkous A, Geng L, Lyshchik A, Hallahan DE, Yazlovitskaya EM. Cytosolic phospholipase A2: targeting cancer through the tumor vasculature. Clin Cancer Res. 2009 15(5):1635-44.

Yang ES, Wang H, Jiang G, Nowsheen S, Fu A, Hallahan DE, Xia F. Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK-dependent repair in mice. J Clin Invest. 2009 119(5):1124-35.

Yazlovitskaya EM, Linkous AG, Thotala DK, Cuneo KC, Hallahan DE. Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium. Cell Death Differ. 2008 15(10):1641-53.

Thotala DK, Hallahan DE, Yazlovitskaya EM. Inhibition of glycogen synthase kinase 3 beta attenuates neurocognitive dysfunction resulting from cranial irradiation. Cancer Res. 2008 68(14):5859-68.

Tu T, Thotala D, Geng L, Hallahan DE, Willey CD. Bone marrow X kinase-mediated signal transduction in irradiated vascular endothelium. Cancer Res. 2008 68(8):2861-9.

Last Updated: 8/4/2011 9:29:38 AM

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