American Association for Cancer Research
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Supplementary Figures 1-2 from NT113, a Pan-ERBB Inhibitor with High Brain Penetrance, Inhibits the Growth of Glioblastoma Xenografts with EGFR Amplification

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posted on 2023-04-03, 14:24 authored by Yasuyuki Yoshida, Tomoko Ozawa, Tsun-Wen Yao, Wang Shen, Dennis Brown, Andrew T. Parsa, Jeffrey J. Raizer, Shi-Yuan Cheng, Alexander H. Stegh, Andrew P. Mazar, Francis J. Giles, Jann N. Sarkaria, Nicholas Butowski, Theodore Nicolaides, C. David James

Supplementary Figure 1: NT113 Chemical Structure; Supplementary Figure 2: A) Relative expression of endogenous wild-type EGFR in parental U87 cells (U87p) vs. U87 cells transduced with EGFRvIII retrovirus (U87vIII). B) Relative expression of EGFRwt, EGFRvIII, ERBB2 and ERBB4 in subcutaneous tumors of GBM12, GBM39, and GBM6.



This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM. Mol Cancer Ther; 13(12); 2919–29. ©2014 AACR.

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