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139 results on '"Huszar, D."'

1. A Novel Intratumoral Microdosing Approach for Simultaneously Evaluating Multiple Drugs and Combinations in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC)

Author

Houlton, J., primary, Cash, H., additional, Xu, H., additional, Swiecicki, P.L., additional, Chinn, S.B., additional, Clayburgh, D.R., additional, Li, R.J., additional, Christian, R.J., additional, Halfpenny, A., additional, vanZante, A., additional, Hatton, B.A., additional, Sottero, K.H.W., additional, Kung, G., additional, Grenley, M.O., additional, Burns, C., additional, Beirne, E., additional, Klinghoffer, R.A., additional, Huszar, D., additional, Berger, A., additional, and Kannan, K., additional

Published
2022
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4. Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-ß-catenin-mediated intestinal tumor growth and regeneration

Author

Phesse, T., Buchert, M., Stuart, E., Flanagan, D., Faux, M., Afshar-Sterle, S., Walker, F., Zhang, H., Nowell, C., Jorissen, R., Tan, C., Hirokawa, Y., Eissmann, M., Poh, A., Malaterre, J., Pearson, H., Kirsch, D., Provero, P., Poli, V., Ramsay, R., Sieber, O., Burgess, A., Huszar, D., Vincan, Elizabeth, Ernst, M., Phesse, T., Buchert, M., Stuart, E., Flanagan, D., Faux, M., Afshar-Sterle, S., Walker, F., Zhang, H., Nowell, C., Jorissen, R., Tan, C., Hirokawa, Y., Eissmann, M., Poh, A., Malaterre, J., Pearson, H., Kirsch, D., Provero, P., Poli, V., Ramsay, R., Sieber, O., Burgess, A., Huszar, D., Vincan, Elizabeth, and Ernst, M.

Abstract

Copyright © 2014 American Association for the Advancement of Science. All Rights Reserved. Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-ß-catenin pathway in the intestinal epithelium. Because Wnt-ß-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-ß-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer.

Published
2014

8. CELL BIOLOGY AND SIGNALING

Author

Furnari, F., primary, Fenton, T., additional, Nathanson, D., additional, de Alberquerque, C. P., additional, Kuga, D., additional, Wanami, A., additional, Dang, J., additional, Yang, H., additional, Tanaka, K., additional, Gao, L., additional, Oba-Shinjo, S., additional, Uno, M., additional, Inda, M.-d.-M., additional, Bachoo, R., additional, James, C. D., additional, DePinho, R., additional, Vandenberg, S., additional, Zhou, H., additional, Marie, S., additional, Mischel, P., additional, Cavenee, W., additional, Szerlip, N., additional, Pedraza, A., additional, Huse, J., additional, Mikkelsen, T., additional, Brennan, C., additional, Castellani, R. J., additional, Ivanova, S., additional, Gerzanich, V. V., additional, Simard, J. M., additional, Ito, M., additional, See, W., additional, Mukherjee, J., additional, Ohba, S., additional, Tan, I.-L., additional, Pieper, R. O., additional, Lukiw, W. J., additional, Culicchia, F., additional, Pogue, A., additional, Bhattacharjee, S., additional, Zhao, Y., additional, Proescholdt, M. A., additional, Merrill, M., additional, Storr, E. M., additional, Lohmeier, A., additional, Brawanski, A., additional, Abraham, S., additional, Jensen, R., additional, Khatua, S., additional, Gopal, U., additional, Du, J., additional, He, F., additional, Golub, T., additional, Isaacs, J. S., additional, Dietrich, J., additional, Kalogirou-Valtis, Y., additional, Ly, I., additional, Scadden, D., additional, Proschel, C., additional, Mayer-Proschel, M., additional, Rempel, S. A., additional, Schultz, C. R., additional, Golembieski, W., additional, Brodie, C., additional, Mathew, L. K., additional, Skuli, N., additional, Mucaj, V., additional, Imtiyaz, H. Z., additional, Venneti, S., additional, Lal, P., additional, Zhang, Z., additional, Davuluri, R. V., additional, Koch, C., additional, Evans, S., additional, Simon, M. C., additional, Ranganathan, P., additional, Clark, P., additional, Salamat, S., additional, Kuo, J. S., additional, Kalejta, R. F., additional, Bhattacharjee, B., additional, Renzette, N., additional, Moser, R. P., additional, Kowalik, T. F., additional, McFarland, B. C., additional, Ma, J.-Y., additional, Langford, C. P., additional, Gillespie, G. Y., additional, Yu, H., additional, Zheng, Y., additional, Nozell, S. E., additional, Huszar, D., additional, Benveniste, E. N., additional, Lawrence, J. E., additional, Cook, N. J., additional, Rovin, R. A., additional, Winn, R. J., additional, Godlewski, J. A., additional, Ogawa, D., additional, Bronisz, A., additional, Lawler, S., additional, Chiocca, E. A., additional, Lee, S. X., additional, Wong, E. T., additional, Swanson, K. D., additional, Liu, K.-w., additional, Feng, H., additional, Kazlauskas, A., additional, Smith, E. M., additional, Symes, K., additional, Hamilton, R. L., additional, Nagane, M., additional, Nishikawa, R., additional, Hu, B., additional, Cheng, S.-Y., additional, Silber, J., additional, Jacobsen, A., additional, Ozawa, T., additional, Harinath, G., additional, Brennan, C. W., additional, Holland, E. C., additional, Sander, C., additional, Huse, J. T., additional, Sengupta, R., additional, Dubuc, A., additional, Ward, S., additional, Yang, L., additional, Northcott, P., additional, Kroll, K., additional, Taylor, M., additional, Wechsler-Reya, R., additional, Rubin, J., additional, Chu, W.-T., additional, Lee, H.-T., additional, Huang, F.-J., additional, Aldape, K., additional, Yao, J., additional, Steeg, P. S., additional, Lu, Z., additional, Xie, K., additional, Huang, S., additional, Sim, H., additional, Agudelo-Garcia, P. A., additional, Viapiano, M. S., additional, Saldivar, J., additional, Dolan, C., additional, Mora, M., additional, Nuovo, G., additional, Cole, S., additional, Stegh, A. H., additional, Ryu, M.-J., additional, Liu, Y., additional, Zhong, X., additional, Marwaha, S., additional, Li, H., additional, Wang, J., additional, Chang, Q., additional, Zhang, J., additional, Ng, H.-K., additional, Poon, W. S., additional, Zhou, L., additional, Pang, J. C., additional, Chan, A., additional, Didier, S., additional, Kwiatkowska, A., additional, Ennis, M., additional, Fortin, S., additional, Rushing, E., additional, Eschbacher, J., additional, Tran, N., additional, Symons, M., additional, Roldan, G., additional, McIntyre, J. B., additional, Easaw, J., additional, Magliocco, A., additional, Wykosky, J., additional, Furnari, F., additional, Lu, D., additional, Mreich, E., additional, Chung, S., additional, Teo, C., additional, Wheeler, H., additional, McDonald, K. L., additional, Lawn, S., additional, Forsyth, P., additional, Sonabend, A. M., additional, Lei, L., additional, Kennedy, B., additional, Soderquist, C., additional, Guarnieri, P., additional, Leung, R., additional, Yun, J., additional, Sisti, J., additional, Castelli, M., additional, Bruce, S., additional, Bruce, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Canoll, P., additional, Lamszus, K., additional, Schulte, A., additional, Gunther, H. S., additional, Riethdorf, S., additional, Phillips, H. S., additional, Westphal, M., additional, Siegal, T., additional, Zrihan, D., additional, Granit, A., additional, Lavon, I., additional, Singh, M., additional, Chandra, J., additional, Nakashima, H., additional, Godlewski, J., additional, Chiocca, A. E., additional, Kapoor, G. S., additional, Poptani, H., additional, Ittyerah, R., additional, O'Rourke, D. M., additional, Sadraei, N. H., additional, Burgett, M., additional, Ahluwalia, M., additional, Tipps, R., additional, Khosla, D., additional, Weil, R., additional, Nowacki, A., additional, Prayson, R., additional, Shi, T., additional, Gladson, C., additional, Moeckel, S., additional, Meyer, K., additional, Bosserhoff, A., additional, Spang, R., additional, Leukel, P., additional, Vollmann, A., additional, Jachnick, B., additional, Stangl, C., additional, Proescholdt, M., additional, Bogdahn, U., additional, Hau, P., additional, Kaur, G., additional, Sun, M., additional, Kaur, R., additional, Bloch, O., additional, Jian, B., additional, Parsa, A. T., additional, Hossain, A., additional, Shinojima, N., additional, Gumin, J., additional, Feng, G., additional, Lang, F. F., additional, Li, L., additional, Yang, C.-R., additional, Chakraborty, S., additional, Hatanpaa, K., additional, Chauncey, S., additional, Jiwani, A., additional, Habib, A., additional, Nguyen, T., additional, Munson, J., additional, Machaidze, R., additional, Kaluzova, M., additional, Bellamkonda, R., additional, Hadjipanayis, C. G., additional, Zhang, Y., additional, McFarland, B., additional, Bredel, M., additional, Lee, S.-H., additional, Zerrouqi, A., additional, Khwaja, F., additional, Devi, N. S., additional, Van Meir, E. G., additional, Haseley, A., additional, Boone, S., additional, Wojton, J., additional, Yu, L., additional, Kaur, B., additional, Wojton, J. A., additional, Naduparambil, J., additional, Denton, N., additional, Chakravarti, A., additional, Conrad, C. A., additional, Wang, X., additional, Sheng, X., additional, Nilsson, C., additional, Marshall, A. G., additional, Emmett, M. R., additional, Hu, Y., additional, Mark, L., additional, Zhou, Y.-H. Z., additional, Dhruv, H., additional, McDonough, W., additional, Armstrong, B., additional, Tuncali, S., additional, Kislin, K., additional, Berens, M., additional, Plas, D., additional, Gallo, C., additional, Stringer, K., additional, Kendler, A., additional, McPherson, C., additional, Castelli, M. A., additional, Ellis, J. A., additional, Assanah, M., additional, Ogden, A., additional, Liang, J., additional, Piao, Y., additional, deGroot, J. F., additional, Gordon, N., additional, Patel, D., additional, Palanichamy, K., additional, Hervey-Jumper, S., additional, Wang, A., additional, He, X., additional, Zhu, T., additional, Heth, J., additional, Muraszko, K., additional, Fan, X., additional, Liu, W. M., additional, Huang, P., additional, Rani, S., additional, Stettner, M. R., additional, Jerry, S., additional, Dai, Q., additional, Kappes, J., additional, Gladson, C. L., additional, Chakravarty, D., additional, Koul, D., additional, Alfred Yung, W. K., additional, Jensen, S. A., additional, Luciano, J., additional, Calvert, A., additional, Nagpal, V., additional, Stegh, A., additional, Kang, S.-H., additional, Yu, M. O., additional, Lee, M.-G., additional, Chi, S.-G., additional, Chung, Y.-G., additional, Cooper, M. K., additional, Valadez, J. G., additional, Grover, V. K., additional, Kouri, F. M., additional, Chin, L., additional, Ahluwalia, M. S., additional, Weil, R. J., additional, McGraw, M., additional, Barnett, G. H., additional, Kang, C., additional, Zou, J., additional, Lan, F., additional, Yue, X., additional, Shi, Z., additional, Zhang, K., additional, Han, L., additional, Pu, P., additional, Seaman, B. F., additional, Tran, N. D., additional, Battiste, J. D., additional, Sirasanagandla, S., additional, Maher, E. A., additional, Sugiarto, S., additional, Persson, A., additional, Munoz, E. G., additional, Waldhuber, M., additional, Stallcup, W., additional, Philips, J., additional, Berger, M. S., additional, Bergers, G., additional, Weiss, W. A., additional, and Petritsch, C., additional

Published
2011
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9. A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors

Author

Infante, J. R., primary, Kurzrock, R., additional, Spratlin, J., additional, Burris, H. A., additional, Eckhardt, S. G., additional, Li, J., additional, Wu, K., additional, Skolnik, J. M., additional, Hylander-Gans, L., additional, Osmukhina, A., additional, Huszar, D., additional, and Herbst, R. S., additional

Published
2011
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10. Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia

Author

Kantarjian, H. M., primary, Padmanabhan, S., additional, Stock, W., additional, Tallman, M. S., additional, Curt, G. A., additional, Li, J., additional, Osmukhina, A., additional, Wu, K., additional, Huszar, D., additional, Borthukar, G., additional, Faderl, S., additional, Garcia-Manero, G., additional, Kadia, T., additional, Sankhala, K., additional, Odenike, O., additional, Altman, J. K., additional, and Minden, M., additional

Published
2011
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11. Cell Biology and Signaling

Author

Long, P. M., primary, Wesley, U. V., additional, Jaworski, D. M., additional, Rana, M., additional, Kiehl, T.-R., additional, So, K., additional, Gould, P., additional, Ajewung, N., additional, Kamnasaran, D., additional, Emmett, M. R., additional, Wang, X., additional, Marshall, A. G., additional, Ji, Y., additional, Fokt, I., additional, Skora, S., additional, Conrad, C. A., additional, Priebe, W., additional, Zhu, H., additional, Cao, X., additional, Keir, S., additional, Ali-Osman, F., additional, Lo, H.-W., additional, Da Fonseca, C. O., additional, Arun, V., additional, Wiley, J. C., additional, Kaur, H., additional, Guha, A., additional, Fenton, K., additional, Abdelwahab, M. G., additional, Stafford, P., additional, Rho, J. M., additional, Preul, M. C., additional, Scheck, A. C., additional, Brossier, N. M., additional, Carroll, S. L., additional, Gajadhar, A., additional, Mukherjee, J., additional, Wolf, A., additional, Hawkins, C., additional, Costa, P., additional, Cardoso, A. L. C., additional, de Almeida, L. P., additional, de Lima, M. C. P., additional, Canoll, P., additional, Bruce, J., additional, Lavon, I., additional, Granit, A., additional, Einstein, O., additional, Ben-Hur, T., additional, Siegal, T., additional, Pang, J. C., additional, Poon, W. S., additional, Zhou, L., additional, Ng, H.-K., additional, Rovin, R. A., additional, Lawrence, J. E., additional, Segula, J. J., additional, Winn, R. J., additional, Patil, S., additional, Burzynski, S. R., additional, Mrowczynski, E., additional, Grela, K., additional, Cheng, S., additional, Liu, K., additional, Feng, H., additional, Bacho, R., additional, Kazlauskas, A., additional, Smith, E. M., additional, Symes, K., additional, Hu, B., additional, Lee, C. Y., additional, Fotovati, A., additional, Dunn, S. E., additional, Proescholdt, M. A., additional, Storr, E.-M., additional, Lohmeier, A., additional, Brawanski, A., additional, Jarzynka, M. J., additional, Ravichandran, K. S., additional, Vuori, K., additional, Tang, C., additional, Nshikawa, R., additional, Johns, T. G., additional, Furnari, F. B., additional, Cavenee, W. K., additional, Zhong, J., additional, O'Neill, G. M., additional, Deleyrolle, L. P., additional, Rahman, M., additional, Dunbar, E. M., additional, Caldeira, M. A., additional, Reynolds, B. A., additional, Liu, X., additional, Yacyshyn, S., additional, Dasgupta, B., additional, Han, X., additional, Yang, X., additional, Wheeler, C. G., additional, Filippova, N., additional, Langford, C. P., additional, Ding, Q., additional, Fathallah, H. M., additional, Gillespie, G. Y., additional, Nabors, L. B., additional, Davidson, T. B., additional, Gortalum, F., additional, Ji, L., additional, Engell, K., additional, Sposto, R., additional, Asgharzadeh, S., additional, Erdreich-Epstein, A., additional, Lawn, S. O., additional, Weiss, S., additional, Senger, D., additional, Forsyth, P., additional, Latha, K., additional, Chumbalkar, V., additional, Li, M., additional, Gururaj, A., additional, Hwang, Y., additional, Maywald, R., additional, Dakeng, S., additional, Dao, L., additional, Baggerly, K., additional, Sawaya, R., additional, Aldape, K., additional, Cavenee, W., additional, Furnari, F., additional, Bogler, O., additional, Arumugam, J., additional, Sim, H., additional, Pineda, C. A., additional, Pan, Y., additional, Viapiano, M. S., additional, Van Schaick, J. A., additional, Akagi, K., additional, Burkett, S., additional, DiFabio, C., additional, Tuskan, R., additional, Walrath, J., additional, Reilly, K., additional, Dai, B., additional, Jing, Z., additional, Kang, S.-H., additional, Li, D., additional, Xie, K., additional, Huang, S., additional, Gong, X., additional, Vuong, Y., additional, Bota, D. A., additional, Stegh, A. H., additional, Inda, M.-d.-M., additional, Bonavia, R., additional, Mukasa, A., additional, Narita, Y., additional, Sah, D., additional, Vandenberg, S., additional, Brennan, C., additional, Johns, T., additional, Bachoo, R., additional, Hadwiger, P., additional, Tan, P., additional, DePinho, R., additional, Kusne, Y., additional, Meerson, A., additional, Rushing, E. J., additional, Yang, W., additional, McDonough, W., additional, Kislin, K., additional, Loftus, J. C., additional, Berens, M., additional, Lu, Z., additional, Ghosh, S., additional, Verma, A., additional, Zhou, H., additional, Chin, S., additional, Bruggers, C., additional, Kestle, J., additional, Khatua, S., additional, Broekman, M. L., additional, Maas, N. S., additional, Skog, J., additional, Breakefield, X. O., additional, Sena-Esteves, M., additional, de Vrij, J., additional, Lamfers, M., additional, Maas, N., additional, Dirven, C., additional, Esteves, M., additional, Broekman, M., additional, Chidambaram, A., additional, Dumur, C. I., additional, Graf, M., additional, Vanmeter, T. E., additional, Fillmore, H. L., additional, Broaddus, W. C., additional, Silber, J., additional, Ozawa, T., additional, Kastenhuber, E., additional, Djaballah, H., additional, Holland, E. C., additional, Huse, J. T., additional, Agnihotri, S., additional, Munoz, D., additional, Han, J. E., additional, Albesiano, E., additional, Pradilla, G., additional, Lim, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed Sadr, M., additional, Anan, M., additional, Seyed Sadr, E., additional, Siu, V., additional, Del Maestro, R., additional, Trinh, G., additional, Le, P., additional, Petrecca, K., additional, Sonabend, A. M., additional, Soderquist, C., additional, Lei, L., additional, Guarnieri, P., additional, Leung, R., additional, Yun, J., additional, Sisti, J., additional, Castelli, M., additional, Bruce, S., additional, Bruce, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Phillips, J. J., additional, Huillard, E., additional, Polley, M.-Y., additional, Rosen, S. D., additional, Rowitch, D. H., additional, Werb, Z., additional, Sarkar, C., additional, Jha, P., additional, Pathak, P., additional, Suri, V., additional, Sharma, M. C., additional, Chattopadhyay, P., additional, Chosdol, K., additional, Suri, A., additional, Gupta, D., additional, Mahapatra, A. K., additional, Kapoor, G. S., additional, Zhan, Y., additional, Boockvar, J. A., additional, O'Rourke, D. M., additional, Kwatra, M. M., additional, Kim, J. W., additional, Park, C.-K., additional, Han, J. H., additional, Park, S. H., additional, Kim, S.-K., additional, Jung, H.-W., additional, Narayanan, R., additional, Levin, B. S., additional, Maeder, M. L., additional, Joung, J. K., additional, Nutt, C. L., additional, Louis, D. N., additional, Dudley, A., additional, Jayaram, P., additional, Pei, Z., additional, Shi, X., additional, Laterra, J., additional, Watkins, P. A., additional, Mawrin, C., additional, Rempel, S. A., additional, McClung, H. M., additional, McFarland, B. C., additional, Nozell, S. E., additional, Huszar, D., additional, Benveniste, E. N., additional, Burton, T., additional, Eisenstat, D. D., additional, Gibson, S. B., additional, Lukiw, W. J., additional, Cui, J. G., additional, Li, Y. Y., additional, Zhao, Y., additional, Culicchia, F., additional, See, W., additional, Pieper, R., additional, Luchman, A., additional, Stechishin, O., additional, Nguyen, S., additional, Kelly, J., additional, Blough, M., additional, Cairncross, G., additional, Shah, S. R., additional, Mohyeldin, A., additional, Adams, H., additional, Garzon-Muvdi, T., additional, Aprhys, C., additional, Quinones-Hinojosa, A., additional, Weeks, A. C., additional, Restrepo, A., additional, Ivanchuk, S., additional, Smith, C., additional, Rutka, J. T., additional, Sengupta, R., additional, Yang, L., additional, Burbassi, S., additional, Zhang, B., additional, Markant, S. L., additional, Yang, Z.-j., additional, Meucci, O., additional, Wechsler-Reya, R. J., additional, Rubin, J. B., additional, Wykosky, J., additional, Chin, L., additional, Auvergne, R. M., additional, Sim, F. J., additional, Wang, S., additional, Chandler-Militello, D., additional, Burch, J., additional, Li, X., additional, Bennet, A., additional, Mohile, N., additional, Pilcher, W., additional, Walter, K., additional, Johnson, M., additional, Achanta, P., additional, Natesan, S., additional, Goldman, S. A., additional, Beauchamp, A. S., additional, Gibo, D. M., additional, Debinski, W., additional, Jiang, H., additional, Martin, V., additional, Gomez-Manzano, C., additional, Johnson, D. G., additional, Alonso, M., additional, White, E. J., additional, Xu, J., additional, McDonnell, T., additional, Shinojima, N., additional, Fueyo, J., additional, Sandhya Rani, M. R., additional, Huang, P., additional, Prayson, R., additional, Hedayat, H., additional, Sloan, A. E., additional, Novacki, A., additional, Ahluwalia, M. S., additional, Tipps, R., additional, Gladson, C. L., additional, Liu, J.-L., additional, Mao, Z., additional, Yung, W. K. A., additional, Bhat, K., additional, Salazar, K., additional, Balasubramaniyan, V., additional, Vaillant, B., additional, Hollingsworth, F., additional, Gumin, J., additional, Diefes, K., additional, Patel, D., additional, Lang, F., additional, Colman, H., additional, Parsyan, A., additional, Shahbazian, D., additional, Alain, T., additional, Martineau, Y., additional, Petroulakis, E., additional, Larsson, O., additional, Gkogkas, C., additional, Topisirovic, I., additional, Mathonnet, G., additional, Tettweiler, G., additional, Hellen, C., additional, Pestova, T., additional, Svitkin, Y., additional, Sonenberg, N., additional, Zerrouqi, A., additional, Pyrzynska, B., additional, Van Meir, E., additional, Twitty, G. B., additional, Hong, S. W., additional, Lee, H. K., additional, Finniss, S., additional, Xiang, C., additional, Cazacu, S., additional, Brodie, C., additional, Ginn, K. F., additional, Wise, A., additional, Farassati, F., additional, Brown, C., additional, Barish, M., additional, deCarvalho, A. C., additional, Hasselbach, L., additional, Nelson, K., additional, Lemke, N., additional, Schultz, L., additional, Mikkelsen, T., additional, Onvani, S., additional, Kongkham, P., additional, Smith, C. A., additional, Bier, A., additional, Hershkovitz, H., additional, Kahana, S., additional, Decarvalho, A., additional, Massey, S. C., additional, and Swanson, K. R., additional

Published
2010
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12. Phenotypic rescue of mutant brown melanocytes by a retrovirus carrying a wild-type tyrosinase-related protein gene

Author

Dc, Bennett, Huszar D, Pj, Laipis, Jaenisch R, and Ian Jackson

Subjects
Melanins, Membrane Glycoproteins, Genetic Vectors, Proteins, Transfection, Mice, Phenotype, Phorbol Esters, Animals, Melanocytes, Moloney murine leukemia virus, Oxidoreductases, Molecular Biology, Cells, Cultured, Developmental Biology
Abstract

A mouse cDNA for the developmentally controlled, melanocyte-specific protein, tyrosinase-related protein 1 (TRP-1), was previously cloned and reported to show genetic linkage with the coat-colour locus brown (b) on mouse chromosome 4. The cDNA has been inserted into a retroviral vector derived from Moloney murine leukaemia virus, under the control of the human histone H4 promoter. This vector was used to infect melanocytes of the immortal line melan-b, which are homozygous for the b mutation and which display light brown pigmentation in culture. Infected cultures containing between 0.2 and 2 copies of provirus per cell displayed an altered phenotype: 20-50 % of cells now had the black to dark brown colour characteristic of cultured wild-type (Black, B/B) mouse melanocytes. Thus the TRP-1 gene complements the brown mutation. We conclude that TRP-1 is the product of the wild-type-b-locus.

Published
1990

27. Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation.

Author

Stubdal, H, Lynch, C A, Moriarty, A, Fang, Q, Chickering, T, Deeds, J D, Fairchild-Huntress, V, Charlat, O, Dunmore, J H, Kleyn, P, Huszar, D, and Kapeller, R

Abstract

The mouse tubby phenotype is characterized by maturity-onset obesity accompanied by retinal and cochlear degeneration. A positional cloning effort to find the gene responsible for this phenotype led to the identification of tub, a member of a novel gene family of unknown function. A splice defect mutation in the 3' end of the tub gene, predicted to disrupt the C terminus of the Tub protein, has been implicated in the genesis of the tubby phenotype. It is not clear, however, whether the Tub mutant protein retains any biological activity, or perhaps has some dominant function, nor is it established that the tubby mutation is itself responsible for all of the observed tubby phenotypes. To address these questions, we generated tub-deficient mice and compared their phenotype to that of tubby mice. Our results demonstrate that tubby is a loss-of-function mutation of the tub gene and that loss of the tub gene is sufficient to give rise to the full spectrum of tubby phenotypes. We also demonstrate that loss of photoreceptors in the retina of tubby and tub-deficient mice occurs by apoptosis. In addition, we show that Tub protein expression is not significantly altered in the ob, db, or melanocortin 4 receptor-deficient mouse model of obesity.

Published
2000

28. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile.

Author

Ji, Y, Wang, N, Ramakrishnan, R, Sehayek, E, Huszar, D, Breslow, J L, and Tall, A R

Abstract

The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptor-mediated. Based on our finding that scavenger receptor BI (SR-BI) promotes free cholesterol (FC) exchange between high density lipoprotein (HDL) and cells, we tested whether SR-BI would effect FC movement in vivo using [(14)C]FC- and [(3)H]cholesteryl ester (CE)-labeled HDL in mice with increased (SR-BI transgenic (Tg)) or decreased (SR-BI attenuated (att)) hepatic SR-BI expression. The initial clearance of HDL FC was increased in SR-BI Tg mice by 72% and decreased in SR-BI att mice by 53%, but was unchanged in apoA-I knockout mice compared with wild-type mice. Transfer of FC to non-HDL and esterification of FC were minor and could not explain differences. The hepatic uptake of FC was increased in SR-BI Tg mice by 34% and decreased in SR-BI att mice by 22%. CE clearance and uptake gave similar results, but with much slower rates. The uptake of HDL FC and CE by SR-BI Tg primary hepatocytes was increased by 2.2- and 2.6-fold (1-h incubation), respectively, compared with control hepatocytes. In SR-BI Tg mice, the initial biliary secretion of [(14)C]FC was markedly increased, whereas increased [(3)H]FC appeared after a slight delay. Thus, in the mouse, a major portion of the clearance of HDL FC from plasma is mediated by SR-BI.

Published
1999

29. Partial purification and characterization of the ribonucleotide reductase induced by herpes simplex virus infection of mammalian cells

Author

Huszar, D and Bacchetti, S

Abstract

In this report we confirm and further characterize the induction of a novel ribonucleotide reductase after herpes simplex virus infection of mammalian cells. Induction of the enzyme was observed at a multiplicity of infection of 1 PFU/cell or greater and was found to be maximal (three- to sixfold the activity in mock-infected controls at 6 to 8 h postinfection at a multiplicity of infection of 10 PFU/cell. Partial purification and subsequent characterization of the reductase activity from infected cells demonstrated the existence of two enzymes which could be separated by precipitation with ammonium sulfate. One of the activities precipitated at between 35 and 55% salt saturation, as did the enzyme from control cells, whereas the novel activity precipitated at 0 to 35% saturation. This latter enzyme was similar to the herpes simplex virus-induced reductase described by others in its lack of requirement for Mg2 and its resistance to inhibition by dTTP and dATP; in addition, we found that it was inhibited by ATP, whereas the enzyme from control cells displayed an absolute requirement for the nucleotide. Both enzymes were equally inhibited by pyridoxal phosphate and showed similar cold and heat stability. The enzyme induced by herpes simplex virus infection, however, was much more labile than the control enzyme upon purification.

Published
1981
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30. Modulation of gene expression in multiple hematopoietic cell lineages following retroviral vector gene transfer.

Author

Magli, M C, Dick, J E, Huszar, D, Bernstein, A, and Phillips, R A

Abstract

Retrovirus vectors offer a simple and highly efficient method for introducing new genes into mammalian cells. Here, we have examined the efficiency of gene transfer into hematopoietic cells with retrovirus vectors carrying the neomycin (neo) resistance gene expressed from different transcriptional regulatory regions. Direct infection of mouse bone marrow cells resulted in high efficiencies of gene transfer into a variety of myeloid progenitor cells, including pluripotent, erythroid, and granulocyte-macrophage colony-forming cells with all the vectors examined. However, the progeny derived from individual pluripotent progenitor cells infected with different vectors differed markedly in the proportion of G418-resistant progenitor cells, as judged by their ability to survive selection in the drug G418. This biological assay suggests that the highest level of expression was observed when the neo gene was expressed from constructs that contained the herpes thymidine kinase promoter rather than the viral long terminal repeat or the simian virus 40 early region promoter. In contrast, neo gene expression was highest in fibroblasts infected with the vector containing the simian virus 40 early region promoter. These results show that high and sustainable levels of gene expression in hematopoietic cells can be obtained with retrovirus vectors containing appropriate transcriptional regulatory regions.

Published
1987
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31. Insertion of a bacterial gene into the mouse germ line using an infectious retrovirus vector.

Author

Huszar, D, Balling, R, Kothary, R, Magli, M C, Hozumi, N, Rossant, J, and Bernstein, A

Abstract

Using a Moloney leukemia virus vector containing the bacterial neo gene, we demonstrate that retrovirus vectors can be used to introduce genes into the mouse germ line. Infection of preimplantation embryos with the vector MLV-NEO.1 resulted in integration of neo sequences in approximately equal to 10% of the progeny mice. One of these animals, mouse F.2, contained approximately six MLV-NEO.1 proviruses at independent integration sites, each present at less than a single copy per cell. This mosaic mouse transmitted one of these proviruses to her offspring, producing a line of transgenic mice carrying a full-length, unrearranged MLV.NEO.1 provirus at a single chromosomal integration site. Mice homozygous at this MLV-NEO.1 locus have also been produced. No expression of the neo gene has been detected in the transgenic mice, either by screening of primary bone marrow or lung cells for resistance to G418 or by RNA transfer blot analysis of RNA from several tissues. In addition, the neo gene was found to be extensively methylated in the transgenic mice; however, treatment of primary cells with 5-azacytidine did not induce G418 resistance. The inactivity of the MLV-NEO.1 provirus in transgenic mice and potential means of eliciting neo expression under these conditions are discussed.

Published
1985
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32. Insertion of a bacterial gene into the mouse germ line using an infectious retrovirus vector.

Author

Huszar, D., Balling, Rudi, Kothary, R., Magli, M. C., Hozumi, N., Rossant, J., Bernstein, A., Huszar, D., Balling, Rudi, Kothary, R., Magli, M. C., Hozumi, N., Rossant, J., and Bernstein, A.

Abstract

Using a Moloney leukemia virus vector containing the bacterial neo gene, we demonstrate that retrovirus vectors can be used to introduce genes into the mouse germ line. Infection of preimplantation embryos with the vector MLV-NEO.1 resulted in integration of neo sequences in approximately equal to 10% of the progeny mice. One of these animals, mouse F.2, contained approximately six MLV-NEO.1 proviruses at independent integration sites, each present at less than a single copy per cell. This mosaic mouse transmitted one of these proviruses to her offspring, producing a line of transgenic mice carrying a full-length, unrearranged MLV.NEO.1 provirus at a single chromosomal integration site. Mice homozygous at this MLV-NEO.1 locus have also been produced. No expression of the neo gene has been detected in the transgenic mice, either by screening of primary bone marrow or lung cells for resistance to G418 or by RNA transfer blot analysis of RNA from several tissues. In addition, the neo gene was found to be extensively methylated in the transgenic mice; however, treatment of primary cells with 5-azacytidine did not induce G418 resistance. The inactivity of the MLV-NEO.1 provirus in transgenic mice and potential means of eliciting neo expression under these conditions are discussed.

Published
1985
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33. New approaches to human monoclonal antibody production: use of transgenic mice

Author

Fishwild, D., Carmack, C., Harding, F., Bernhard, S., O'Donnell, S., Munoz-O'Regan, D., Bengoechea, T., Rojas, V., Mashayekh, R., Trounstine, M., Lapachet, E., Woodhouse, C., Kay, R., Huszar, D., and Lonberg, N.

Subjects
Monoclonal antibodies -- Health aspects, Genetically modified mice -- Usage, Business, Health care industry
Abstract

According to an abstract submitted by the authors to the 4th International Conference on Human Antibodies and Hybridomas, held April 26-28, 1995, in Amsterdam, The Netherlands, 'As the limitations of [...]

Published
1995

35. Genetic Engineering of Mouse and Human Stem Cells

Author

Bernstein, A., primary, Dick, J.E., additional, Huszar, D., additional, Robson, I., additional, Rossant, J., additional, Magli, C., additional, Estrov, Z., additional, Freedman, M., additional, and Phillips, R.A., additional

Published
1986
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38. The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis

Author

Mario Taffurelli, Qing Chang, David Lyden, Dennis Huszar, Rosandra N. Kaplan, Elisa de Stanchina, Selena Granitto, Jacqueline Bromberg, Xinmin Zhang, Norihiro Nishimoto, Jesse W. Cotari, Marjan Berishaj, Donatella Santini, Katia Manova, Massimiliano Bonafè, Grégoire Altan-Bonnet, Laura Daly, Ming O. Li, Sizhi Paul Gao, Larry Norton, Mary L. Alpaugh, Eirini Bournazou, Jared Wels, Till Martin Theilen, Claudio Ceccarelli, Pasquale Sansone, Chang Q, Bournazou E, Sansone P, Berishaj M, Gao SP, Daly L, Wels J, Theilen T, Granitto S, Zhang X, Cotari J, Alpaugh ML, de Stanchina E, Manova K, Li M, Bonafe M, Ceccarelli C, Taffurelli M, Santini D, Altan-Bonnet G, Kaplan R, Norton L, Nishimoto N, Huszar D, Lyden D, and Bromberg J

Subjects
0303 health sciences, Cancer Research, Tumor microenvironment, Angiogenesis, Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease_cause, medicine.disease, lcsh:RC254-282, INTERLEUKIN 6, Metastasis, 03 medical and health sciences, 0302 clinical medicine, BREAST CANCER, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, medicine, Myeloid-derived Suppressor Cell, STAT protein, Carcinogenesis, Janus kinase, 030304 developmental biology
Abstract

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

Published
2013

39. Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment.

Author

Derry JMJ, Burns C, Frazier JP, Beirne E, Grenley M, DuFort CC, Killingbeck E, Leon M, Williams C, Gregory M, Houlton J, Clayburgh D, Swiecicki P, Huszar D, Berger A, and Klinghoffer RA

Subjects
Humans, Enzyme Inhibitors, Tumor Microenvironment, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Head and Neck Neoplasms drug therapy
Abstract

Purpose: Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVO) with spatial biology readouts to directly assess drug effects in patient tumors in situ., Experimental Design: In a first-of-its-kind phase 0 clinical trial, we explored the effects of an investigational stage SUMOylation-activating enzyme (SAE) inhibitor, subasumstat (TAK-981) in 12 patients with head and neck carcinoma (HNC). Patients scheduled for tumor resection received percutaneous intratumor injections of subasumstat and vehicle control 1 to 4 days before surgery, resulting in spatially localized and graded regions of drug exposure (∼1,000-2,000 μm in diameter). Drug-exposed (n = 214) and unexposed regions (n = 140) were compared by GeoMx Digital Spatial Profiler, with evaluation at single-cell resolution in a subset of these by CosMx Spatial Molecular Imager., Results: Localized regions of subasumstat exposure revealed SUMO pathway inhibition, elevation of type I IFN response, and inhibition of cell cycle across all tumor samples. Single-cell analysis by CosMx demonstrated cell-cycle inhibition specific to the tumor epithelium, and IFN pathway induction commensurate with a TME shift from immune-suppressive to immune-permissive., Conclusions: Pairing CIVO with spatial profiling enabled detailed investigation of response to subasumstat across a diverse sampling of native and intact TME. We demonstrate that drug mechanism of action can be directly evaluated in a spatially precise manner in the most translationally relevant setting: an in situ human tumor., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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40. A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells.

Author

Hanel W, Lata P, Youssef Y, Tran H, Tsyba L, Sehgal L, Blaser BW, Huszar D, Helmig-Mason J, Zhang L, Schrock MS, Summers MK, Chan WK, Prouty A, Mundy-Bosse BL, Chen-Kiang S, Danilov AV, Maddocks K, Baiocchi RA, and Alinari L

Abstract

Background: Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin's lymphoma. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is known about its oncogenic role in MCL., Methods: Levels of sumoylation enzymes and sumoylated proteins were quantified in MCL cell lines and primary MCL patient samples by scRNA sequencing and immunoblotting. The sumoylation enzyme SAE2 was genetically and pharmacologically targeted with shRNA and TAK-981 (subasumstat). The effects of SAE2 inhibition on MCL proliferation and cell cycle were evaluated using confocal microscopy, live-cell microscopy, and flow cytometry. Immunoprecipitation and orbitrap mass spectrometry were used to identify proteins targeted by sumoylation in MCL cells., Results: MCL cells have significant upregulation of the sumoylation pathway at the level of the enzymes SAE1 and SAE2 which correlated with poor prognosis and induction of mitosis associated genes. Selective inhibition of SAE2 with TAK-981 results in significant MCL cell death in vitro and in vivo with mitotic dysregulation being an important mechanism of action. We uncovered a sumoylation program in mitotic MCL cells comprised of multiple pathways which could be directly targeted with TAK-981. Centromeric localization of topoisomerase 2A, a gene highly upregulated in SAE1 and SAE2 overexpressing MCL cells, was lost with TAK-981 treatment likely contributing to the mitotic dysregulation seen in MCL cells., Conclusions: This study not only validates SAE2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies., (© 2022. The Author(s).)

Published
2022
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41. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation.

Author

Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, and Huszar D

Subjects
Antibody-Dependent Cell Cytotoxicity, Antigens, CD20, Cell Line, Tumor, Humans, Killer Cells, Natural, Macrophages metabolism, Rituximab metabolism, Rituximab pharmacology, Rituximab therapeutic use, Lymphoma drug therapy, Lymphoma metabolism, Sumoylation
Abstract

Small ubiquitin-like modifier (SUMO) is a member of a ubiquitin-like protein superfamily. SUMOylation is a reversible posttranslational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of type 1 interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor subasumstat (TAK-981) in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and natural killer (NK) cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pretreatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20+ target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated enhanced antitumor activity of TAK-981 and rituximab in CD20+ lymphoma xenograft models. Combination of TAK-981 with anti-CD38 antibody daratumumab also resulted in enhanced antitumor activity. TAK-981 is currently being studied in phase 1 clinical trials (#NCT03648372, #NCT04074330, #NCT04776018, and #NCT04381650; www.clinicaltrials.gov) for the treatment of patients with lymphomas and solid tumors., (© 2022 by The American Society of Hematology.)

Published
2022
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42. A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models.

Author

Lightcap ES, Yu P, Grossman S, Song K, Khattar M, Xega K, He X, Gavin JM, Imaichi H, Garnsey JJ, Koenig E, Zhang H, Lu Z, Shah P, Fu Y, Milhollen MA, Hatton BA, Riceberg J, Shinde V, Li C, Minissale J, Yang X, England D, Klinghoffer RA, Langston S, Galvin K, Shapiro G, Pulukuri SM, Fuchs SY, and Huszar D

Subjects
Immunity, Sumoylation
Abstract

SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8 + T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.

Published
2021
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43. Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.

Author

Grimster NP, Anderson E, Alimzhanov M, Bebernitz G, Bell K, Chuaqui C, Deegan T, Ferguson AD, Gero T, Harsch A, Huszar D, Kawatkar A, Kettle JG, Lyne P, Read JA, Rivard Costa C, Ruston L, Schroeder P, Shi J, Su Q, Throner S, Toader D, Vasbinder M, Woessner R, Wang H, Wu A, Ye M, Zheng W, and Zinda M

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Biological Availability, Cell Line, Crystallography, X-Ray, Humans, Janus Kinase 1 chemistry, Janus Kinase 1 metabolism, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Janus Kinase 3 metabolism, Mice, Phosphorylation drug effects, STAT3 Transcription Factor metabolism, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Janus Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
Abstract

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).

Published
2018
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44. Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

Author

Kapoor S, Natarajan K, Baldwin PR, Doshi KA, Lapidus RG, Mathias TJ, Scarpa M, Trotta R, Davila E, Kraus M, Huszar D, Tron AE, Perrotti D, and Baer MR

Subjects
Animals, Benzothiazoles pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Membrane Potential, Mitochondrial, Mice, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational, Proteolysis, Proteome metabolism, Reactive Oxygen Species metabolism, Apoptosis genetics, Gene Duplication, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics
Abstract

Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2018
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45. Next-generation sequencing identifies a novel ELAVL1-TYK2 fusion gene in MOLM-16, an AML cell line highly sensitive to the PIM kinase inhibitor AZD1208.

Author

Tron AE, Keeton EK, Ye M, Casas-Selves M, Chen H, Dillman KS, Gale RE, Stengel C, Zinda M, Linch DC, Lai Z, Khwaja A, and Huszar D

Subjects
Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Leukemic drug effects, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute pathology, Protein Kinase Inhibitors therapeutic use, Biphenyl Compounds therapeutic use, ELAV-Like Protein 1 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Oncogene Proteins, Fusion genetics, TYK2 Kinase genetics, Thiazolidines therapeutic use
Published
2016
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46. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress.

Author

Doshi KA, Trotta R, Natarajan K, Rassool FV, Tron AE, Huszar D, Perrotti D, and Baer MR

Subjects
Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Biphenyl Compounds administration & dosage, Biphenyl Compounds pharmacology, Cytarabine pharmacology, Drug Synergism, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 genetics, Proto-Oncogene Proteins c-pim-1 metabolism, Reactive Oxygen Species metabolism, Signal Transduction, Thiazolidines administration & dosage, Thiazolidines pharmacology, Topoisomerase II Inhibitors administration & dosage, DNA Damage, Leukemia, Myeloid, Acute drug therapy, Oxidative Stress drug effects, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Topoisomerase II Inhibitors pharmacology, fms-Like Tyrosine Kinase 3 metabolism
Abstract

Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD., Competing Interests: AET is an employee of AstraZeneca and DH was an employee of AstraZeneca. The other authors have no competing financial interests in relation to the work described.

Published
2016
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47. JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Author

Gao SP, Chang Q, Mao N, Daly LA, Vogel R, Chan T, Liu SH, Bournazou E, Schori E, Zhang H, Brewer MR, Pao W, Morris L, Ladanyi M, Arcila M, Manova-Todorova K, de Stanchina E, Norton L, Levine RL, Altan-Bonnet G, Solit D, Zinda M, Huszar D, Lyden D, and Bromberg JF

Subjects
Adenocarcinoma enzymology, Adenocarcinoma genetics, Adenocarcinoma pathology, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Humans, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Lung Neoplasms enzymology, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Protein Kinase Inhibitors pharmacology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Lung Neoplasms diet therapy, Mutation
Abstract

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC., (Copyright © 2016, American Association for the Advancement of Science.)

Published
2016
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48. Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma.

Author

Ezell SA, Wang S, Bihani T, Lai Z, Grosskurth SE, Tepsuporn S, Davies BR, Huszar D, and Byth KF

Subjects
Cell Line, Tumor, Humans, Lymphoma, Large B-Cell, Diffuse pathology, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation drug effects, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt metabolism, Ribosomal Protein S6 metabolism, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Lymphoma, Large B-Cell, Diffuse drug therapy, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, TOR Serine-Threonine Kinases metabolism
Abstract

Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL.

Published
2016
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49. Identification of azabenzimidazoles as potent JAK1 selective inhibitors.

Author

Vasbinder MM, Alimzhanov M, Augustin M, Bebernitz G, Bell K, Chuaqui C, Deegan T, Ferguson AD, Goodwin K, Huszar D, Kawatkar A, Kawatkar S, Read J, Shi J, Steinbacher S, Steuber H, Su Q, Toader D, Wang H, Woessner R, Wu A, Ye M, and Zinda M

Subjects
Animals, Cell Cycle drug effects, Cell Death drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Female, Humans, Imidazoles chemical synthesis, Imidazoles chemistry, Janus Kinase 1 metabolism, Mice, Mice, Nude, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, STAT3 Transcription Factor metabolism, Structure-Activity Relationship, Imidazoles pharmacology, Janus Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, STAT3 Transcription Factor antagonists & inhibitors
Abstract

We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2016
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50. The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells.

Author

Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, and Reuther GW

Subjects
Cell Line, Tumor, Cell Proliferation drug effects, Cells, Cultured, Drug Synergism, Humans, Imidazoles pharmacology, Immunoblotting, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mutation, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, Myeloproliferative Disorders pathology, Nitriles, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 metabolism, Pyridazines pharmacology, Pyrimidines, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Tumor Stem Cell Assay, bcl-Associated Death Protein metabolism, Apoptosis drug effects, Biphenyl Compounds pharmacology, Janus Kinase 2 antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Pyrazoles pharmacology, Thiazolidines pharmacology
Abstract

Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and risk of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in patients are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. Members of the PIM family of serine/threonine kinases are induced by JAK/STAT signaling, regulate hematopoietic stem cell growth, protect hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming properties. We hypothesized that PIM kinases may offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells as well as primary MPN patient cells with the PIM kinase inhibitors SGI-1776 and AZD1208 and the JAK2 inhibitor ruxolitinib. While MPN model cells were rather insensitive to PIM inhibitors, combination of PIM inhibitors with ruxolitinib led to a synergistic effect on MPN cell growth due to enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically suppressed, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was associated with activation of BAD, inhibition of downstream components of the mTOR pathway, including p70S6K and S6 protein, and activation of 4EBP1. Importantly, PIM inhibitors re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis. Finally, exogenous expression of PIM1 induced ruxolitinib resistance in MPN model cells. These data indicate that PIMs may play a role in MPNs and that combining PIM and JAK2 kinase inhibitors may offer a more efficacious therapeutic approach for MPNs over JAK2 inhibitor mono-therapy.

Published
2015
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