Ralph Weichselbaum, M.D.

Signal Transduction Pathways Following Exposure to Ionizing Radiation; Gene Therapy

Research Summary

Our laboratory is studying 1) signal transduction pathways following exposure of mammalian cells to ionizing radiation and 2) gene therapy in the treatment of neoplastic disease. Recent studies have suggested that radiation exposure is associated with the expression of the c-jun/fos, Egr, and NF-kB gene families. We proposed that the activation of transcription factors is important in transduction of early signals to the expression of late genes which result in the biological response to x-ray-induced damage. Egr-1 and c-jun induction are central to tumor promotion, proliferation, and cycle of radiation and are activated by DNA-damaging agents in mammalian cells. We have defined the DNA elements and mechanisms responsible for radiation activation of Egr-1 and jun. We have extended our work to examine cytoplasmic signaling cascades that induce radiation-induced signals to the nucleus, including MAP kinase, the ribosomal protein S6 kinase pp90rsk, and p56/p53lyn. Gene therapy is generally not well localized. We proposed that ionizing radiation could be used to activate the transcription of exogenous genes that encodes cytotoxic or radioprotective proteins. To test this model, we have generated a vector expressing TNF-alpha under the control of the radiation-responsive Egr-1 promoter. When this construct was used in an experimental animal system, we observed an increase in tumor cures without an increase in normal tissue toxicity.

Selected Papers

Hallahan DE, Virudachalam S, Kuchibhotla J, Kufe DW, Weichselbaum RR. (1994). Membrane-derived second messenger regulates x-ray-mediated TNF-alpha gene induction. Proc Natl Acad Sci USA, 91:4897-4901.

Kharbanda S, Saleem A, Shafman T, Emoto Y, Weichselbaum RR, Kufe DW. (1994). Activation of the pp90rsk and mitogen-activated serine/threonine protein kinases by ionizing radiation. Proc Natl Acad Sci USA, 91:5416-5420.

Weichselbaum RR, Hallahan DE, Beckett MA, Mauceri J, Lee H, Sukhatme VP, Kufe DW. (1994). Gene therapy targeted by radiation preferentially radiosensitizes tumor cells. Cancer Res, 54:4266-4269.

Haraf DJ, Rubin SJ, Sweeney P, Kuchnir FT, Sutton HG, Chodak GW, and Weichselbaum RR. (1995). Photon Neutron Mixed-Beam Radiotherapy of Locally Advanced Prostate Cancer. International Journal of Radiation Oncology, Biology, Physics 33:3-14.

Vokes EE, Stupp R, Haraf D, Moran W, Malone D, Wenig B, Sweeney P, and Weichselbaum RR. (1995). Hydroxyurea with Continuous Infusion Paclitaxel, 5-Fluorouracil, and Concomitant Radiotherapy for Poor-Prognosis Head and Neck Cancer. Seminar of Oncology 22: 47-52.

Vokes EE, Haraf DJ, Stenson K, Stupp R, Malone D, Levin J, Weichselbaum RR. (1995). The Role of Paclitaxel in the Treatment of Head and Neck Cancer. Seminar of Oncology 22: 8-12.

Krishnasamy S, Vokes EE, Dohrmann GJ, Mick R, Garcia JC, Kolker JD, Wollman RL, Hekmatpanah J, and Weichselbaum, RR. (1995). Concomitant Chemoradiotherapy, Neutron Boost, and Adjuvant Chemotherapy for Anaplastic Astrocytoma and Glioblastoma Multiforme. Cancer Investigations 13: 453-459.

Heimann R, Powers C, Halpern HJ, Michel AG, Ewing CA, Wyman B, Recant W, Weichselbaum RR. (1996). Breast Preservation in Stage I and II Carcinoma of the Breast. Cancer 78: 1722-1730.

Datta R, Kojima H, Banach D, Bump NJ, Talanian RV, Alnemri E, Weichselbaum RR, Wong WW, Kufe D. (1996). Activation of a Crm-A-insensitive, p35-sensitive Pathway in Ionizing Radiation-induced Apoptosis: Journal of Biological Chemistry 272:.1065-70.

Haraf DJ, Weichselbaum RR, Vokes EE. (1996). Re-irradiation with Concomitant Chemotherapy of Unresectable Recurrent Head and Neck Cancer: A Potentially Curable Disease. Annls.Oncol. 7: 913-918.

Vijayakumar S, Vaida F, Weichselbaum RR, Hellman S. (1997). Race and the Will Rogers Phenomenon in Prostate Cancer, The Cancer Journal, IV: 27-34,1997.

Vokes EE, Liebowitz DN, Weichselbaum RR. (1997). Nasopharyngeal Carcinoma, Lancet 350: 1087-91.

Mundt AJ, Weichselbaum RR. (1997). Tumors of The Soft Tissue, 2nd Edition, DasGupta TK, Chaudhuri PK, (eds.), Appleton & Lange (publs.), Stanford, CT. Radiation Therapy of Soft Tissue Tumors Chapter 17.

Yuan ZM, Utsugisawa T, Huang Y, Ishiko T, Nakada S, Kharbanda S, Weichselbaum RR, Kufe D. (1997). Inhibition of PI 3-kinase by c-Abl in the genotoxic stress response. Journal of Biological Chemistry 272: 23485-23488.

Chung TDK, Mauceri HJ, Hallahan DE, Yu JJ, Chung S, Grdina WL, Yajnik S, Weichselbaum R. R., Kufe DW. (1998). "Tumor necrosis factor- based gene therapy enhances radiation cytotoxicity in human prostate cancer." Cancer Gene Therapy, V 6, 344-349.

Yuan ZM, Kharbanda S, Kufe D. (1998). "Involvement of the c-Abl tyrosine kinase in the apoptotic response to anti-cancer agents." Hickman J and Dive C, eds. Cancer Chemotherapy and Apoptosis. Humana Press.

Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff GA, Kufe D.W.and Weichselbaum R. R.  (1998). "Potentiation of the Anti-tumor Effect of Ionizing Radiation by Brief Concomitant Exposures to Angiostatin." Cancer Research, 58 5686-5689.

Kies MS, Haraf DF, Athanasiadis I, Kozloff M, Mittal B, Pelzer H, Rademaker AW, Wenig B, Vokes EE, Weichselbaum RR. (1998). "Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival." Journal of Clinical Oncology, 16 #8 2715-2721.

Kumar S, Pandey P, Bharti A, Jin S, Weichselbaum RR, Weaver D, Kufe D, Kharbanda S. (1998). "Regulation of DNA-dependent protein kinase by the Lyn tyrosine kinase." Journal of Biological Chemistry, 273 25654-58.

Mauceri HJ, Nanna NN, Staba MJ, Beckett MA, Kufe DK and Weichselbaum RR. (1999). "Radiation-Inducible genetherapy." C.R. Acad. Sci. Paris, Sciences de la vie/Life Sciences, 322 225-228.

Hannig J, Yu J, Beckett M, Weichselbaum RR and Lee RC. (1999). Poloxamine 1107 sealing of radiopermeabilized erythrocyte membranes." Int. J. Radiat. Biol. 75 3, 379-385.

Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman, S, Beckett MA, Sukhatme VP, Soff GA, Kufe DW, Weichselbaum RR. (1999). "Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin." Cancer Research 58 5686-5689.

Vokes EE, Haraf DJ, Brockstein E, Weichselbaum RR. (1999). "Paclitaxel, 5-Fluorouracil, Hydroxyurea, and Concomitant Radiation Therapy for Poor-Prognosis Head and Neck Cancer." Seminars in Radiation Oncology, 9, 2, Suppl 1 70-76.