Center for Matrix Biology - Vanderbilt University and Medical Center

Dennis E. Hallahan, M.D.
Professor in the Department of Radiation Oncology

	Office Address:	B-1034 PRB
	Mailing Address:	B-1034 PRB Nashville, TN 5671
	Lab address:
	Phone:	(615) 343-9244
		email \| website

Secondary appointment in the Cancer Biology department.

Research Summary

The goal of this project is to intensify therapy specifically at sites of neoplasia while minimizing cytotoxic therapy within normal tissues. We study signal transduction pathways that regulate cancer cell viability. We develop drugs to improve cancer response to therapy.
We also study drug delivery targeted specifically to the microvasculature of neoplasms. When tumor blood vessels are treated with ionizing radiation, they respond by expressing neoantigens that can be targeted for drug delivery. To study radiation-inducible neoantigens in tumor microvasculature, we utilized proteomics, genomics and phage display libraries. Phage peptide libraries were administered, by tail vein injection into mice bearing irradiated tumors in order to identify radiation-inducible receptors within tumor microvasculature. Ligand-conjugated nanoparticles bind to the radiation-activated receptor, obliterate tumor blood flow and significantly increase tumor regression and growth delay in irradiated tumors. Radiation-guided drug delivery is a new paradigm for immunoconjugates targeted to tumor blood vessels.
We have identified several radiation-inducible neoantigens expressed within irradiated tumor blood vessels. For example, P-selectin is sequestered within storage reservoirs in vascular endothelium and platelets and translocates to the vascular lumen following irradiation. Antibodies will now be prioritized for their affinity for radiation-induced antigens within the microvasculature of cancers biopsied after irradiation. Antibodies with the greatest binding will be selected in clinical trials using mass spectrometry and gamma camera imaging. The goal of the proposed research is to target drug delivery to these radiation-induced neoantigens through the use of antibody conjugates.
Our second project is the identification of new molecular targets for cancer therapy. Tumor microvasculature is a therapeutic target in the treatment of cancer. We have found that ionizing radiation induces the activation of PI3K/Akt, which in turn regulates endothelial cell viability during treatment with radiotherapy. Inhibition of this signaling pathway enhances the cytotoxic effects of radiation in tumor vascular endothelium resulting in enhanced tumor control. The goals of the proposed research are to study the mechanisms by which ionizing radiation activates the PI3K/Akt signaling pathway. This research will lead to potential new molecular targets for therapy. We study inhibitors of this signal transduction pathway that are pipeline compounds for clinical trials. The proposed specific aims combine both basic and translational research with the intention of developing new strategies for the treatment of cancer. The importance of this study is that new molecular targets for radiation sensitization will be identified.
Our third research program studies the mechanisms by which radiation cause programmed cell death in progenitor cells within each organ. We have found that the GSK3beta signal transduction pathway is required for this radiation-induced tissue injury. Inhibitors of this pathway protect normal tissues from injurt that results from cancer therapy.

Research Keywords

Apoptosis, Cancer, Gene therapy, Malignancy, Mouse, Pharmacokinetics, Post-transcriptional modification, Signal transduction, Vascular Biology,

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Associated initiative(s):

Tumor Microenvironment

Career opportunities:
None currently available

Selected Publications

» Huamani, J, Willey, C, Thotala, D, Niermann, KJ, Reyzer, M, Leavitt, L, Jones, C, Fleishcher, A, Caprioli, R, Hallahan, DE, Kim, DW Differential efficacy of combined therapy with radiation and AEE788 in high and low EGFR-expressing androgen-independent prostate tumor models Int J Radiat Oncol Biol Phys 2008. 71:237-46

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

» Han, Z, Fu, A, Wang, H, Diaz, R, Geng, L, Onishko, H, Hallahan, DE Noninvasive assessment of cancer response to therapy Nat Med 2008. 14:343-9

» Niermann, KJ, Fleischer, AC, Huamani, J, Yankeelov, TE, Kim, DW, Wilson, WD, Hallahan, DE Measuring tumor perfusion in control and treated murine tumors: correlation of microbubble contrast-enhanced sonography to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography J Ultrasound Med 2007. 26:749-56

» Geng, L, Cuneo, KC, Cooper, MK, Wang, H, Sekhar, K, Fu, A, Hallahan, DE Hedgehog signaling in the murine melanoma microenvironment Angiogenesis 2007. :

» Cuneo, KC, Tu, T, Geng, L, Fu, A, Hallahan, DE, Willey, CD HIV protease inhibitors enhance the efficacy of irradiation Cancer Res 2007. 67:4886-93

» Geng, L, Cuneo, KC, Fu, A, Tu, T, Atadja, PW, Hallahan, DE Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer Cancer Res 2006. 66:11298-304

» Tan, J, Geng, L, Yazlovitskaya, EM, Hallahan, DE Protein Kinase B/Akt-Dependent Phosphorylation of Glycogen Synthase Kinase-3{beta} in Irradiated Vascular Endothelium Cancer Res 2006. 66:2320-7

» Stacy, DR, Ely, K, Massion, PP, Yarbrough, WG, Hallahan, DE, Sekhar, KR, Freeman, ML Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas Head Neck 2006. 28:813-8

» Geng, L, Shinohara, ET, Kim, D, Tan, J, Osusky, K, Shyr, Y, Hallahan, DE STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma Int J Radiat Oncol Biol Phys 2006. 64:263-71

» Cuneo, KC, Geng, L, Tan, J, Brousal, J, Shinohara, ET, Osusky, K, Fu, A, Shyr, Y, Wu, H, Hallahan, DE SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation Int J Radiat Oncol Biol Phys 2006. 64:1197-203

» Albert, JM, Cao, C, Geng, L, Leavitt, L, Hallahan, DE, Lu, B Integrin alpha v beta 3 antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models Int J Radiat Oncol Biol Phys 2006. 65:1536-43

» Kim, DW, Huamani, J, Fu, A, Hallahan, DE Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy Int J Radiat Oncol Biol Phys 2006. 64:38-46

» Zhuang, J, Zhang, J, Willers, H, Wang, H, Chung, JH, van Gent, DC, Hallahan, DE, Powell, SN, Xia, F Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining Cancer Res 2006. 66:1401-8

» Kim, DW, Huamani, J, Niermann, KJ, Lee, H, Geng, L, Leavitt, LL, Baheza, RA, Jones, CC, Tumkur, S, Yankeelov, TE, Fleischer, AC, Hallahan, DE Noninvasive assessment of tumor vasculature response to radiation-mediated, vasculature-targeted therapy using quantified power Doppler sonography: implications for improvement of therapy schedules J Ultrasound Med 2006. 25:1507-17

» Kim, KW, Mutter, RW, Cao, C, Albert, JM, Freeman, M, Hallahan, DE, Lu, B Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling J Biol Chem 2006. 281:36883-90

» Cao, C, Shinohara, ET, Subhawong, TK, Geng, L, Woon Kim, K, Albert, JM, Hallahan, DE, Lu, B Radiosensitization of lung cancer by nutlin, an inhibitor of murine double minute 2 Mol Cancer Ther 2006. 5:411-7

» Shinohara, ET, Cao, C, Niermann, K, Mu, Y, Zeng, F, Hallahan, DE, Lu, B Enhanced radiation damage of tumor vasculature by mTOR inhibitors Oncogene 2005. :

» Shinohara, ET, Gonzalez, A, Massion, PP, Chen, H, Li, M, Freyer, AS, Olson, SJ, Andersen, JJ, Shyr, Y, Carbone, DP, Johnson, DH, Hallahan, DE, Lu, B Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma Cancer 2005. 103:1685-92

» Shinohara, ET, Geng, L, Tan, J, Chen, H, Shir, Y, Edwards, E, Halbrook, J, Kesicki, EA, Kashishian, A, Hallahan, DE DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs Cancer Res 2005. 65:4987-92

» Cao, C, Shinohara, ET, Niermann, KJ, Donnelly, EF, Chen, X, Hallahan, DE, Lu, B Murine double minute 2 as a therapeutic target for radiation sensitization of lung cancer Mol Cancer Ther 2005. 4:1137-45

» DeBusk, Laura M, Hallahan, Dennis E, Lin, Pengnian Charles Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway Exp Cell Res 2004. 298:167-77

» Cao, C, Mu, Y, Hallahan, DE, Lu, B XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer Oncogene 2004. 23:7047-52

» Geng, Ling, Tan, Jiahuai, Himmelfarb, Eric, Schueneman, Aaron, Niermann, Ken, Fu, Allie, Cuneo, Kyle, Kesicki, Edward A., Treiberg, Jennifer, Hayflick, Joel S., Hallahan, Dennis E. A Specific Antagonist of the p110{delta} Catalytic Component of Phosphatidylinositol 3''-Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction Cancer Res 2004. 64:4893-4899

» Lu, Bo, Mu, Yi, Cao, Carolyn, Zeng, Fenghua, Schneider, Sylke, Tan, Jiahui, Price, Jim, Chen, Jun, Freeman, Michael, Hallahan, Dennis E Survivin as a therapeutic target for radiation sensitization in lung cancer Cancer Res 2004. 64:2840-5

» Osusky, KL, Hallahan, DE, Fu, A, Ye, F, Shyr, Y, Geng, L The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels Angiogenesis 2004. 7:225-33

» Lu, B, Gonzalez, A, Massion, PP, Shyr, Y, Shaktour, B, Carbone, DP, Hallahan, DE Nuclear survivin as a biomarker for non-small-cell lung cancer Br J Cancer 2004. 91:537-40

» Lu, Bo, Geng, Ling, Musiek, Amy, Tan, Jiahui, Cao, Carolyn, Donnelly, Edwin, McMahon, Gerald, Choy, Hak, Hallahan, Dennis E Broad spectrum receptor tyrosine kinase inhibitor, SU6668, sensitizes radiation via targeting survival pathway of vascular endothelium Int J Radiat Oncol Biol Phys 2004. 58:844-50

» Tan, Jiahuai, Hallahan, Dennis E Growth factor-independent activation of protein kinase B contributes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response Cancer Res 2003. 63:7663-7

» Hallahan, D.E., L. Geng, C. Qu, S. Scarfone, Todd Giorgio, Donnelly, E, Gao, X, Clanton, J Integrin-mediated targeting of drug delivery to irradiated tumor blood vessels Cancer Cell 2003. 3:63-74

» Schueneman, Aaron J, Himmelfarb, Eric, Geng, Ling, Tan, Jiahua, Donnelly, Edwin, Mendel, Dirk, McMahon, Gerald, Hallahan, Dennis E SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models Cancer Res 2003. 63:4009-16

» Hallahan, Dennis E, Geng, Ling, Shyr, Yu Effects of intercellular adhesion molecule 1 (ICAM-1) null mutation on radiation-induced pulmonary fibrosis and respiratory insufficiency in mice J Natl Cancer Inst 2002. 94:733-41

» Edwards, Eric, Geng, Ling, Tan, J, Onishko, Halina, Donnelly, Edwin, Hallahan, Dennis E Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation Cancer Res 2002. 62:4671-7

» Hallahan, D E, Geng, L, Cmelak, A J, Chakravarthy, A B, Martin, W, Scarfone, C, Gonzalez, A Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature J Control Release 2001. 74:183-91

» Geng, L, Donnelly, E, McMahon, G, Lin, P C, Sierra-Rivera, E, Oshinka, H, Hallahan, D E Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy Cancer Res 2001. 61:2413-9

» Stoeckli, M, Chaurand, P, Hallahan, D E, Caprioli, R M Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues Nat Med 2001. 7:493-6

» Hallahan, D E, Qu, S, Geng, L, Cmelak, A, Chakravarthy, A, Martin, W, Scarfone, C, Giorgio, T Radiation-mediated control of drug delivery Am J Clin Oncol 2001. 24:473-80

» Hallahan, D.E., and Virudachalam, S ICAM-1 knockout abrogates radiation-induced pulmonary inflammation Proc. Natl. Acad. Sci. USA 1997. 94:6432-6437

» Hallahan, D.E., Mauceri, H.J., Seung, L.P., Dunphy, E.J., Toledano, A., Hellman, S., Kufe, D.W., and Weichselbaum, R.R Spatial and temporal control of gene therapy by ionizing radiation Nature Med. 1995. 1:786-791

» Hallahan, D.E., Varudachalam, S., Kuchibhotla, J., Kufe, D.W., and Weichselbaum, R.R Membrane-derived second messenger regulates x-ray-mediated TNF alpha gene induction Proc. Natl. Acad. Sci. 1994. 91:4897-4901

» Hallahan, D.E., Sukhatme, V.P., Sherman, M.L., Virudachalam, S., Kufe, D., and Weichselbaum, R.R Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN Proc. Natl. Acad. Sci. USA 1991. 88:2156-2160

» Hallahan, D.E., Beckett, M.A., Kufe, D., and Weichselbaum, R.R The interaction between recombinant human tumor necrosis factor and radiation in 13 human tumor cell lines Proc. Natl. Acad. Sci. USA 1990. 19:69-74

» Hallahan, D.E., Spriggs, D.R., Beckett, M.A., Kufe, D.W., and Weichselbaum, R.R Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation Proc. Natl. Acad. Sci. USA 1989. 86:10104-10107