生物活性

• 描述Colony-Stimulating-Factor Receptor-1 (CSF-1R) is a tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. CSF-1R promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. CSF-1R also promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration. In response to ligand binding, CSF-1R activates several signaling pathways. Reports inferred that CSF-1R may be involved in cancer progression. Edicotinib, also termed JNJ-40346527, is a selective colony-stimulating factor-1 (CSF-1) receptor inhibitor. In lung cancer H1299 cells, edicotinib concentration dependently suppressed the level of Tyr ⁷²³, and the effect was obvious at the concentration of 250 nM. Edicotinib also concentration dependently inhibited the colony formation ability of lung cancer Calu-1, A549, H1975 and H1299 cell lines ^[5]. In a subcutaneous C57BL6 mice model of lung carcinoma established by implantation of LLC cells, edicotinib was administered at dose 20 mg/kg 6 days per week p.o.. The results indicated that this dose and schedule of edicotinib in combination of CXCR2 antagonist SB225002 administered at dose 2mg/kg 6 days a week i.p. had significant anti-tumor activity. The same combination of these two drugs in a subcutaneous mice model of B16F10 melanoma was also efficient ^[6]. According to another report, in a H1299 lung cancer xenograft established on NOD/SCID mice subcutaneously，treatment of edicotinib at the dose of 20 mg/kg by daily oral gavage for 16 days, in combination of cisplatin at the i.p. dose of 4 mg/kg once a week for 2 weeks had significant anti-tumor activity ^[5].

• 动物研究
  剂量	Mice: 5 mg/kg - 20 mg/kg[3] (p.o.), 3 mg/kg - 100 mg/kg[4] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03177460	Malignant Neoplasms of Male Ge... more >>nital Organs Prostate Cancer Adenocarcinoma of the Prostate Collapse <<	Phase 1	Recruiting	June 2020	United States, Texas ... more >> University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Clinical Research Operations       sksubudhi@mdanderson.org Collapse <<
  NCT01572519	Relapsed or Refractory Hodgkin... more >> Lymphoma Collapse <<	Phase 1	Completed	-	France ... more >> Lille, France Villejuif, France Germany Köln, Germany Würzburg, Germany Collapse <<
  NCT01597739	Arthritis, Rheumatoid	Phase 2	Completed	-	-

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• 参考文献

• [1] von Tresckow B, Morschhauser F, et al. An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma. Clin Cancer Res. 2015 Apr 15;21(8):1843-50.

  [2] Genovese MC, Hsia E, et al. Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy. J Rheumatol. 2015 Oct;42(10):1752-60.

  [3] Manthey CL, Moore BA, et al. The CSF-1-receptor inhibitor, JNJ-40346527 (PRV-6527), reduced inflammatory macrophage recruitment to the intestinal mucosa and suppressed murine T cell mediated colitis. PLoS One. 2019 Nov 11;14(11):e0223918.

  [4] Mancuso R, Fryatt G, et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264.

  [5] Pass HI, Lavilla C, Canino C, Goparaju C, Preiss J, Noreen S, Blandino G, Cioce M. Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin. Oncotarget. 2016 Aug 30;7(35):56408-56421. doi: 10.18632/oncotarget.10895. PMID: 27486763; PMCID: PMC5302923.

  [6] Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, Hashimoto A, Vonteddu P, Behera R, Goins MA, Mulligan C, Nam B, Hockstein N, Denstman F, Shakamuri S, Speicher DW, Weeraratna AT, Chao T, Vonderheide RH, Languino LR, Ordentlich P, Liu Q, Xu X, Lo A, Puré E, Zhang C, Loboda A, Sepulveda MA, Snyder LA, Gabrilovich DI. Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell. 2017 Nov 13;32(5):654-668.e5. doi: 10.1016/j.ccell.2017.10.005. PMID: 29136508; PMCID: PMC5827952.

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