1.Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells.
Chon HJ1, Lee Y1, Bae KJ1, Byun BJ2, Kim SA3, Kim J4. Amino Acids. 2016 Mar 19. [Epub ahead of print]
Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase family. TNIK was first identified as a kinase that is involved in regulating cytoskeletal organization in many types of cells, and it was recently proposed as a novel therapeutic target in several types of human cancers. Although previous studies suggest that TNIK plays a pivotal role in cancer cell survival and prognosis, its function in hematological cancer cell survival has not been investigated. Here we investigated the relationship between TNIK function and cell viability in multiple myeloma IM-9 cells using TNIK small interfering RNA (siRNA) transfection and dovitinib treatment. Treatment of IM-9 cells with TNIK siRNA and dovitinib treatment reduced cell proliferation. The ATP competing kinase assay and western blot analysis showed that dovitinib strongly inhibited both the interaction of TNIK with ATP (K i, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4.
2.Randomized, Open-Label Phase 2 Study Comparing Frontline Dovitinib vs Sorafenib in Patients With Advanced Hepatocellular Carcinoma.
Cheng AL1, Thongprasert S2, Lim HY3, Sukeepaisarnjaroen W4, Yang TS5, Wu CC6, Chao Y7, Chan SL8, Kudo M9, Ikeda M10, Kang YK11, Pan H12, Numata K13, Han G14, Balsara B15, Zhang Y15, Rodriguez AM16, Zhang Y15, Wang Y15, Poon RT17. Hepatology. 2016 Apr 15. doi: 10.1002/hep.28600. [Epub ahead of print]
Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on/2 days off; n = 82) vs sorafenib (400 mg, twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. Primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) per local investigator, respectively. Eligible patients had progressed after or were ineligible for surgical and/or locoregional therapies. Median OS (95% CI) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib.
3.Eruptive milia and comedones during treatment with dovitinib.
Kimes K1, Beasley K, Dalton SR. Dermatol Online J. 2015 Sep 17;21(9). pii: 13030/qt8kw141mb.
Dovitinib (TKI258) is a multi-targeted receptor tyrosine kinase inhibitor currently under clinical trials for a wide variety of cancers. Well-known side effects include nausea, vomiting, diarrhea, and fatigue. To date, there have only been only two reported cases with skin manifestations as a side effect. We report a case of eruptive facial milia and comedones in the setting of dovitinib treatment for metastatic gastrointestinal cancer. This case is unique as the clinical presentation was more rapid in onset and showed an absence of inflammatory lesions. Although the pathogenesis for skin manifestations is presently unknown, we present this case to increase awareness of potentially under-reported cutaneous side effects.
4.Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET.
Hernández-Agudo E1, Mondejar T1, Soto-Montenegro ML2, Megías D3, Mouron S1, Sanchez J1, Hidalgo M4, Lopez-Casas PP4, Mulero F5, Desco M6, Quintela-Fandino M7. Mol Oncol. 2015 Dec 22. pii: S1574-7891(15)00247-1. doi: 10.1016/j.molonc.2015.12.011. [Epub ahead of print]
BACKGROUND: Rationalization of antiangiogenics requires biomarkers. Vascular re-normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with 18F-misonidazole ([18F]-FMISO, a probe that detects hypoxia) PET, in response to window-of-opportunity (WoO) treatment with the antiangiogenic dovitinib.
