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2. Utilizing PK and PD Biomarkers to Guide the First-in-Human Starting Dose Selection of MTBT1466A: A Novel Humanized Monoclonal Anti-TGFβ3 Antibody for the Treatment of Fibrotic Diseases

Author

Yadav, Rajbharan, Sukumaran, Siddharth, Lutman, Jeff, Mitra, Mayur S., Halpern, Wendy, Sun, Tianhe, Setiadi, A. Francesca, Neighbors, Margaret, Sheng, X. Rebecca, Yip, Victor, Shen, Ben-Quan, Liu, Chang, Han, Lyrialle, Ovacik, Ayse Meric, Wu, Yan, Glickstein, Sara, Kunder, Rebecca, Arron, Joseph R., Pan, Lin, Kamath, Amrita V., and Stefanich, Eric G.

Published
2023
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3. Simulation‐based evaluation of personalized dosing approaches for anti‐FGFR/KLB bispecific antibody fazpilodemab.

Author

Yoshida, Kenta, Poon, Victor, Dash, Ajit, Kunder, Rebecca, Chinn, Leslie, and Kågedal, Matts

Subjects
NON-alcoholic fatty liver disease, BISPECIFIC antibodies, MARKOV processes, DYNAMIC simulation, DRUG development, CLINICAL trials
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. [ABSTRACT FROM AUTHOR]

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

Author

Tang, Fei, primary, Kunder, Rebecca, additional, Chu, Tom, additional, Hains, Avis, additional, Nguyen, Allen, additional, McBride, Jacqueline M., additional, Zhong, Yu, additional, Santagostino, Sara, additional, Wilson, Maria, additional, Trenchak, Abigail, additional, Chen, Liuxi, additional, Ly, Justin, additional, Moein, Anita, additional, Lewin‐Koh, Nicholas, additional, Raghavan, Vibha, additional, Osaghae, Uyi, additional, Wynne, Chris, additional, Owen, Ryan, additional, and Place, David, additional

Published
2023
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5. Collagen Vascular Diseases

Author

McCaffrey, Lauren B., Brandling-Bennett, Heather A., Khorsand, Kate O., Mombourguette, Joy Lynn, Kunder, Rebecca S., Sun, Grace S., Washington, Nina T., Ahmad, Regina-Celeste, Yang, Shelley, Liu, Fan, Fogel, Alexander, Teng, Joyce M. C., Teng, Joyce M.C., editor, Marqueling, Ann L., editor, and Benjamin, Latanya T., editor

Published
2017
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11. Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation

Author

Chen, Hubert, primary, Kunder, Rebecca, additional, Zou, Yixuan, additional, Staton, Tracy, additional, Zhu, Rui, additional, Galanter, Joshua, additional, Gugelmann, Hallam, additional, Owen, Ryan, additional, Grimbaldeston, Michele A., additional, Chang, Joanna K., additional, Durk, Matthew R., additional, Eliahu, Avi, additional, Wilson, Mark S., additional, Choy, David F., additional, Wilson, Maria, additional, Black, Melissa, additional, Doppen, Marjan, additional, Kung, Stacey, additional, Oldfield, Karen, additional, Sparks, Jenny, additional, Beasley, Richard, additional, and Braithwaite, Irene, additional

Published
2022
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12. Collagen Vascular Diseases

Author

McCaffrey, Lauren B., primary, Brandling-Bennett, Heather A., additional, Khorsand, Kate O., additional, Mombourguette, Joy Lynn, additional, Kunder, Rebecca S., additional, Sun, Grace S., additional, Washington, Nina T., additional, Ahmad, Regina-Celeste, additional, Yang, Shelley, additional, Liu, Fan, additional, Fogel, Alexander, additional, and Teng, Joyce M. C., additional

Published
2016
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14. Inhaled JAK inhibitor GDC-4379 reduces FeNO in patients with mild asthma

Author

Chen, Hubert, primary, Kunder, Rebecca, additional, Zou, Yixuan, additional, Gugelmann, Hallam, additional, Galanter, Joshua, additional, Zhu, Rui, additional, Owen, Ryan, additional, Staton, Tracy, additional, Wright, Matthew, additional, Durk, Matthew, additional, Eliahu, Avi, additional, Wilson, Maria, additional, Beasley, Richard, additional, and Braithwaite, Irene, additional

Published
2021
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15. International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

Author

Chalhoub, Nathalie E., Wenderfer, Scott E., Levy, Deborah M., Rouster-Stevens, Kelly, Aggarwal, Amita, Savani, Sonia I., Ruth, Natasha M., Arkachaisri, Thaschawee, Qiu, Tingting, Merritt, Angela, Onel, Karen, Goilav, Beatrice, Khubchandani, Raju P., Deng, Jianghong, Fonseca, Adriana R., Ardoin, Stacy P., Ciurtin, Coziana, Kasapcopur, Ozgur, Jelusic, Marija, Huber, Adam M., Ozen, Seza, Klein-Gitelman, Marisa S., Appenzeller, Simone, Cavalcanti, André, Fotis, Lampros, Lim, Sern Chin, Silva, Rodrigo M., Miramontes, Julia Ramírez, Rosenwasser, Natalie L., Saad-Magalhaes, Claudia [UNESP], Schonenberg-Meinema, Dieneke, Scott, Christiaan, Silva, Clovis A., Enciso, Sandra, Terreri, Maria T., Torres-Jimenez, Alfonso-Ragnar, Trachana, Maria, Al-Mayouf, Sulaiman M., Devarajan, Prasad, Huang, Bin, Brunner, Hermine I., Abulaban, Khalid, Aguiar, Cassyanne, Ahn, Sun-Young, Akoghlanian, Shoghik, Al-Abrawi, Safiya, Aljaberi, Najla, Alperin, Risa, Angeles-Han, Sheila, Ardalan, Kaveh, Bader-Meunier, Brigitte, Balboni, Imelda, Barbar-Smiley, Fatima, Baxter, Sarah, Beary, John, Boneparth, Alexis, Brakeman, Paul, Bridges, John, Burgos-Vargas, Ruben, Cabral, David A., Cameto, Juan, Carter, Caitlin, Chang, Joyce, Chédeville, Gaëlle, Chhakchhuak, Christine, Chiraseveenuprapund, Peter, Cifuentes Alvarado, Mayra, Concannon, Anthony, Cooper, Jennifer, Cron, Randy, De Carvalho, Luciana Martins, De Quattro, Kimberly, De Ranieri, Deirdre, Dizon, Brian, Donnelly Wrigley, Catherine, Duong, Minh Dien, Eberhard, Anne, Ede, Kaleo, Edelheit, Barbara, Edens, Cuoghi, Espada, Graciela, Farhey, Yolanda, Flores, Francisco, Fritz, Deborah, Ganguli, Suhas, Gilbert, Mileka, Gittar, Patsy, Greenbaum, Larry, Grom, Alexei, Gulati, Gaurav, Harry, Onengiya, Hayward, Kristen, Henrickson, Michael, Hersh, Aimee, Hiraki, Linda, Hiskey, Megan, Hoffmann, Sarah, Hollander, Matthew, Hom, Christine, Houk, Lawrence, Houk, J. Brian, Hsieh, Elena W.Y., Hsu, Joyce, Jensen, Paul, Joos, Rik, Jurado, Rosario, Jusan Fiorot, Fernanda, Kallash, Mahmoud, Kamphuis, Sylvia, Keltsev, Vladimir, Khanna, Surabhi, Kim, Susan, Kimseng, Karen Joy, Knight, Andrea, Kunder, Rebecca, Lai, Jamie, Laskin, Benjamin, Lewandowski, Laura, Lim, Lily, Linda, Wagner-Weiner, Lo, Mindy, Lovell, Daniel, Luggen, Michael, Madison, Jacqueline, Mansuri, Asif, Martin, Lorena, Mason, Sherene, Miller, Michael, Mina, Rina, Mohammed, Abdul, Moncrieffe, Halima, Moorthy, Lakshmi, Morgan, Esi, Mosquera, Angela, Muntel, Emily, Muscal, Eyal, Myones, Barry, Nocton, James, Ogbu, Ekemini, Okamura, Daryl, Olson, Judyann, Orrock, Janet, Paim-Marques, Luciana, Pain, Clare, Park, Catherine, Patel, Pooja, Pereira, Maria, Prado, Rogerio do, Radhakrishna, Suhas, Rheault, Michelle, Ridgway, William, Riskalla, Mona, Ronis, Tova, Sadun, Rebecca, Sagcal-Gironella, Anna Carmela, Santos, Maria carolina, Schikler, Kenneth, AL Suwairi, Wafaa, Siddiqi, Nabeela, Silva, Marco Felipe, Singh-Grewal, Davinder, Smitherman, Emily, Smolewska, Elzbieta, Son, Mary Beth, Srinivasalu, Hemalatha, Sule, Sangeeta, Susic, Gordana, Syed, Reema, Thatayatikom, Akaluck, Ting, Tracy, Toth, Mary, Turnier, Jessica, Vashisht, Priyanka, Vega Fernandez, Patricia, Velasquez, Monica, von Scheven, Emily, Wahezi, Dawn, Ware, Avis, Wu, Eveline, Yan, Jacqueline, Yildirim-Toruner, Cagri, Zamparo, Celso, Zhang, Yujuan, Lawson, Erica, Graduate School, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, University of Cincinnati College of Medicine, Baylor College of Medicine, The Hospital for Sick Children and The University of Toronto, Emory University and Children's Healthcare of Atlanta, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Medical University of South Carolina, KK Women's and Children's Hospital, Cincinnati Children's Hospital Medical Center, Hospital for Special Surgery, Albert Einstein College of Medicine, SRCC Children's Hospital, Capital Medical University and National Center for Children's Health, Universidade Federal do Rio de Janeiro (UFRJ), Nationwide Children's Hospital, University College London, Istanbul University-Cerrahpasa, University of Zagreb School of Medicine, IWK Health Centre and Dalhousie University, Hacettepe University, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Universidade Estadual de Campinas (UNICAMP), Universidade Federal de Pernambuco (UFPE), National and Kapodistian University of Athens, University Teknologi MARA, Instituto Mexicano del Seguro Social, University of Washington and Seattle Children's Hospital, Universidade Estadual Paulista (UNESP), Amsterdam University Medical Center, Red Cross War Memorial Children's Hospital and University of Cape Town, Universidade de São Paulo (USP), Hospital de la Beneficencia Española, Universidade Federal de São Paulo (UNIFESP), National Medical Center La Raza, Aristotle University of Thessaloniki, King Faisal Specialist Hospital and Research Center and Alfaisal University, and University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center

Subjects
Male, medicine.medical_specialty, Adolescent, medicine.drug_class, Immunology, Lupus nephritis, Renal function, Article, Rheumatology, childhood-onset systemic lupus erythematosus, corticosteroids, lupus nephritis, treatment, Internal medicine, Biopsy, Immunology and Allergy, Medicine, Humans, Lupus Erythematosus, Systemic, Dosing, Age of Onset, Child, Glucocorticoids, Retrospective Studies, Kidney, Proteinuria, medicine.diagnostic_test, business.industry, food and beverages, medicine.disease, Lupus Nephritis, Clinical trial, medicine.anatomical_structure, Corticosteroid, Female, medicine.symptom, business
Abstract

Made available in DSpace on 2022-04-28T19:49:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Arthritis Foundation Institute of Clinical and Translational Sciences Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Diabetes and Digestive and Kidney Diseases National Center for Advancing Translational Sciences 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. University of Cincinnati College of Medicine Baylor College of Medicine The Hospital for Sick Children and The University of Toronto Emory University and Children's Healthcare of Atlanta Sanjay Gandhi Postgraduate Institute of Medical Sciences Medical University of South Carolina KK Women's and Children's Hospital Cincinnati Children's Hospital Medical Center Hospital for Special Surgery Albert Einstein College of Medicine SRCC Children's Hospital Capital Medical University and National Center for Children's Health Universidade Federal do Rio de Janeiro Nationwide Children's Hospital University College London Cerrahpasa Medical School Istanbul University-Cerrahpasa University of Zagreb School of Medicine IWK Health Centre and Dalhousie University Hacettepe University Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago University of Campinas Hospital das Clínicas da Universidade Federal de Pernambuco National and Kapodistian University of Athens University Teknologi MARA Instituto Mexicano del Seguro Social University of Washington and Seattle Children's Hospital São Paulo State University Amsterdam University Medical Center Red Cross War Memorial Children's Hospital and University of Cape Town Universidade de São Paulo Hospital de la Beneficencia Española Universidade Federal de São Paulo National Medical Center La Raza Aristotle University of Thessaloniki King Faisal Specialist Hospital and Research Center and Alfaisal University University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center São Paulo State University CNPq: 303422/2015-7 FAPESP: FAPESP 2015/03756-4 National Institute of Arthritis and Musculoskeletal and Skin Diseases: P30-AR-076316 National Institute of Diabetes and Digestive and Kidney Diseases: P50-DK-096418 National Institute of Arthritis and Musculoskeletal and Skin Diseases: R34-AR-071651 National Center for Advancing Translational Sciences: T32-AR-050958

Published
2021

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

Author

Schanberg, Laura E., primary, Ramanan, Athimalaipet V., additional, De Benedetti, Fabrizio, additional, Beukelman, Timothy, additional, Eakin, Guy S., additional, Del Gaizo, Vincent, additional, Ringold, Sarah, additional, Vesely, Richard, additional, Schrandt, Suzanne, additional, Jaki, Thomas, additional, Bili, Androniki, additional, Chung, James B., additional, De Bono, Stephanie, additional, Douglass, Wendy, additional, Enejosa, Jeffrey V., additional, Kanik, Keith S., additional, Knobe, Karin, additional, Kunder, Rebecca, additional, Leite‐Schnell, Juliana C., additional, Suehiro, Ricardo Maisse, additional, Wong, Robert L., additional, Mieszkalski, Kelly L., additional, Marrow, Laura C., additional, Siebenaler, Kristin, additional, Fraulo, Elizabeth, additional, and Kimura, Yukiko, additional

Published
2019
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18. FRI0150 GS-9876, A NOVEL, HIGHLY SELECTIVE, SYK INHIBITOR IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY

Author

Kivitz, Alan, primary, Mehta, Daksha, additional, Matzkies, Franziska, additional, Mozaffarian, Afsaneh, additional, Kunder, Rebecca, additional, DI Paolo, Julie A., additional, Mozaffarian, Neelufar, additional, Hsueh, Sean, additional, Kim, Jiyun, additional, Jiang, Wendy, additional, Liu, Lin, additional, Sundy, John, additional, and Genovese, Mark C., additional

Published
2019
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19. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial

Author

Mease, Philip, primary, Coates, Laura C, additional, Helliwell, Philip S, additional, Stanislavchuk, Mykola, additional, Rychlewska-Hanczewska, Anna, additional, Dudek, Anna, additional, Abi-Saab, Walid, additional, Tasset, Chantal, additional, Meuleners, Luc, additional, Harrison, Pille, additional, Besuyen, Robin, additional, Van der Aa, Annegret, additional, Mozaffarian, Neelufar, additional, Greer, Joy M, additional, Kunder, Rebecca, additional, Van den Bosch, Filip, additional, and Gladman, Dafna D, additional

Published
2018
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22. Pediatric Plastic Bronchitis: Case Report and Retrospective Comparative Analysis of Epidemiology and Pathology

Author

Kunder, Rebecca, Kunder, Christian, Sun, Heather Y., Berry, Gerald, Messner, Anna, Frankovich, Jennifer, Roth, Stephen, and Mark, John

Subjects
Article Subject
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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25. T cell co-stimulatory factors: Crossing the minefield between rheumatology and oncology.

Author

Greisen, Stinne, Kunder, Rebecca, and Deleuran, Bent

Subjects
*AUTOIMMUNE disease treatment, *RHEUMATISM treatment, *TUMOR treatment, *ANTIGENS, *T cells
Abstract

The author discusses T cell co-stimulatory factors that orchestrate the sequence of immune checkpoints that occur before the T cell becomes a fully-activated memory T cell. Topics mentioned include exploitation of the CD28 system to improve immune-mediated tumour recognition, members of the tumor necrosis factor superfamily that have co-stimulatory activity, and the importance of OX40 ligand for T and B cell response.

Published
2017
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26. Fibroblast growth factor receptor 1/Klothoβ agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: A phase 1b randomized trial.

Author

Wong C, Dash A, Fredrickson J, Lewin-Koh N, Chen S, Yoshida K, Liu Y, Gutierrez J, and Kunder R

Subjects
Humans, Receptor, Fibroblast Growth Factor, Type 1 therapeutic use, Double-Blind Method, Triglycerides, Lipids, Non-alcoholic Fatty Liver Disease drug therapy, Diabetes Mellitus, Type 2 drug therapy
Abstract

Background and Aims: BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD., Approach and Results: Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose-proportional increases in exposure. The treatment-emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure-dependent increases in high-density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high-exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low-, medium-, and high-exposure tertiles, respectively, compared with 0.1% with placebo at Day 85., Conclusions: BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. ( ClinicalTrials.gov : NCT03060538)., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Published
2023
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27. WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.

Author

Dwyer MA, Joseph JD, Wade HE, Eaton ML, Kunder RS, Kazmin D, Chang CY, and McDonnell DP

Subjects
Autocrine Communication physiology, Blotting, Western, Cadherins genetics, Cadherins metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Survival drug effects, Gene Expression Regulation, Neoplastic, HCT116 Cells, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Humans, MSX1 Transcription Factor genetics, MSX1 Transcription Factor metabolism, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Nitriles pharmacology, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, RNA Interference, Receptors, Estrogen genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction physiology, Thiazoles pharmacology, Transcription Factors genetics, Transcription Factors metabolism, Transcriptional Activation, Wnt Proteins genetics, beta Catenin genetics, ERRalpha Estrogen-Related Receptor, Cell Movement physiology, Receptors, Estrogen metabolism, Wnt Proteins metabolism, beta Catenin metabolism
Abstract

Elevated expression of the orphan nuclear receptor estrogen-related receptor α (ERRα) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how its activity is regulated remain unknown. Using a chemical biology approach, it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited the transcriptional activity of ERRα. The significance of this association was revealed in a series of biochemical and genetic experiments that show that (a) ERRα, β-catenin (β-cat), and lymphoid enhancer-binding factor-1 form macromolecular complexes in cells, (b) ERRα transcriptional activity is enhanced by β-cat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERRα or β-cat. Furthermore, silencing of ERRα and β-cat expression individually or together dramatically reduced the migratory capacity of breast, prostate, and colon cancer cells in vitro. This increased migration could be attributed to the ERRα/β-cat-dependent induction of WNT11. Specifically, using (a) conditioned medium from cells overexpressing recombinant WNT11 or (b) WNT11 neutralizing antibodies, we were able to show that this protein was the key mediator of the promigratory activities of ERRα/β-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERRα and β-cat that influences the migratory capacity of cancer cells., (Copyright © 2010 AACR.)

Published
2010
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