Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

• Published in: The New England journal of medicine Vol. 373; no. 5; pp. 428 - 437
• Main Authors: Tap, William D, Wainberg, Zev A, Anthony, Stephen P, Ibrahim, Prabha N, Zhang, Chao, Healey, John H, Chmielowski, Bartosz, Staddon, Arthur P, Cohn, Allen Lee, Shapiro, Geoffrey I, Keedy, Vicki L, Singh, Arun S, Puzanov, Igor, Kwak, Eunice L, Wagner, Andrew J, Von Hoff, Daniel D, Weiss, Glen J, Ramanathan, Ramesh K, Zhang, Jiazhong, Habets, Gaston, Zhang, Ying, Burton, Elizabeth A, Visor, Gary, Sanftner, Laura, Severson, Paul, Nguyen, Hoa, Kim, Marie J, Marimuthu, Adhirai, Tsang, Garson, Shellooe, Rafe, Gee, Carolyn, West, Brian L, Hirth, Peter, Nolop, Keith, van de Rijn, Matt, Hsu, Henry H, Peterfy, Charles, Lin, Paul S, Tong-Starksen, Sandra, Bollag, Gideon
• Format: Journal Article
• Language: English
• Published: United States Massachusetts Medical Society 30.07.2015
• Subjects: Adult; Aged; Aminopyridines - administration & dosage; Aminopyridines - adverse effects; Aminopyridines - pharmacokinetics; Colony-stimulating factor; Conformation; Crystallography; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Drug therapy; Edema; Fatigue; Female; Genes; Giant Cell Tumors - drug therapy; Giant Cell Tumors - pathology; Humans; Kinases; Macrophage colony-stimulating factor; Male; Middle Aged; Nausea; Patients; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - pharmacokinetics; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Soft Tissue Neoplasms - drug therapy; Soft Tissue Neoplasms - pathology; Solid tumors; Taste disorders; Tendons - pathology; Tumor Burden; Tumors
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa1411366

The authors developed a novel CSF1R inhibitor, PLX3397, and conducted a phase 1 study. An extension cohort of 23 patients with tenosynovial giant-cell tumor was included to assess the phase 2 chosen dose; 12 patients had a response, and 7 had stable disease. Tenosynovial giant-cell tumor, historically known as pigmented villonodular synovitis, 1 is a rare, locally aggressive neoplasm of the joint or tendon sheath. 2 It is characterized by a proliferation of synoviocytes that initiate the development of the tumor and attract histiocytes, hemosiderin-laden macrophages, and other inflammatory cells. Surgical resection is the primary treatment 3 ; however, diffuse tenosynovial giant-cell tumor is more difficult to resect and often involves total synovectomy, joint replacement, or amputation. 4 There are no approved systemic therapies. A neoplastic clone usually constitutes only a small minority of the cells in tenosynovial giant-cell tumors. These neoplastic cells often express colony-stimulating factor . . .