Targeting EGFR in Brain Cancer

Epidermal growth factor receptor (EGFR), a member of the ERBB/HER subfamily of receptor tyrosine kinases, is a clinically validated target in multiple cancer indications. Aberrant activation of the EGFR kinase through gene amplification and mutation promotes survival, proliferation, and migration of tumor cells. Due to this well-established role of EGFR in tumorigenesis, EGFR-targeting agents have been approved for treatment of cancers, such as non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, and colorectal cancer. However, aberrant EGFR activity is also implicated in central nervous system (CNS) tumors including glioblastoma multiforme (GBM), the most common malignant brain cancer in adults, as well as brain metastases in approximately half of NSCLC patients. Most GBM tumors overexpress either normal (wild type) EGFR receptor or a truncated EGFR mutant termed vIII, a constitutively active variant unique to tumor cells. Overexpression of either wild type or this variant receptor correlates with poor prognosis in GBM patients. Frame deletion and amino acid substitution mutations in EGFR are found in brain metastases of NSCLC patients. Therefore, targeting wild type and mutant EGFR is an attractive strategy for the treatment of GBM and brain metastases of NSCLC.

Both GBM and NSCLC patients with brain metastases have a poor prognosis with a median survival time of less than 15 months. In recent years, the development of small molecule inhibitors of EGFR tyrosine kinase activity has progressed rapidly, leading to the approval of compounds such as erlotinib and afatinib for the treatment of EGFR mutant-NSCLC. However, use of these compounds in clinical trials for GBM have resulted in modest and few responses, due at least in part to a failure of these drugs to adequately penetrate the blood-brain barrier (BBB), a protective barrier separating the brain from the blood. Efflux transporters in the brain epithelium limit the amount of drug crossing the BBB. Thus, there is a strong unmet medical need for BBB-penetrant therapeutics that can effectively target EGFR and deliver therapeutic levels of unbound drug to CNS tumors.

Incorporation of fluorine into small molecules can improve BBB penetration. Trillium has applied its unique fluorine-based medicinal chemistry platform to design multiple proprietary classes of brain-penetrant, selective, and potent small molecule EGFR inhibitors with excellent oral bioavailability. A combination of molecular design, fluorine-based chemical synthesis, and extensive biological testing has led to the identification of a broad suite of novel EGFR compounds including lead molecule TTI-2341, a novel orally available brain-penetrant, irreversible EGFR inhibitor, that appears to be a viable and competitive drug candidate for the treatment of brain cancers and brain metastases.


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