Small molecule inhibitors with a therapeutic window for EGFR signaling variants in glioblastoma

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Project Summary The epidermal growth factor receptor (EGFR) gene is mutated or amplified in over half of GBMs, and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease and these failures cannot be attributed strictly to poor brain penetrance. We posit that the failure to date of EGFR TKIs for GBM reflects lack of a therapeutic window. A lesson learned from application of EGFR inhibitors in non-small cell lung cancer (NSCLC) is that mutant-selectivity is absolutely required. Without selectivity, systemic inhibition of wild-type (WT) EGFR signaling is the dose-limiting toxicity. In NSCLC, activating mutations in the tyrosine kinase domain confer enhanced sensitivity to certain EGFR TKIs relative to WT EGFR, allowing true mutant-selective inhibition. The EGFR genetic aberrations in glioblastoma (GBM) create constitutive, ligand-independent signaling via signal generating domains that are almost exclusively WT in structure. Our objective is to create EGFR TKIs with a therapeutic window for aberrant EGFR signaling in GBM. We have two specific aims. Aim 1, is to test the hypothesis that an EGFR TKI with an allosteric mechanism of action will selectively block ligand-independent EGFR signaling in GBM while sparing ligand-activated EGFR systemically, thereby providing a therapeutic window that allows effective treatment of EGFR-driven GBMs. In preliminary studies, we have developed small-molecule allosteric inhibitors that potently inhibit WT EGFR (IC50 < 100 nM in biochemical assays) and have a good oral mouse PK profile and are brain-penetrant. Guided by efficacy studies in patient-derived GBM neurosphere and xenograft models, we expect to identify a compound suitable for clinical development in the first grant year, to enable clinical translation in the out years. Aim 2, exploits CM93, a novel third generation EGFR TKI that is highly brain-penetrant – so much so that it actually displays a positive brain/plasma ratio. We will test the hypothesis that CM93 can provide a de facto “tissue-based” therapeutic window allowing effective inhibition of EGFR in the tumor with relative sparing of the receptor systemically. Towards this end, we will conduct a first-in-human, phase 1, dose-escalation and dose-expansion study, as well as a surgical “window of opportunity” study to determine the maximum tolerated dose, evaluate the safety, pharmacokinetics, pharmacodynamics and clinical effects of orally administered CM93 in subjects with recurrent glioblastoma characterized by EGFR mutation or amplification. Studies on clinical materials will be facilitated by our Pharmacological and Genomics Imaging Core (PGIC). The PGIC will allow us to quantify intra-tumoral accumulation of CM93 using MALDI mass spectrometry imaging and to define the impact of CM93 treatment on tumor heterogeneity using single cell sequencing. Collectively, these studies promise to yield new targeted therapeutics for EGFR-driven GBMs and provide a molecular understanding of determinants of sensitivity and resistance to these agents.