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1. International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Author

Chalhoub, N.E. Wenderfer, S.E. Levy, D.M. Rouster-Stevens, K. Aggarwal, A. Savani, S.I. Ruth, N.M. Arkachaisri, T. Qiu, T. Merritt, A. Onel, K. Goilav, B. Khubchandani, R.P. Deng, J. Fonseca, A.R. Ardoin, S.P. Ciurtin, C. Kasapcopur, O. Jelusic, M. Huber, A.M. Ozen, S. Klein-Gitelman, M.S. Appenzeller, S. Cavalcanti, A. Fotis, L. Lim, S.C. Silva, R.M. Miramontes, J.R. Rosenwasser, N.L. Saad-Magalhaes, C. Schonenberg-Meinema, D. Scott, C. Silva, C.A. Enciso, S. Terreri, M.T. Torres-Jimenez, A.-R. Trachana, M. Al-Mayouf, S.M. Devarajan, P. Huang, B. Brunner, H.I. Abulaban, K. Aguiar, C. Ahn, S.-Y. Akoghlanian, S. Al-Abrawi, S. Aljaberi, N. Alperin, R. Angeles-Han, S. Ardalan, K. Bader-Meunier, B. Balboni, I. Barbar-Smiley, F. Baxter, S. Beary, J. Boneparth, A. Brakeman, P. Bridges, J. Burgos-Vargas, R. Cabral, D.A. Cameto, J. Carter, C. Chang, J. Chédeville, G. Chhakchhuak, C. Chiraseveenuprapund, P. Cifuentes Alvarado, M. Concannon, A. Cooper, J. Cron, R. De Carvalho, L.M. De Quattro, K. De Ranieri, D. Dizon, B. Donnelly Wrigley, C. Duong, M.D. Eberhard, A. Ede, K. Edelheit, B. Edens, C. Espada, G. Farhey, Y. Flores, F. Fritz, D. Ganguli, S. Gilbert, M. Gittar, P. Greenbaum, L. Grom, A. Gulati, G. Harry, O. Hayward, K. Henrickson, M. Hersh, A. Hiraki, L. Hiskey, M. Hoffmann, S. Hollander, M. Hom, C. Houk, L. Houk, J.B. Hsieh, E.W.Y. Hsu, J. Jensen, P. Joos, R. Jurado, R. Jusan Fiorot, F. Kallash, M. Kamphuis, S. Keltsev, V., (deceased) Khanna, S. Kim, S. Kimseng, K.J. Knight, A. Kunder, R. Lai, J. Laskin, B. Lewandowski, L. Lim, L. Linda, W.-W. Lo, M. Lovell, D. Luggen, M. Madison, J. Mansuri, A. Martin, L. Mason, S. Miller, M. Mina, R. Mohammed, A. Moncrieffe, H. Moorthy, L. Morgan, E. Mosquera, A. Muntel, E. Muscal, E. Myones, B. Nocton, J. Ogbu, E. Okamura, D. Olson, J. Orrock, J. Paim-Marques, L. Pain, C. Park, C. Patel, P. Pereira, M. Prado, R.D. Radhakrishna, S. Rheault, M. Ridgway, W. Riskalla, M. Ronis, T. Sadun, R. Sagcal-Gironella, A.C. Santos, M.C. Schikle and Chalhoub, N.E. Wenderfer, S.E. Levy, D.M. Rouster-Stevens, K. Aggarwal, A. Savani, S.I. Ruth, N.M. Arkachaisri, T. Qiu, T. Merritt, A. Onel, K. Goilav, B. Khubchandani, R.P. Deng, J. Fonseca, A.R. Ardoin, S.P. Ciurtin, C. Kasapcopur, O. Jelusic, M. Huber, A.M. Ozen, S. Klein-Gitelman, M.S. Appenzeller, S. Cavalcanti, A. Fotis, L. Lim, S.C. Silva, R.M. Miramontes, J.R. Rosenwasser, N.L. Saad-Magalhaes, C. Schonenberg-Meinema, D. Scott, C. Silva, C.A. Enciso, S. Terreri, M.T. Torres-Jimenez, A.-R. Trachana, M. Al-Mayouf, S.M. Devarajan, P. Huang, B. Brunner, H.I. Abulaban, K. Aguiar, C. Ahn, S.-Y. Akoghlanian, S. Al-Abrawi, S. Aljaberi, N. Alperin, R. Angeles-Han, S. Ardalan, K. Bader-Meunier, B. Balboni, I. Barbar-Smiley, F. Baxter, S. Beary, J. Boneparth, A. Brakeman, P. Bridges, J. Burgos-Vargas, R. Cabral, D.A. Cameto, J. Carter, C. Chang, J. Chédeville, G. Chhakchhuak, C. Chiraseveenuprapund, P. Cifuentes Alvarado, M. Concannon, A. Cooper, J. Cron, R. De Carvalho, L.M. De Quattro, K. De Ranieri, D. Dizon, B. Donnelly Wrigley, C. Duong, M.D. Eberhard, A. Ede, K. Edelheit, B. Edens, C. Espada, G. Farhey, Y. Flores, F. Fritz, D. Ganguli, S. Gilbert, M. Gittar, P. Greenbaum, L. Grom, A. Gulati, G. Harry, O. Hayward, K. Henrickson, M. Hersh, A. Hiraki, L. Hiskey, M. Hoffmann, S. Hollander, M. Hom, C. Houk, L. Houk, J.B. Hsieh, E.W.Y. Hsu, J. Jensen, P. Joos, R. Jurado, R. Jusan Fiorot, F. Kallash, M. Kamphuis, S. Keltsev, V., (deceased) Khanna, S. Kim, S. Kimseng, K.J. Knight, A. Kunder, R. Lai, J. Laskin, B. Lewandowski, L. Lim, L. Linda, W.-W. Lo, M. Lovell, D. Luggen, M. Madison, J. Mansuri, A. Martin, L. Mason, S. Miller, M. Mina, R. Mohammed, A. Moncrieffe, H. Moorthy, L. Morgan, E. Mosquera, A. Muntel, E. Muscal, E. Myones, B. Nocton, J. Ogbu, E. Okamura, D. Olson, J. Orrock, J. Paim-Marques, L. Pain, C. Park, C. Patel, P. Pereira, M. Prado, R.D. Radhakrishna, S. Rheault, M. Ridgway, W. Riskalla, M. Ronis, T. Sadun, R. Sagcal-Gironella, A.C. Santos, M.C. Schikle

Abstract

Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3–5). Validation of the SSR for up to 6 months post–kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials. © 2021, American College of Rheumatology

Published
2022

2. International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Author

Chalhoub, N.E. Wenderfer, S.E. Levy, D.M. Rouster-Stevens, K. Aggarwal, A. Savani, S.I. Ruth, N.M. Arkachaisri, T. Qiu, T. Merritt, A. Onel, K. Goilav, B. Khubchandani, R.P. Deng, J. Fonseca, A.R. Ardoin, S.P. Ciurtin, C. Kasapcopur, O. Jelusic, M. Huber, A.M. Ozen, S. Klein-Gitelman, M.S. Appenzeller, S. Cavalcanti, A. Fotis, L. Lim, S.C. Silva, R.M. Miramontes, J.R. Rosenwasser, N.L. Saad-Magalhaes, C. Schonenberg-Meinema, D. Scott, C. Silva, C.A. Enciso, S. Terreri, M.T. Torres-Jimenez, A.-R. Trachana, M. Al-Mayouf, S.M. Devarajan, P. Huang, B. Brunner, H.I. Abulaban, K. Aguiar, C. Ahn, S.-Y. Akoghlanian, S. Al-Abrawi, S. Aljaberi, N. Alperin, R. Angeles-Han, S. Ardalan, K. Bader-Meunier, B. Balboni, I. Barbar-Smiley, F. Baxter, S. Beary, J. Boneparth, A. Brakeman, P. Bridges, J. Burgos-Vargas, R. Cabral, D.A. Cameto, J. Carter, C. Chang, J. Chédeville, G. Chhakchhuak, C. Chiraseveenuprapund, P. Cifuentes Alvarado, M. Concannon, A. Cooper, J. Cron, R. De Carvalho, L.M. De Quattro, K. De Ranieri, D. Dizon, B. Donnelly Wrigley, C. Duong, M.D. Eberhard, A. Ede, K. Edelheit, B. Edens, C. Espada, G. Farhey, Y. Flores, F. Fritz, D. Ganguli, S. Gilbert, M. Gittar, P. Greenbaum, L. Grom, A. Gulati, G. Harry, O. Hayward, K. Henrickson, M. Hersh, A. Hiraki, L. Hiskey, M. Hoffmann, S. Hollander, M. Hom, C. Houk, L. Houk, J.B. Hsieh, E.W.Y. Hsu, J. Jensen, P. Joos, R. Jurado, R. Jusan Fiorot, F. Kallash, M. Kamphuis, S. Keltsev, V., (deceased) Khanna, S. Kim, S. Kimseng, K.J. Knight, A. Kunder, R. Lai, J. Laskin, B. Lewandowski, L. Lim, L. Linda, W.-W. Lo, M. Lovell, D. Luggen, M. Madison, J. Mansuri, A. Martin, L. Mason, S. Miller, M. Mina, R. Mohammed, A. Moncrieffe, H. Moorthy, L. Morgan, E. Mosquera, A. Muntel, E. Muscal, E. Myones, B. Nocton, J. Ogbu, E. Okamura, D. Olson, J. Orrock, J. Paim-Marques, L. Pain, C. Park, C. Patel, P. Pereira, M. Prado, R.D. Radhakrishna, S. Rheault, M. Ridgway, W. Riskalla, M. Ronis, T. Sadun, R. Sagcal-Gironella, A.C. Santos, M.C. Schikler, K. AL Suwairi, W. Siddiqi, N. Silva, M.F. Singh-Grewal, D. Smitherman, E. Smolewska, E. Son, M.B. Srinivasalu, H. Sule, S. Susic, G. Syed, R. Thatayatikom, A. Ting, T. Toth, M. Turnier, J. Vashisht, P. Vega Fernandez, P. Velasquez, M. von Scheven, E. Wahezi, D. Ware, A. Wu, E. Yan, J. Yildirim-Toruner, C. Zamparo, C. Zhang, Y. Lawson, E. for the Childhood Arthritis Rheumatology Research Alliance Lupus Nephritis Work Group the Pediatric Rheumatology European Society Lupus Working Party

Abstract

Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3–5). Validation of the SSR for up to 6 months post–kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials. © 2021, American College of Rheumatology

Published
2022

3. Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis

Author

Schanberg, L.E., Ramanan, A.V., De Benedetti, F., Beukelman, T., Eakin, G.S., Del Gaizo, V., Ringold, S., Vesely, R., Schrandt, S., Jaki, T., Bili, A., Chung, J.B., De Bono, S., Douglass, W., Enejosa, J.V., Kanik, K.S., Knobe, K., Kunder, R., Leite-Schnell, J.C., Suehiro, R.M., Wong, R.L., Mieszkalski, K.L., Marrow, L.C., Siebenaler, K., Fraulo, E., Kimura, Y., Schanberg, L.E., Ramanan, A.V., De Benedetti, F., Beukelman, T., Eakin, G.S., Del Gaizo, V., Ringold, S., Vesely, R., Schrandt, S., Jaki, T., Bili, A., Chung, J.B., De Bono, S., Douglass, W., Enejosa, J.V., Kanik, K.S., Knobe, K., Kunder, R., Leite-Schnell, J.C., Suehiro, R.M., Wong, R.L., Mieszkalski, K.L., Marrow, L.C., Siebenaler, K., Fraulo, E., and Kimura, Y.

Abstract

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA‐approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1‐day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Published
2019

4. Abstract P2-06-18: Withdrawn

Author

Kunder, R, primary, Fernandez Dunne, S, additional, Clutter, M, additional, Cristofanilli, M, additional, Mendillo, M, additional, Vasilopoulos, A, additional, and Horiuchi, D, additional

Published
2019
Full Text
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5. ESRRA (estrogen-related receptor alpha)

Author

Kunder R Stein and DP McDonnell

Subjects
Cancer Research, Estrogen-related receptor alpha, chemistry.chemical_compound, Oncology, Chemistry, Genetics, Alpha (ethology), Hematology, Receptor, Molecular biology, Transcription factor, Gene, DNA
Abstract

Review on ESRRA (estrogen-related receptor alpha), with data on DNA, on the protein encoded, and where the gene is implicated.

Published
2011
Full Text
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7. MEDULLOBLASTOMA

Author

Vaidyanathan, G., primary, Gururangan, S., additional, Bigner, D., additional, Zalutsky, M., additional, Morfouace, M., additional, Shelat, A., additional, Megan, J., additional, Freeman, B. B., additional, Robinson, S., additional, Throm, S., additional, Olson, J. M., additional, Li, X.-N., additional, Guy, K. R., additional, Robinson, G., additional, Stewart, C., additional, Gajjar, A., additional, Roussel, M., additional, Sirachainan, N., additional, Pakakasama, S., additional, Anurathapan, U., additional, Hansasuta, A., additional, Dhanachai, M., additional, Khongkhatithum, C., additional, Hongeng, S., additional, Feroze, A., additional, Lee, K.-S., additional, Gholamin, S., additional, Wu, Z., additional, Lu, B., additional, Mitra, S., additional, Cheshier, S., additional, Northcott, P., additional, Lee, C., additional, Zichner, T., additional, Lichter, P., additional, Korbel, J., additional, Wechsler-Reya, R., additional, Pfister, S., additional, Project, I. P. T., additional, Li, K. K.-W., additional, Xia, T., additional, Ma, F. M. T., additional, Zhang, R., additional, Zhou, L., additional, Lau, K.-M., additional, Ng, H.-K., additional, Lafay-Cousin, L., additional, Chi, S., additional, Madden, J., additional, Smith, A., additional, Wells, E., additional, Owens, E., additional, Strother, D., additional, Foreman, N., additional, Packer, R., additional, Bouffet, E., additional, Wataya, T., additional, Peacock, J., additional, Taylor, M. D., additional, Ivanov, D., additional, Garnett, M., additional, Parker, T., additional, Alexander, C., additional, Meijer, L., additional, Grundy, R., additional, Gellert, P., additional, Ashford, M., additional, Walker, D., additional, Brent, J., additional, Cader, F. Z., additional, Ford, D., additional, Kay, A., additional, Walsh, R., additional, Solanki, G., additional, Peet, A., additional, English, M., additional, Shalaby, T., additional, Fiaschetti, G., additional, Baulande, S., additional, Gerber, N., additional, Baumgartner, M., additional, Grotzer, M., additional, Hayase, T., additional, Kawahara, Y., additional, Yagi, M., additional, Minami, T., additional, Kanai, N., additional, Yamaguchi, T., additional, Gomi, A., additional, Morimoto, A., additional, Hill, R., additional, Kuijper, S., additional, Lindsey, J., additional, Schwalbe, E., additional, Barker, K., additional, Boult, J., additional, Williamson, D., additional, Ahmad, Z., additional, Hallsworth, A., additional, Ryan, S., additional, Poon, E., additional, Ruddle, R., additional, Raynaud, F., additional, Howell, L., additional, Kwok, C., additional, Joshi, A., additional, Nicholson, S. L., additional, Crosier, S., additional, Wharton, S., additional, Robson, K., additional, Michalski, A., additional, Hargrave, D., additional, Jacques, T., additional, Pizer, B., additional, Bailey, S., additional, Swartling, F., additional, Petrie, K., additional, Weiss, W., additional, Chesler, L., additional, Clifford, S., additional, Kitanovski, L., additional, Prelog, T., additional, Kotnik, B. F., additional, Debeljak, M., additional, Grotzer, M. A., additional, Gevorgian, A., additional, Morozova, E., additional, Kazantsev, I., additional, Iukhta, T., additional, Safonova, S., additional, Kumirova, E., additional, Punanov, Y., additional, Afanasyev, B., additional, Zheludkova, O., additional, Grajkowska, W., additional, Pronicki, M., additional, Cukrowska, B., additional, Dembowska-Baginska, B., additional, Lastowska, M., additional, Murase, A., additional, Nobusawa, S., additional, Gemma, Y., additional, Yamazaki, F., additional, Masuzawa, A., additional, Uno, T., additional, Osumi, T., additional, Shioda, Y., additional, Kiyotani, C., additional, Mori, T., additional, Matsumoto, K., additional, Ogiwara, H., additional, Morota, N., additional, Hirato, J., additional, Nakazawa, A., additional, Terashima, K., additional, Fay-McClymont, T., additional, Walsh, K., additional, Mabbott, D., additional, Sturm, D., additional, Northcott, P. A., additional, Jones, D. T. W., additional, Korshunov, A., additional, Pfister, S. M., additional, Kool, M., additional, Hooper, C., additional, Hawes, S., additional, Kees, U., additional, Gottardo, N., additional, Dallas, P., additional, Siegfried, A., additional, Bertozzi, A. I., additional, Sevely, A., additional, Loukh, N., additional, Munzer, C., additional, Miquel, C., additional, Bourdeaut, F., additional, Pietsch, T., additional, Dufour, C., additional, Delisle, M. B., additional, Kawauchi, D., additional, Rehg, J., additional, Finkelstein, D., additional, Zindy, F., additional, Phoenix, T., additional, Gilbertson, R., additional, Trubicka, J., additional, Borucka-Mankiewicz, M., additional, Ciara, E., additional, Chrzanowska, K., additional, Perek-Polnik, M., additional, Abramczuk-Piekutowska, D., additional, Jurkiewicz, D., additional, Luczak, S., additional, Kowalski, P., additional, Krajewska-Walasek, M., additional, Sheila, C., additional, Lee, S., additional, Foster, C., additional, Manoranjan, B., additional, Pambit, M., additional, Berns, R., additional, Fotovati, A., additional, Venugopal, C., additional, O'Halloran, K., additional, Narendran, A., additional, Hawkins, C., additional, Ramaswamy, V., additional, Taylor, M., additional, Singhal, A., additional, Hukin, J., additional, Rassekh, R., additional, Yip, S., additional, Singh, S., additional, Duhman, C., additional, Dunn, S., additional, Chen, T., additional, Rush, S., additional, Fuji, H., additional, Ishida, Y., additional, Onoe, T., additional, Kanda, T., additional, Kase, Y., additional, Yamashita, H., additional, Murayama, S., additional, Nakasu, Y., additional, Kurimoto, T., additional, Kondo, A., additional, Sakaguchi, S., additional, Fujimura, J., additional, Saito, M., additional, Arakawa, T., additional, Arai, H., additional, Shimizu, T., additional, Jurkiewicz, E., additional, Daszkiewicz, P., additional, Drogosiewicz, M., additional, Hovestadt, V., additional, Buchhalter, I., additional, Jager, N. N., additional, Stuetz, A., additional, Johann, P., additional, Schmidt, C., additional, Ryzhova, M., additional, Landgraf, P., additional, Hasselblatt, M., additional, Schuller, U., additional, Yaspo, M.-L., additional, von Deimling, A., additional, Eils, R., additional, Modi, A., additional, Patel, M., additional, Berk, M., additional, Wang, L.-x., additional, Plautz, G., additional, Camara-Costa, H., additional, Resch, A., additional, Lalande, C., additional, Kieffer, V., additional, Poggi, G., additional, Kennedy, C., additional, Bull, K., additional, Calaminus, G., additional, Grill, J., additional, Doz, F., additional, Rutkowski, S., additional, Massimino, M., additional, Kortmann, R.-D., additional, Lannering, B., additional, Dellatolas, G., additional, Chevignard, M., additional, Solecki, D., additional, McKinnon, P., additional, Olson, J., additional, Hayden, J., additional, Ellison, D., additional, Buss, M., additional, Remke, M., additional, Lee, J., additional, Caspary, T., additional, Castellino, R., additional, Sabel, M., additional, Gustafsson, G., additional, Fleischhack, G., additional, Benesch, M., additional, Navajas, A., additional, Reddingius, R., additional, Delisle, M.-B., additional, Lafon, D., additional, Sevenet, N., additional, Pierron, G., additional, Delattre, O., additional, Ecker, J., additional, Oehme, I., additional, Mazitschek, R., additional, Lodrini, M., additional, Deubzer, H. E., additional, Kulozik, A. E., additional, Witt, O., additional, Milde, T., additional, Patmore, D., additional, Boulos, N., additional, Wright, K., additional, Boop, S., additional, Janicki, T., additional, Burzynski, S., additional, Burzynski, G., additional, Marszalek, A., additional, Triscott, J., additional, Green, M., additional, Rassekh, S. R., additional, Toyota, B., additional, Dunham, C., additional, Dunn, S. E., additional, Liu, K.-W., additional, Pei, Y., additional, Genovesi, L., additional, Ji, P., additional, Davis, M., additional, Ng, C. G., additional, Cho, Y.-J., additional, Jenkins, N., additional, Copeland, N., additional, Wainwright, B., additional, Tang, Y., additional, Schubert, S., additional, Nguyen, B., additional, Masoud, S., additional, Lee, A., additional, Willardson, M., additional, Bandopadhayay, P., additional, Bergthold, G., additional, Atwood, S., additional, Whitson, R., additional, Qi, J., additional, Beroukhim, R., additional, Tang, J., additional, Oro, A., additional, Link, B., additional, Bradner, J., additional, Vallero, S. G., additional, Bertin, D., additional, Basso, M. E., additional, Milanaccio, C., additional, Peretta, P., additional, Cama, A., additional, Mussano, A., additional, Barra, S., additional, Morana, G., additional, Morra, I., additional, Nozza, P., additional, Fagioli, F., additional, Garre, M. L., additional, Darabi, A., additional, Sanden, E., additional, Visse, E., additional, Stahl, N., additional, Siesjo, P., additional, Vaka, D., additional, Vasquez, F., additional, Weir, B., additional, Cowley, G., additional, Keller, C., additional, Hahn, W., additional, Gibbs, I. C., additional, Partap, S., additional, Yeom, K., additional, Martinez, M., additional, Vogel, H., additional, Donaldson, S. S., additional, Fisher, P., additional, Perreault, S., additional, Guerrini-Rousseau, L., additional, Pujet, S., additional, Kieffer-Renaux, V., additional, Raquin, M. A., additional, Varlet, P., additional, Longaud, A., additional, Sainte-Rose, C., additional, Valteau-Couanet, D., additional, Staal, J., additional, Lau, L. S., additional, Zhang, H., additional, Ingram, W. J., additional, Cho, Y. J., additional, Hathout, Y., additional, Brown, K., additional, Rood, B. R., additional, Handler, M., additional, Hankinson, T., additional, Kleinschmidt-Demasters, B. K., additional, Hutter, S., additional, Jones, D. T., additional, Kagawa, N., additional, Hirayama, R., additional, Kijima, N., additional, Chiba, Y., additional, Kinoshita, M., additional, Takano, K., additional, Eino, D., additional, Fukuya, S., additional, Yamamoto, F., additional, Nakanishi, K., additional, Hashimoto, N., additional, Hashii, Y., additional, Hara, J., additional, Yoshimine, T., additional, Wang, J., additional, Guo, C., additional, Yang, Q., additional, Chen, Z., additional, Filipek, I., additional, Swieszkowska, E., additional, Tarasinska, M., additional, Perek, D., additional, Kebudi, R., additional, Koc, B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Wolff, J., additional, Darendeliler, E., additional, Kerl, K., additional, Gronych, J., additional, McGlade, J., additional, Endersby, R., additional, Hii, H., additional, Johns, T., additional, Sastry, J., additional, Murphy, D., additional, Ronghe, M., additional, Cunningham, C., additional, Cowie, F., additional, Jones, R., additional, Calisto, A., additional, Sangra, M., additional, Mathieson, C., additional, Brown, J., additional, Phuakpet, K., additional, Larouche, V., additional, Bartels, U., additional, Ishida, T., additional, Hasegawa, D., additional, Miyata, K., additional, Ochi, S., additional, Saito, A., additional, Kozaki, A., additional, Yanai, T., additional, Kawasaki, K., additional, Yamamoto, K., additional, Kawamura, A., additional, Nagashima, T., additional, Akasaka, Y., additional, Soejima, T., additional, Yoshida, M., additional, Kosaka, Y., additional, von Bueren, A., additional, Goschzik, T., additional, Kortmann, R., additional, von Hoff, K., additional, Friedrich, C., additional, Muehlen, A. z., additional, Warmuth-Metz, M., additional, Soerensen, N., additional, Deinlein, F., additional, Zwiener, I., additional, Faldum, A., additional, Kuehl, J., additional, KRAMER, K., additional, -Taskar, N. P., additional, Zanzonico, P., additional, Humm, J. L., additional, Wolden, S. L., additional, Cheung, N.-K. V., additional, Venkataraman, S., additional, Alimova, I., additional, Harris, P., additional, Birks, D., additional, Balakrishnan, I., additional, Griesinger, A., additional, Foreman, N. K., additional, Vibhakar, R., additional, Margol, A., additional, Robison, N., additional, Gnanachandran, J., additional, Hung, L., additional, Kennedy, R., additional, Vali, M., additional, Dhall, G., additional, Finlay, J., additional, Erdrich-Epstein, A., additional, Krieger, M., additional, Drissi, R., additional, Fouladi, M., additional, Gilles, F., additional, Judkins, A., additional, Sposto, R., additional, Asgharzadeh, S., additional, Peyrl, A., additional, Chocholous, M., additional, Holm, S., additional, Grillner, P., additional, Blomgren, K., additional, Azizi, A., additional, Czech, T., additional, Gustafsson, B., additional, Dieckmann, K., additional, Leiss, U., additional, Slavc, I., additional, Babelyan, S., additional, Dolgopolov, I., additional, Pimenov, R., additional, Mentkevich, G., additional, Gorelishev, S., additional, Laskov, M., additional, von Bueren, A. O., additional, Nowak, J., additional, Kortmann, R. D., additional, Mynarek, M., additional, Muller, K., additional, Gerber, N. U., additional, Ottensmeier, H., additional, Kwiecien, R., additional, Yankelevich, M., additional, Boyarshinov, V., additional, Glekov, I., additional, Ozerov, S., additional, Gorelyshev, S., additional, Popa, A., additional, Subbotina, N., additional, Martin, A. M., additional, Nirschl, C., additional, Polanczyk, M., additional, Bell, R., additional, Martinez, D., additional, Sullivan, L. M., additional, Santi, M., additional, Burger, P. C., additional, Taube, J. M., additional, Drake, C. G., additional, Pardoll, D. M., additional, Lim, M., additional, Li, L., additional, Wang, W.-G., additional, Pu, J.-X., additional, Sun, H.-D., additional, Ruggieri, R., additional, Symons, M. H., additional, Vanan, M. I., additional, Bolin, S., additional, Schumacher, S., additional, Zeid, R., additional, Yu, F., additional, Vue, N., additional, Gibson, W., additional, Paolella, B., additional, Swartling, F. J., additional, Kieran, M. W., additional, Bradner, J. E., additional, Maher, O., additional, Khatua, S., additional, Tarek, N., additional, Zaky, W., additional, Gupta, T., additional, Mohanty, S., additional, Kannan, S., additional, Jalali, R., additional, Kapitza, E., additional, Denkhaus, D., additional, Muhlen, A. z., additional, van Vuurden, D. G., additional, Garami, M., additional, Fangusaro, J., additional, Davidson, T. B., additional, da Costa, M. J. G., additional, Sterba, J., additional, Clifford, S. C., additional, Finlay, J. L., additional, Schmidt, R., additional, Felsberg, J., additional, Skladny, H., additional, Cremer, F., additional, Reifenberger, G., additional, Kunder, R., additional, Sridhar, E., additional, Moiyadi, A. A., additional, Goel, A., additional, Goel, N., additional, Shirsat, N., additional, Othman, R., additional, Storer, L., additional, Kerr, I., additional, Coyle, B., additional, Law, N., additional, Smith, M. L., additional, Greenberg, M., additional, Laughlin, S., additional, Malkin, D., additional, Liu, F., additional, Moxon-Emre, I., additional, Scantlebury, N., additional, Nasir, A., additional, Onion, D., additional, Lourdusamy, A., additional, Grabowska, A., additional, Cai, Y., additional, Bradshaw, T., additional, de Medeiros, R. S. S., additional, Beaugrand, A., additional, Soares, S., additional, Epelman, S., additional, Wang, W., additional, Sultan, M., additional, Wechsler-Reya, R. J., additional, Zapatka, M., additional, Radlwimmer, B., additional, Alderete, D., additional, Baroni, L., additional, Lubinieki, F., additional, Auad, F., additional, Gonzalez, M. L., additional, Puya, W., additional, Pacheco, P., additional, Aurtenetxe, O., additional, Gaffar, A., additional, Gros, L., additional, Cruz, O., additional, Calvo, C., additional, Shinojima, N., additional, Nakamura, H., additional, Kuratsu, J.-i., additional, Hanaford, A., additional, Eberhart, C., additional, Archer, T., additional, Tamayo, P., additional, Pomeroy, S., additional, Raabe, E., additional, De Braganca, K., additional, Gilheeney, S., additional, Khakoo, Y., additional, Kramer, K., additional, Wolden, S., additional, Dunkel, I., additional, Lulla, R. R., additional, Laskowski, J., additional, Goldman, S., additional, Gopalakrishnan, V., additional, Shih, D., additional, Wang, X., additional, Faria, C., additional, Raybaud, C., additional, Tabori, U., additional, Rutka, J., additional, Jacobs, S., additional, De Vathaire, F., additional, Diallo, I., additional, Llanas, D., additional, Verez, C., additional, Diop, F., additional, Kahlouche, A., additional, Puget, S., additional, Thompson, E., additional, Prince, E., additional, Amani, V., additional, Sin-Chan, P., additional, Lu, M., additional, Kleinman, C., additional, Spence, T., additional, Picard, D., additional, Ho, K. C., additional, Chan, J., additional, Majewski, J., additional, Jabado, N., additional, Dirks, P., additional, Huang, A., additional, Madden, J. R., additional, Donson, A. M., additional, Mirsky, D. M., additional, Dubuc, A., additional, Mack, S., additional, Gendoo, D., additional, Luu, B., additional, MacDonald, T., additional, Van Meter, T., additional, Croul, S., additional, Laureano, A., additional, Brugmann, W., additional, Denman, C., additional, Singh, H., additional, Huls, H., additional, Moyes, J., additional, Sandberg, D., additional, Silla, L., additional, Cooper, L., additional, and Lee, D., additional

Published
2014
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8. EPIDEMIOLOGY

Author

Khatua, S., primary, Brown, R., additional, Pearlman, M., additional, Vats, T., additional, Satge, D., additional, Stiller, C., additional, Rutkowski, S., additional, von Bueren, A. O., additional, Lacour, B., additional, Sommelet, D., additional, Nishi, M., additional, Massimino, M., additional, Garre, M.-L., additional, Moreno, F., additional, Hasle, H., additional, Jakab, Z., additional, Greenberg, M., additional, von der Weid, N., additional, Kuehni, C., additional, Zurriaga, O., additional, Vicente, M.-L., additional, Peris-Bonet, R., additional, Benesch, M., additional, Vekemans, M., additional, Sullivan, S., additional, Rickert, C., additional, Fisher, P. G., additional, Von Behren, J., additional, Nelson, D. O., additional, Reynolds, P., additional, Fukuoka, K., additional, Yanagisawa, T., additional, Suzuki, T., additional, Koga, T., additional, Wakiya, K., additional, Adachi, J.-i., additional, Mishima, K., additional, Fujimaki, T., additional, Matsutani, M., additional, Nishikawa, R., additional, Gidding, C., additional, Schieving, J., additional, Wesseling, P., additional, Ligtenberg, M., additional, Hoogerbrugge, N., additional, Jongmans, M., additional, Crosier, S., additional, Nicholson, S. L., additional, Robson, K., additional, Jacques, T., additional, Wharton, S., additional, Bown, N., additional, Michalski, A., additional, Pizer, B., additional, Clifford, S., additional, Sanden, E., additional, Visse, E., additional, Siesjo, P., additional, Darabi, A., additional, Nousome, D., additional, Lupo, P. J., additional, Scheurer, M. E., additional, Nulman, I., additional, Barrera, M., additional, Maxwell, C., additional, Koren, G., additional, Gorelyshev, S., additional, Matuev, K., additional, Lubnin, A., additional, Laskov, M., additional, Lemeneva, N., additional, Mazerkina, N., additional, Khuhlaeva, E., additional, Muller, K., additional, Bruns, F., additional, Pietsch, T., additional, Kortmann, R.-D., additional, Krishnatry, R., additional, Shirsat, N., additional, Kunder, R., additional, Epari, S., additional, Gupta, T., additional, Kurkure, P., additional, Vora, T., additional, Arora, B., additional, Moiyadi, A., additional, Jalali, R., additional, Swieszkowska, E., additional, Dembowska-Baginska, B., additional, Drogosiewicz, M., additional, Filipek, I., additional, Perek-Polnik, M., additional, Grajkowska, W., additional, Perek, D., additional, Johnston, D., additional, Cyr, J., additional, Strother, D., additional, Lafay-Cousin, L., additional, Fryer, C., additional, Scheinemann, K., additional, Carret, A.-S., additional, Fleming, A., additional, Larouche, V., additional, Bouffet, E., additional, Friedrich, C., additional, Gnekow, A. K., additional, Fleischhack, G., additional, Kramm, C. M., additional, Fruehwald, M. C., additional, Muller, H. L., additional, Calaminus, G., additional, Kordes, U., additional, Faldum, A., additional, Warmuth-Metz, M., additional, Kortmann, R. D., additional, Jung, I., additional, Kaatsch, P., additional, Caretti, V., additional, Bugiani, M., additional, Boor, I., additional, Schellen, P., additional, Vandertop, W. P., additional, Noske, D. P., additional, Kaspers, G., additional, Wurdinger, T., additional, Robinson, G., additional, Chingtagumpala, M., additional, Adesina, A., additional, Dalton, J., additional, Santi, M., additional, Sievert, A., additional, Wright, K., additional, Armstrong, G., additional, Boue, D., additional, Olshefski, R., additional, Scott, S., additional, Huang, A., additional, Cohn, R., additional, Gururangan, S., additional, Bowers, D., additional, Gilbertson, R., additional, Gajjar, A., additional, Ellison, D., additional, Chick, E., additional, Donson, A., additional, Owens, E., additional, Smith, A. A., additional, Madden, J. R., additional, Foreman, N. K., additional, Bakry, D., additional, Aronson, M., additional, Durno, C., additional, Hala, R., additional, Farah, R., additional, Amayiri, N., additional, Alharbi, Q., additional, Shamvil, A., additional, Ben-Shachar, S., additional, Constantini, S., additional, Rina, D., additional, Ellise, J., additional, Keiles, S., additional, Pollet, A., additional, Qaddoumi, I., additional, Gallinger, S., additional, Malkin, D., additional, Hawkins, C., additional, Tabori, U., additional, Trivedi, M., additional, Goodden, J., additional, Chumas, P., additional, Tyagi, A., additional, O'kane, R., additional, O'Kane, R., additional, Crimmins, D., additional, Picton, S., additional, and Elliott, M., additional

Published
2012
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9. Cutting-edge approaches to B-cell depletion in autoimmune diseases.

Author

Robinson WH, Fiorentino D, Chung L, Moreland LW, Deodhar M, Harler MB, Saulsbery C, and Kunder R

Subjects
Humans, Animals, T-Lymphocytes immunology, Antibodies, Bispecific therapeutic use, Antibodies, Bispecific immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal immunology, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Autoimmune Diseases immunology, Autoimmune Diseases therapy, B-Lymphocytes immunology, Lymphocyte Depletion methods, Immunotherapy, Adoptive methods
Abstract

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases., Competing Interests: WR has received consulting fees from IGM Biosciences. DF has received consulting fees from IGM Biosciences, Kyverna Therapeutics, Argenx, Priovant Therapeutics, Pfizer, Biogen, Bristol Meyers Squibb, and Serono. LC has received consulting fees from IGM Biosciences, Kyverna Therapeutics, Mitsubishi Tanabe, Lilly, Janssen, Mediar Therapeutics, and Genentech. LM serves as a member of independent data safety monitoring boards for Boehringer Ingelheim and Celltrion. MD, MH, CS, and RK are employees of IGM Biosciences., (Copyright © 2024 Robinson, Fiorentino, Chung, Moreland, Deodhar, Harler, Saulsbery and Kunder.)

Published
2024
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10. A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers.

Author

Han LW, Jamalian S, Hsu JC, Sheng XR, Yang X, Yang X, Monemi S, Hassan S, Yadav R, Tuckwell K, Kunder R, Pan L, and Glickstein S

Abstract

Introduction: Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs)., Methods: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations., Results: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C max ) and area under the concentration-time curve from time 0 to infinity (AUC 0-inf ) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition., Conclusion: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy., Trial Registration: ISRCTN13175485., (© 2024. The Author(s).)

Published
2024
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11. Simulation-based evaluation of personalized dosing approaches for anti-FGFR/KLB bispecific antibody fazpilodemab.

Author

Yoshida K, Poon V, Dash A, Kunder R, Chinn L, and Kågedal M

Subjects
Humans, Klotho Proteins
Abstract

Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows., (© 2024 Genentech, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2024
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12. First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Author

Tang F, Kunder R, Chu T, Hains A, Nguyen A, McBride JM, Zhong Y, Santagostino S, Wilson M, Trenchak A, Chen L, Ly J, Moein A, Lewin-Koh N, Raghavan V, Osaghae U, Wynne C, Owen R, and Place D

Subjects
Humans, Healthy Volunteers, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Double-Blind Method, Administration, Oral, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein
Abstract

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1β and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development., (© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2023
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13. Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer.

Author

Kunder R, Velyunskiy M, Dunne SF, Cho BK, Kanojia D, Begg L, Orriols AM, Fleming-Trujillo E, Vadlamani P, Vialichka A, Bolin R, Perrino JN, Roth D, Clutter MR, Zielinski-Mozny NA, Goo YA, Cristofanilli M, Mendillo ML, Vassilopoulos A, and Horiuchi D

Subjects
Cell Line, Tumor, Cell Proliferation, Humans, Proteasome Endopeptidase Complex metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-pim-1, Triple Negative Breast Neoplasms metabolism
Abstract

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Published
2022
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14. Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

Author

Schanberg LE, Ramanan AV, De Benedetti F, Beukelman T, Eakin GS, Del Gaizo V, Ringold S, Vesely R, Schrandt S, Jaki T, Bili A, Chung JB, De Bono S, Douglass W, Enejosa JV, Kanik KS, Knobe K, Kunder R, Leite-Schnell JC, Suehiro RM, Wong RL, Mieszkalski KL, Marrow LC, Siebenaler K, Fraulo E, and Kimura Y

Subjects
Adolescent, Child, Congresses as Topic, Humans, Stakeholder Participation, Antirheumatic Agents therapeutic use, Arthritis, Juvenile drug therapy, Drug Development organization & administration
Abstract

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans., (© 2019, American College of Rheumatology.)

Published
2019
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15. Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas.

Author

Bharambe HS, Paul R, Panwalkar P, Jalali R, Sridhar E, Gupta T, Moiyadi A, Shetty P, Kazi S, Deogharkar A, Masurkar S, Yogi K, Kunder R, Gadewal N, Goel A, Goel N, Chinnaswamy G, Ramaswamy V, and Shirsat NV

Subjects
Animals, Carcinogenesis genetics, Carcinogenesis metabolism, Cell Line, Tumor, Cerebellar Neoplasms genetics, Cerebellar Neoplasms mortality, Cohort Studies, HEK293 Cells, Humans, Medulloblastoma genetics, Medulloblastoma mortality, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs genetics, Neoplasm Grading methods, Survival Rate trends, Xenograft Model Antitumor Assays methods, Cerebellar Neoplasms metabolism, Down-Regulation physiology, Gene Expression Regulation, Neoplastic, Medulloblastoma metabolism, MicroRNAs biosynthesis
Abstract

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Low expression of miR-204 in the Group 3 / Group 4 tumors identify a highly aggressive subset of tumors having poor overall survival, in the two independent cohorts of medulloblastomas. Downregulation of miR-204 expression correlates with poor survival within the Group 4 as well indicating it as a valuable risk-stratification marker in the subgroup. Restoration of miR-204 expression in multiple medulloblastoma cell lines was found to inhibit their anchorage-independent growth, invasion potential and tumorigenicity. IGF2R was identified as a novel target of miR-204. MiR-204 expression resulted in downregulation of both M6PR and IGF2R that transport lysosomal proteases from the Golgi apparatus to the lysosomes. Consistent with this finding, miR-204 expression resulted in reduction in the levels of the lysosomal proteases in medulloblastoma cells. MiR-204 expression also resulted in inhibition of autophagy that is known to be dependent on the lysosomal degradation pathway and LC3B, a known miR-204 target. Treatment with HDAC inhibitors resulted in upregulation of miR-204 expression in medulloblastoma cells, suggesting therapeutic role for these inhibitors in the treatment of medulloblastomas. In summary, miR-204 is not only a valuable risk stratification marker in the combined cohort of Group 3 / Group 4 medulloblastomas as well as in the Group 4 itself, that has paucity of good prognostication markers, but also has therapeutic potential as indicated by its tumor suppressive effect on medulloblastoma cells.

Published
2019
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16. T cell co-stimulatory factors.

Author

Greisen S, Kunder R, and Deleuran B

Subjects
Humans, Autoimmune Diseases immunology, Costimulatory and Inhibitory T-Cell Receptors immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology, TCF Transcription Factors immunology
Published
2017
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17. PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.

Author

Horiuchi D, Camarda R, Zhou AY, Yau C, Momcilovic O, Balakrishnan S, Corella AN, Eyob H, Kessenbrock K, Lawson DA, Marsh LA, Anderton BN, Rohrberg J, Kunder R, Bazarov AV, Yaswen P, McManus MT, Rugo HS, Werb Z, and Goga A

Subjects
Animals, Blotting, Western, Cell Line, Tumor, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Female, Humans, In Situ Nick-End Labeling, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental genetics, Mice, Transgenic, Microscopy, Fluorescence, Prognosis, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-pim-1 metabolism, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Triple Negative Breast Neoplasms drug therapy, Xenograft Model Antitumor Assays, Carcinoma, Ductal, Breast metabolism, Mammary Neoplasms, Experimental metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Triple Negative Breast Neoplasms metabolism
Abstract

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

Published
2016
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18. Real-time PCR assay based on the differential expression of microRNAs and protein-coding genes for molecular classification of formalin-fixed paraffin embedded medulloblastomas.

Author

Kunder R, Jalali R, Sridhar E, Moiyadi A, Goel N, Goel A, Gupta T, Krishnatry R, Kannan S, Kurkure P, Deopujari C, Shetty P, Biyani N, Korshunov A, Pfister SM, Northcott PA, and Shirsat NV

Subjects
Adolescent, Adult, Case-Control Studies, Cerebellar Neoplasms genetics, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellum metabolism, Cerebellum pathology, Child, Child, Preschool, Female, Follow-Up Studies, Gene Expression Profiling, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Infant, Male, Medulloblastoma genetics, Medulloblastoma mortality, Medulloblastoma pathology, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Paraffin Embedding, Prognosis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Wnt Proteins genetics, Wnt Proteins metabolism, Young Adult, Cerebellar Neoplasms classification, Medulloblastoma classification, MicroRNAs genetics, Real-Time Polymerase Chain Reaction methods
Abstract

Background: Medulloblastoma has recently been found to consist of 4 molecularly and clinically distinct subgroups: WNT, Sonce hedgehog (SHH), Group 3, and Group 4. Deregulated microRNA expression is known to contribute to pathogenesis and has been shown to have diagnostic and prognostic potential in the classification of various cancers., Methods: Molecular subgrouping and microRNA expression analysis of 44 frozen and 59 formalin-fixed paraffin embedded medulloblastomas from an Indian cohort were carried out by real-time RT-PCR assay., Results: The differential expression of 9 microRNAs in the 4 molecular subgroups was validated in a set of 101 medulloblastomas. The tumors in the WNT subgroup showed significant (P < .0001) overexpression of miR-193a-3p, miR-224, miR-148a, miR-23b, and miR-365. Reliable classification of medulloblastomas into the 4 molecular subgroups was obtained using a set of 12 protein-coding genes and 9 microRNAs as markers in a real-time RT-PCR assay with an accuracy of 97% as judged by the Prediction Analysis of Microarrays. Age at diagnosis, histology, gender-related incidence, and the relative survival rates of the 4 molecular subgroups in the present Indian cohort were found to be similar to those reported for medulloblastomas from the American and European subcontinent. Non-WNT, non-SHH medulloblastomas underexpressing miR-592 or overexpressing miR-182 were found to have significantly inferior survival rates, indicating utility of these miRNAs as markers for risk stratification., Conclusions: The microRNA based real-time PCR assay is rapid, simple, inexpensive, and useful for molecular classification and risk stratification of medulloblastomas, in particular formalin-fixed paraffin embedded tissues, wherein the expression profile of protein-coding genes is often less reliable due to RNA fragmentation.

Published
2013
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19. Optimizing the management of neuromyelitis optica and spectrum disorders in resource poor settings: Experience from the Mangalore demyelinating disease registry.

Author

Pandit L, Mustafa S, Kunder R, Shetty R, Misri Z, Pai S, and Shetty R

Abstract

Background: In resource-poor settings, the management of neuromyelitis optica (NMO) and NMO spectrum (NMOS) disorders is limited because of delayed diagnosis and financial constraints., Aim: To device a cost-effective strategy for the management of NMO and related disorders in India., Materials and Methods: A cost-effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients., Results: Forty-five patients (65%) had a relapse from the onset and included NMO (n = 20), recurrent transverse myelitis (RTM; n = 10), and recurrent optic neuritis (ROPN; n = 15). In 38 (84.4%) patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5), NMO (n = 1), and RTM (n = 1). They had a second attack after a median interval of 1 ± 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM), of which 20 (80%) remained ambulant at follow-up of 3 ± 1.9 years. Twelve patients (17%) with median expanded disability status scale (EDSS) of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%). Irrespective of the NMO-IgG status, the treatment compliant patients (44.4%) showed significant improvement in EDSS (P ≤ 0.001)., Conclusions: Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set-up. NMO and NMOS disorders contributed to 14.9% (45/303) of all demyelinating disorders in our registry.

Published
2013
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20. Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology.

Author

Kunder R, Kunder C, Sun HY, Berry G, Messner A, Frankovich J, Roth S, and Mark J

Abstract

Plastic bronchitis (PB) is a pathologic condition in which airway casts develop in the tracheobronchial tree causing airway obstruction. There is no standard treatment strategy for this uncommon condition. We report an index patient treated using an emerging multimodal strategy of directly instilled and inhaled tissue plasminogen activator (t-PA) as well as 13 other cases of PB at our institution between 2000 and 2012. The majority of cases (n = 8) occurred in patients with congenital heart disease. Clinical presentations, treatments used, histopathology of the casts, and patient outcomes are reviewed. Further discussion is focused on the epidemiology of plastic bronchitis and a systematic approach to the histologic classification of casts. Comorbid conditions identified in this study included congenital heart disease (8), pneumonia (3), and asthma (2). Our institutional prevalence rate was 6.8 per 100,000 patients, and our case fatality rate was 7%.

Published
2013
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21. The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.

Author

Chang CY, Kazmin D, Jasper JS, Kunder R, Zuercher WJ, and McDonnell DP

Subjects
Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Carrier Proteins genetics, Cell Proliferation drug effects, Female, Humans, Nitriles pharmacology, RNA-Binding Proteins, Receptors, Estrogen antagonists & inhibitors, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, Signal Transduction, Thiazoles pharmacology, ERRalpha Estrogen-Related Receptor, Breast Neoplasms metabolism, Receptor, ErbB-2 metabolism, Receptor, IGF Type 1 metabolism, Receptors, Estrogen physiology
Abstract

A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated receptor activity. Importantly, this signature also predicted the ability of an ERRα antagonist, XCT790, to inhibit proliferation in cellular models of breast cancer. Using a chemical genomic approach, it was determined that activation of the Her2/IGF-1R signaling pathways and subsequent C-MYC stabilization upregulate the expression of peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1β), an obligate cofactor for ERRα activity. PGC-1β knockdown in breast cancer cells impaired ERRα signaling and reduced cell proliferation, implicating a functional role for PGC-1β/ERRα in the pathogenesis of breast cancers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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22. Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway.

Author

Gokhale A, Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A, Mamidipally C, Noronha S, Kannan S, and Shirsat NV

Subjects
Gene Expression Profiling, Humans, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Brain Neoplasms genetics, Medulloblastoma genetics, MicroRNAs genetics, Signal Transduction, Wnt Proteins metabolism
Abstract

Aim: Medulloblastoma is a malignant brain tumor that occurs predominantly in children. Current risk stratification based on clinical parameters is inadequate for accurate prognostication. MicroRNA expression is known to be deregulated in various cancers and has been found to be useful in predicting tumor behavior. In order to get a better understanding of medulloblastoma biology, miRNA profiling of medulloblastomas was carried out in parallel with expression profiling of protein-coding genes., Materials and Methods: miRNA profiling of medulloblastomas was carried out using Taqman Low Density Array v 1.0 having 365 human microRNAs. In parallel, genome-wide expression profiling of protein-coding genes was carried out using Affymetrix gene 1.0 ST arrays., Results: Both the profiling studies identified four molecular subtypes of medulloblastomas. Expression levels of select protein-coding genes and miRNAs could classify an independent set of medulloblastomas. Twelve of 31 medulloblastomas were found to overexpress genes belonging to the canonical WNT signaling pathway and carry a mutation in CTNNB1 gene. A number of miRNAs like miR-193a, miR-224/miR-452 cluster, miR-182/miR-183/miR-96 cluster, and miR-148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas. Exogenous expression of miR-193a and miR-224, two miRNAs that have the highest WNT pathway specific upregulation, was found to inhibit proliferation, increase radiation sensitivity and reduce anchorage-independent growth of medulloblastoma cells., Conclusion: Expression level of tumor/metastasis suppressive miRNAs in the WNT signaling associated medulloblastomas is likely to determine their response to treatment, and thus, these miRNAs would be important biomarkers for risk stratification within the WNT signaling associated medulloblastomas.

Published
2010
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