Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor
Abstract
BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).
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PLX3397 also inhibits c-Kit and, at higher doses, Flt3 receptor tyrosine kinases.
“it can also inhibit c-Kit and, at higher concentrations, Flt3 receptor tyrosine kinases”
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Cites
DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., Gallagher, W. M., Wadhwani, N., Keil, S. D., Junaid, S. A., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8274.cd-10-0028 · Cited by 1,715 · see citing works
Self-citationWhole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis
PETERFY, C. G., Guermazi, A., Zaïm, S., Tirman, P. F. J., Miaux, Y., White, D. L., Kothari, M., Lü, Y., Fye, K. H., Zhao, S., et al. (2003) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2003.11.003 · Cited by 1,542 · see citing works
Self-citationRies, C. H., Cannarile, M. A., Hoves, S., Benz, J., Wartha, K., Runza, V., Rey-Giraud, F., Pradel, L. P., Feuerhake, F., Klaman, I., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.05.016 · Cited by 1,384 · see citing works
Mitchem, J. B., Brennan, D. J., Knolhoff, B. L., Belt, B. A., Zhu, Y., Sanford, D. E., Belaygorod, L., Carpenter, D. H., Collins, L. I., Piwnica-Worms, D. R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2731 · Cited by 943 · see citing works
Self-citationØstergaard, M., PETERFY, C. G., Conaghan, P. G., et al. (2003) · PubMed · Cited by 706 · see citing works
Self-citationMcTigue, M. A., Murray, B. W., Chen, J. H., Deng, Y.-L., Solowiej, J. E., & Kania, R. S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1207759109 · Cited by 606 · see citing works
Xu, J., Escamilla, J., Mok, S., David, J., Priceman, S. J., West, B. L., Bollag, G. E., McBride, W. H., & Wu, L. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3981 · Cited by 571 · see citing works
Self-citationWest, R. B., Rubin, B. P., Miller, M. A., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507321103 · Cited by 570 · see citing works
Coniglio, S. J., Eugenin, E., Dobrenis, K., Stanley, E. R., West, B. L., Symons, M. H., & Segall, J. E. (2012) · Molecular Medicine · doi:10.2119/molmed.2011.00217 · Cited by 429 · see citing works
Self-citationCassier, P. A., Gelderblom, H. A. J., Stacchiotti, S., et al. (2011) · Cancer · doi:10.1002/cncr.26409 · Cited by 266 · see citing works
Cupp, J. S., Miller, M. A., Montgomery, K. D., Nielsen, T. O., OʼConnell, J. X., Huntsman, D. D., van de Rijn, M., Gilks, C. B., & West, R. B. (2007) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e31802b86f8 · Cited by 245 · see citing works
Radi, Z. A., Koza‐Taylor, P., Bell, R. R., Obert, L., Runnels, H. A., BEEBE, J. S., Lawton, M. P., & Sadis, S. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.03.029 · Cited by 145 · see citing works
Prada, C. E., Jousma, E., Rizvi, T. A., Wu, J., Dunn, R. S., Mayes, D. A., Cancelas, J. A., Dombi, E., Kim, M., West, B. L., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1056-7 · Cited by 143 · see citing works
Self-citationPatwardhan, P. P., Surriga, O., Beckman, M. J., de Stanchina, E., DeMatteo, R. P., Tap, W. D., & Schwartz, G. K. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2576 · Cited by 118 · see citing works
Self-citationTreatment of tenosynovial giant cell tumor and pigmented villonodular synovitis
Ravi, V., Wang, W., & Lewis, V. O. (2011) · Current Opinion in Oncology · doi:10.1097/cco.0b013e328347e1e3 · Cited by 108 · see citing works
Martin, R. C. G., Osborne, D. L., Edwards, M. J., et al. (2000) · Oncology Reports · doi:10.3892/or.7.2.413 · Cited by 104 · see citing works
Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor
Zhang, C., Ibrahim, P. N., Zhang, J., Burton, E. A., Habets, G. G. M., Zhang, Y., Powell, B., West, B. L., Matusow, B., Tsang, G., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1219457110 · Cited by 98 · see citing works
Self-citationThe 2.7 Å Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain
Walter, M., Lucet, I. S., Patel, O., et al. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.01.036 · Cited by 74 · see citing works
Pigmented Villonodular Synovitis: Current Concepts About Diagnosis and Management
Verspoor, F. G. M., van der Geest, I. C. M., Vegt, E., et al. (2013) · Future Oncology · doi:10.2217/fon.13.124 · Cited by 60 · see citing works
Rubin, B. P. (2007) · Skeletal Radiology · doi:10.1007/s00256-006-0249-3 · Cited by 58 · see citing works
Conformation-Specific Effects of Raf Kinase Inhibitors
Wang, X., & Kim, J. Y. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300613w · Cited by 49 · see citing works
Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis.
Molena, B., Sfriso, P., Oliviero, F., et al. (2011) · PubMed · Cited by 20 · see citing works
Pigmented villonodular synovitis: dedicated PET imaging findings
Amber, I. B., Clark, B. J., & Greene, G. S. (2013) · BMJ Case Reports · doi:10.1136/bcr-2013-009401 · Cited by 14 · see citing works
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Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
Self-citationPalucka, A. K., & Coussens, L. M. (2016) · Cell · doi:10.1016/j.cell.2016.01.049 · Cited by 843 · see citing works
Spangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 700 · see citing works
Self-citationKumar, V., Donthireddy, L., Marvel, D., Condamine, T., Wang, F., Lavilla-Alonso, S., Hashimoto, A., Vonteddu, P., Behera, R., Goins, M. A., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.10.005 · Cited by 653 · see citing works
Self-citationUshach, I., & Zlotnik, A. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ru0316-144r · Cited by 551 · see citing works
Zhu, Y., Yang, J., Xu, D., Gao, X.-M., Zhang, Z., Hsu, J. L., Li, C.-W., Lim, S.-O., Sheng, Y.-Y., Zhang, Y., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-318419 · Cited by 419 · see citing works
Self-citationElmore, M. R. P., Hohsfield, L. A., Kramár, E. A., Soreq, L., Lee, R. J., Pham, S. T., Najafi, A. R., Spangenberg, E. E., Wood, M. A., West, B. L., et al. (2018) · Aging Cell · doi:10.1111/acel.12832 · Cited by 380 · see citing works
Self-citationHarnessing tumor‐associated macrophages as aids for cancer immunotherapy
Li, X., Liu, R., Su, X., Pan, Y., Han, X., Shao, C., & Shi, Y. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1102-3 · Cited by 364 · see citing works
T cell–induced CSF1 promotes melanoma resistance to PD1 blockade
Neubert, N. J., Schmittnaegel, M., Bordry, N., Nassiri, S., Wald, N., Martignier, C., Tillé, L., Homicsko, K., Damsky, W., Maby-El Hajjami, H., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan3311 · Cited by 308 · see citing works
Elimination of microglia improves cognitive function following cranial irradiation
Acharya, M. M., Green, K. N., Allen, B. D., Najafi, A. R., Syage, A., Minasyan, H., Le, M. T., Kawashita, T., Giedzinski, E., Parihar, V. K., et al. (2016) · Scientific Reports · doi:10.1038/srep31545 · Cited by 259 · see citing works
Self-citationMicroglial repopulation resolves inflammation and promotes brain recovery after injury: RICE et al.
Rice, R. A., Pham, J., Lee, R. J., Najafi, A. R., West, B. L., & Green, K. N. (2017) · Glia · doi:10.1002/glia.23135 · Cited by 228 · see citing works
“As CSF1R inhibitors are currently used in the clinic, and more are being developed (Tap et al., 2015), these molecules offer a powerful tool against neuroinflammation.”
BackgroundInfluentialSelf-citationCrapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N. (2020) · Brain · doi:10.1093/brain/awz363 · Cited by 157 · see citing works
Activated microglia drive demyelination via <scp>CSF1R</scp> signaling
Marzan, D. E., Brügger‐Verdon, V., West, B. L., Liddelow, S., Samanta, J., & Salzer, J. L. (2021) · Glia · doi:10.1002/glia.23980 · Cited by 147 · see citing works
“complementary studies in which we pharmacologically depleted microglia with a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397 (PLX) (Tap et al., 2015), we further demonstrate that small numbers of surviving microglia rapidly repopulate the CNS during”
BackgroundSelf-citationA limited capacity for microglial repopulation in the adult brain
Najafi, A. R., Crapser, J., Jiang, S., Ng, W., Mortazavi, A., West, B. L., & Green, K. N. (2018) · Glia · doi:10.1002/glia.23477 · Cited by 99 · see citing works
Self-citationJohnson, N. R., Yuan, P., Castillo, E., Lopez, T. P., Yue, W., Bond, A., Rivera, B. M., Sullivan, M. C., Hirouchi, M., Giles, K., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35753-w · Cited by 46 · see citing works
Giricz, O., Mo, Y., Dahlman, K. B., Cotto-Rios, X. M., Vardabasso, C., Nguyen, H., Matusow, B., Bartenstein, M., Polishchuk, V., Johnson, D. B., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120422 · Cited by 40 · see citing works
Self-citationLiu, F., Hu, H., Chen, G., Lin, Y., Li, W., Liu, Z., Chen, C., Li, X., Sun, S., Zhang, L., et al. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.108849 · Cited by 4 · see citing works
- Authors
- Tap, W. D., Wainberg, Z. A., Anthony, S. P., Ibrahim, P. N., Zhang, C., Healey, J. H., Chmielowski, B., Staddon, A. P., Cohn, A. L., Shapiro, G. I., Keedy, V. L., Singh, A. S., Puzanov, I., Kwak, E. L., Wagner, A. J., Von Hoff, D. D., Weiss, G. J., Ramanathan, R. K., Zhang, J., Habets, G., Zhang, Y., Burton, E. A., Visor, G., Sanftner, L., Severson, P., Nguyen, H., Kim, M. J., Marimuthu, A., Tsang, G., Shellooe, R., Gee, C., West, B. L., Hirth, P., Nolop, K., van de Rijn, M., Hsu, H. H., Peterfy, C., Lin, P. S., Tong-Starksen, S., & Bollag, G.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- Plexxikon (United States) (US)
- University of Pennsylvania (US)
- Rocky Mountain Cancer Centers (US)
- Dana-Farber Cancer Institute (US)
- Vanderbilt University Medical Center (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-07-30
- Volume
- 373
- Issue
- 5
- Pages
- 428-437
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W982662479
- Cited by
- 582
- References
- 23
- Citations by year
- 2026: 30 · 2025: 47 · 2024: 66 · 2023: 62 · 2022: 65 · 2021: 61 · 2020: 65 · 2019: 50 · 2018: 54 · 2017: 40 · 2016: 30 · 2015: 7 · 2014: 2 · 2013: 1
- FWCI
- 36.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Musculoskeletal synovial abnormalities and treatments
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Keywords
- tenosynovial giant cell tumor, CSF1R inhibitor, PLX3397, colony-stimulating factor 1, kinase autoinhibition, structure-based drug design, oral kinase inhibitor, dose escalation, tumor response, adverse events
- MeSH terms
- Adult, Aged, Aminopyridines, Dose-Response Relationship, Drug, Female, Giant Cell Tumors, Humans, Male, Middle Aged, Pyrroles, Soft Tissue Neoplasms, Tendons, Receptor, Macrophage Colony-Stimulating Factor, Crystallography, X-Ray, Tumor Burden, Drug Discovery
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