posted on 2023-11-08, 18:40authored byKathryn
M. Pflug, Dong W. Lee, Ashutosh Tripathi, Vytas A. Bankaitis, Kevin Burgess, Raquel Sitcheran
Glioblastoma (GBM)
is a highly aggressive form of brain
cancer
with a poor prognosis and limited treatment options. The ALK and c-MET
inhibitor Crizotinib has demonstrated preclinical therapeutic potential
for newly diagnosed GBM, although its efficacy is limited by poor
penetration of the blood brain barrier. Here, we identify Crizotinib
as a novel inhibitor of nuclear factor-κB (NF-κB)-inducing
kinase, which is a key regulator of GBM growth and proliferation.
We further show that the conjugation of Crizotinib to a heptamethine
cyanine dye, or a near-infrared dye (IR-Crizotinib), attenuated glioma
cell proliferation and survival in vitro to a greater
extent than unconjugated Crizotinib. Moreover, we observed increased
IR-Crizotinib localization to orthotopic mouse xenograft GBM tumors,
which resulted in impaired tumor growth in vivo.
Overall, IR-Crizotinib exhibited improved intracranial chemotherapeutic
delivery and tumor localization with concurrent inhibition of NIK
and noncanonical NF-κB signaling, thereby reducing glioma growth in vitro, as well as in vivo, and increasing
survival in a preclinical rodent model.