For the first time our scientists have developed a suite of pre-clinical models to evaluate brain penetration of small molecule inhibitors and have shown their translatability in the clinical setting.
Approximately 40% of patients with non-small cell lung cancer (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) experience disease progression during treatment due to brain metastasis.
Until now, pre-clinical assessment of brain penetration has been difficult due to technical challenges in establishing cellular and animal models to mimic the blood brain barrier (BBB) and different stages of metastasis. Our scientists in Innovative Medicines and Early Development (IMED) Biotech Unit in Asia have developed a suite of cellular and mouse models that can be used to assess if a drug crosses the BBB to demonstrate its anti-tumour activity.
In the recent issue of Science Translational Medicine our scientists show how these models are being used to support the discovery and development of novel EGFR inhibitors for brain metastases and report early signs of translation in the clinical setting.
By engineering cell lines with human transporter genes the team are able to assess if the drug is a substrate of key transporters located on the BBB. Equally novel, the team have used microsurgery techniques to establish the brain metastatic models in mice to mimic different stages of the tumour development. These models have been used to assess BBB penetration of a drug as well as its anti-tumour activity.
“We have been able to use the pre-clinical brain models to set criteria for patient selection for our EGFR inhibitor currently in assessment in Phase 1 clinical trials for brain metastasis” says Dr. Pamela Yang, Preclinical Project Leader and Medical Science Director, IMED Biotech Unit in Asia. “In this paper, we report exciting emerging data from two patients showing excellent blood brain barrier penetration of this molecule and its encouraging anti-tumour activity. This gives us confidence in using these models to support discovery and development of new drugs targeting brain tumours in the future.”
Identification of clinically-relevant tumour resistance mechanisms is one of AstraZeneca’s key priority areas of science in Oncology. By developing pre-clinical models that provide evidence of target inhibition and effect helps us to embark on early clinical trial investigation with confidence to develop more precise and targeted therapies with durable clinical responses.