PRECLINICAL EVALUATION OF A NOVEL ERBB INHIBITOR OPTIMIZED FOR CNS BIODISTRIBUTION
Led by C. David James at University of California, San Francisco
1. EGFR overexpression and/or mutation occurs in approximately 40% of glioblastoma (GBM). Moreover, the TCGA project revealed potential involvement of additional ERBB receptors (EGFR is one of four ERBB family members) in GBM, especially HER2/NEU. Although small molecule inhibitors directed at EGFR have achieved clinical validation in NSCLC, clinical trials of the same agents in GBM have yielded disappointing results, with poor penetration of the blood brain being a likely contributor to such results, combined with the fact that EGFR mutations in GBM are distinct from those occurring in NSCLC.
2. NT-113, developed by Dr. Wang Shen of NewGen Therapeutics
(http://www.newgenther.com/) is a potent irreversible pan-ERBB inhibitor that preferentially
accumulates in the brain at concentrations greater than 4 times that of plasma, when dosed orally. Researchers at UCSF in the laboratory of Professor C, David James, PhD, have recently determined potent anti brain tumor activity with a significant improvement in survival in an intracranial mouse xenograft study using a human GBM cell line that is driven by high level expression of the GBM-specific EGFRvIII mutation. In addition, NT-113 has shown activity against GBM cell lines that do not overexpress either normal or mutant EGFR, suggesting that NT-113 efficacy may extend to other molecular variants of GBM.
3. We propose testing NT-113 in four additional xenograft models, GBM12, GBM26, U87 and U87vIII, for response to NT-113, erlotinib, and lapatinib. The demonstration of NT-113 antitumor activity against each of these models would support the potential utility of NT-113 in treating GBMs beyond the 40% of patients that overexpress EGFR or that have EGFR mutation. The results of our study will also address efficacy of NT-113, in relation to 2 competing small molecule inhibitors, and, if successful, would validate a clinical trial testing of NT-113 in treating GBM patients.
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