Vanderbilt University School of Medicine

Freeman, Michael L. , Ph.D.
Interim Chair, Department of Radiation Oncology
Professor of Radiation Oncology
Professor of Cancer Biology
Professor of Radiology and Radiological Sciences

Lab Url: N/A

Phone Number: 343-9244


Freeman, Michael's picture

Office Address   Mailing Address

B-1034 PRB

1161 21st Avenue, South MCN CCC-1121 37232-2675

Research Keywords
Drug Discovery/Radiation Sensitizers, Development of novel compounds that target tumor angiogenesis, Nrf2/Keap1 in cancer and inflammation, Smad-mediated transcription in cancer.

Research Description
Radiation Oncology leverages cutting edge advancements in physics and engineering for the treatment of cancer. Co-registration of diagnostic data sets into a coherent 3D-treatment plan allows individualized precision tumor targeting. Radiation oncology has the potential to provide outstanding personalized cancer treatment. However, cancer cell radioresistance and normal tissue injury represent two important limitations that can limit the ability of ionizing radiation to provide local/regional control of tumor growth. To addresses these limitations our laboratory initiated a cancer drug discovery program that seeks to develop efficacious radiation sensitizers. Two-indol-3-yl-methylenequinuclidin-3-ols and 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H) trione have been synthesized and are currently being evaluated using defined DNA substrates, cell-based and murine mouse models. Elucidating the underlying mechanisms that drive the pathophysiology of normal tissue injury produced by ionizing radiation is also a focus of this laboratory. A holistic approach is used that encompasses well defined biochemical assays, cell-based assays such as ChIP Exo and transcriptome profiling, as well as GEMMs.

Hallahan, DE, Freeman, ML. Thoughts on the future of research, teaching, and testing in the biological sciences of radiation oncology. Int J Radiat Oncol Biol Phys, 88(1), 1-2, 2014.

Schultz, MA, Hagan, SS, Datta, A, Zhang, Y, Freeman, ML, Sikka, SC, Abdel-Mageed, AB, Mondal, D. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells. PLoS One, 9(1), e87204, 2014.

Sekhar, KR, Benamar, M, Venkateswaran, A, Sasi, S, Penthala, NR, Crooks, PA, Hann, SR, Geng, L, Balusu, R, Abbas, T, Freeman, ML. Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization. Int J Radiat Oncol Biol Phys, 89(5), 1106-14, 2014.

Venkateswaran, A, Sekhar, KR, Levic, DS, Melville, DB, Clark, TA, Rybski, WM, Walsh, AJ, Skala, MC, Crooks, PA, Knapik, EW, Freeman, ML. The NADH oxidase ENOX1, a critical mediator of endothelial cell radiosensitization, is crucial for vascular development. Cancer Res, 74(1), 38-43, 2014.

Venkateswaran, A, Friedman, DB, Walsh, AJ, Skala, MC, Sasi, S, Rachakonda, G, Crooks, PA, Freeman, ML, Sekhar, KR. The novel antiangiogenic VJ115 inhibits the NADH oxidase ENOX1 and cytoskeleton-remodeling proteins. Invest New Drugs, 31(3), 535-44, 2013.

Rana, T, Schultz, MA, Freeman, ML, Biswas, S. Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL. Free Radic Biol Med, 53(12), 2298-307, 2012.

Dworski, R, Han, W, Blackwell, TS, Hoskins, A, Freeman, ML. Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo. Free Radic Biol Med, 51(2), 516-21, 2011.

Sekhar, KR, Reddy, YT, Reddy, PN, Crooks, PA, Venkateswaran, A, McDonald, WH, Geng, L, Sasi, S, Van Der Waal, RP, Roti, JL, Salleng, KJ, Rachakonda, G, Freeman, ML. The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization. Clin Cancer Res, 17(20), 6490-9, 2011.

Zhao, Z, Chen, Y, Wang, J, Sternberg, P, Freeman, ML, Grossniklaus, HE, Cai, J. Age-related retinopathy in NRF2-deficient mice. PLoS One, 6(4), e19456, 2011.

Pruitt, R, Sasi, N, Freeman, ML, Sekhar, KR. Radiosensitization of cancer cells by hydroxychalcones. Bioorg Med Chem Lett, 20(20), 5997-6000, 2010.

Rachakonda, G, Sekhar, KR, Jowhar, D, Samson, PC, Wikswo, JP, Beauchamp, RD, Datta, PK, Freeman, ML. Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene, 29(25), 3703-14, 2010.

Reddy, YT, Sekhar, KR, Sasi, N, Reddy, PN, Freeman, ML, Crooks, PA. Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents. Bioorg Med Chem Lett, 20(2), 600-2, 2010.

Segal, BH, Han, W, Bushey, JJ, Joo, M, Bhatti, Z, Feminella, J, Dennis, CG, Vethanayagam, RR, Yull, FE, Capitano, M, Wallace, PK, Minderman, H, Christman, JW, Sporn, MB, Chan, J, Vinh, DC, Holland, SM, Romani, LR, Gaffen, SL, Freeman, ML, Blackwell, TS. NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One, 5(3), e9631, 2010. PMCID:2838778

Sekhar, KR, Rachakonda, G, Freeman, ML. Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol, 244(1), 21-6, 2010.

Venkateswaran, A, Reddy, YT, Sonar, VN, Muthusamy, V, Crooks, PA, Freeman, ML, Sekhar, KR. Antiangiogenic properties of substituted (Z)-(??)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives. Bioorg Med Chem Lett, 20(24), 7323-6, 2010.

Geng, L, Rachakonda, G, Morr??, DJ, Morr??, DM, Crooks, PA, Sonar, VN, Roti Roti, JL, Rogers, BE, Greco, S, Ye, F, Salleng, KJ, Sasi, S, Freeman, ML, Sekhar, KR. Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature. FASEB J, , , 2009.

Brown, SL, Sekhar, KR, Rachakonda, G, Sasi, S, Freeman, ML. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res, 68(2), 364-8, 2008.

Burk, RF, Hill, KE, Nakayama, A, Mostert, V, Levander, XA, Motley, AK, Johnson, DA, Johnson, JA, Freeman, ML, Austin, LM. Selenium deficiency activates mouse liver Nrf2-ARE but vitamin E deficiency does not. Free Radic Biol Med, 44(8), 1617-23, 2008. PMCID:2346531

Fukuyo, Y, Inoue, M, Nakajima, T, Higashikubo, R, Horikoshi, NT, Hunt, C, Usheva, A, Freeman, ML, Horikoshi, N. Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. Cancer Res, 68(15), 6324-30, 2008. PMCID:2693332

Rachakonda, G, Xiong, Y, Sekhar, KR, Stamer, SL, Liebler, DC, Freeman, ML. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol, 21(3), 705-10, 2008.

Al-Ghananeem, AM, Albayati, ZF, Malkawi, A, Sonar, VN, Freeman, ML, Crooks, PA. A pharmacokinetic study on Z-(+/-)-2-(1-benzylindole-3-yl-methylene)azabicyclo[2.2.2]octane-3-ol; a novel radio-sensitization agent. Cancer Chemother Pharmacol, , , 2007.

Biswas, S, Guix, M, Rinehart, C, Dugger, TC, Chytil, A, Moses, HL, Freeman, ML, Arteaga, CL. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest, 117(5), 1305-13, 2007. PMCID:1838926

Brunoldi, EM, Zanoni, G, Vidari, G, Sasi, S, Freeman, ML, Milne, GL, Morrow, JD. Cyclopentenone prostaglandin, 15-deoxy-Delta12,14-PGJ2, is metabolized by HepG2 cells via conjugation with glutathione. Chem Res Toxicol, 20(10), 1528-35, 2007.

Freeman, ML. A commentary on "Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis". Free Radic Biol Med, 42(8), 1131-2, 2007.

Gao, L, Wang, J, Sekhar, KR, Yin, H, Yared, NF, Schneider, SN, Sasi, S, Dalton, TP, Anderson, ME, Chan, JY, Morrow, JD, Freeman, ML. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J Biol Chem, 282(4), 2529-37, 2007.

Pi, J, Bai, Y, Reece, JM, Williams, J, Liu, D, Freeman, ML, Fahl, WE, Shugar, D, Liu, J, Qu, W, Collins, S, Waalkes, MP. Molecular mechanism of human Nrf2 activation and degradation: Role of sequential phosphorylation by protein kinase CK2. Free Radic Biol Med, 42(12), 1797-806, 2007. PMCID:1950666

Sekhar, KR, Sonar, VN, Muthusamy, V, Sasi, S, Laszlo, A, Sawani, J, Horikoshi, N, Higashikubo, R, Bristow, RG, Borrelli, MJ, Crooks, PA, Lepock, JR, Roti Roti, JL, Freeman, ML. Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Cancer Res, 67(2), 695-701, 2007.

Sonar, VN, Thirupathi Reddy, Y, Sekhar, KR, Sasi, S, Freeman, ML, Crooks, PA. Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents. Bioorg Med Chem Lett, 17(24), 6821-4, 2007.

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, 28(9), 813-8, 2006.

Andrei V. Bakin, Konjeti R. Sekhar, Cammie Rinehart, Xuexian Yan, Michael J. Meredith, Carlos L. Arteaga, and Michael L. Freeman. . Smad3-ATF3 signaling mediates TGF-b suppression of genes encoding Phase II detoxifying proteins. . Free Radical Biology & Medicine., 38, 375-387, 2005.

Bakin, AV, Stourman, NV, Sekhar, KR, Rinehart, C, Yan, X, Meredith, MJ, Arteaga, CL, Freeman, ML. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Free Radic Biol Med, 38(3), 375-87, 2005.

Cao, C, Shinohara, ET, Li, H, Niermann, KJ, Kim, KW, Sekhar, KR, Gleave, M, Freeman, M, Lu, B. Clusterin as a therapeutic target for radiation sensitization in a lung cancer model. Int J Radiat Oncol Biol Phys, 63(4), 1228-36, 2005.

Hong, F, Freeman, ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. . Chem Res. Toxicol, 19, 1917-1926, 2005.

Hong, F, Sekhar, KR, Freeman, ML, Liebler, DC. Specific patterns of electrophile adduction trigger keap1 ubiquitination and NRF2 activation. J Biol Chem, , , 2005.

Ginger L. Milne, Guiseppe Zanoni, Soumya Sasi, Giovanni Vidari, Erik S. Musiek, Michael L. Freeman, and Jason D. Morrow. The Cyclopentenone Product of Lipid Peroxidation, 15-A2t-Isoprostane, is Efficiently Metabolized by HepG2 Cells Via Conjugation with Glutathione. Chem Res. Tox. 17: 17-25, 2004.. Chem Res., 17, 17-25, 2004.

Lu B, Mu Y, Cao C, Zeng F, Schneider S, Tan J, Price J, Chen J, Freeman M, Hallahan DE.. Survivin as a therapeutic target for radiation sensitization in lung cancer. . Cancer Res., 64, 2840-2845, 2004.

Milne, Ginger L, Zanoni, Giuseppe, Porta, Alessio, Sasi, Soumya, Vidari, Giovanni, Musiek, Erik S, Freeman, Michael L, Morrow, Jason D. The cyclopentenone product of lipid peroxidation, 15-A2t-isoprostane, is efficiently metabolized by HepG2 cells via conjugation with glutathione. Chem Res Toxicol, 17(1), 17-25, 2004.

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