DRES-12. QUANTIFYING INDIVIDUALIZED ABT-414 SENSITIVITY AND BLOOD-BRAIN BARRIER PENETRANCE FROM SERIAL IMAGING OF PATIENT-DERIVED XENOGRAFTS MODELS OF GLIOBLASTOMA

Abstract

Abstract INTRODUCTION Glioblastoma (GBM) is an aggressive primary brain tumor, known for its poor prognosis. Due to its diffuse invasiveness into normal-appearing brain, localized treatments such as surgical resection and radiotherapy are typically supplemented with chemotherapy. However, to reach invading tumor cells, such antineoplastic drugs must cross the blood-brain barrier (BBB). That is, while angiogenesis induces BBB breakdown in dense tumor regions, the BBB remains rather intact for invading GBM cells. As a result, it is unclear whether BBB-impermeable drugs are delivered at a sufficient level to be effective. METHODS In order to study heterogeneity in BBB breakdown, experiments were conducted using both flank and intracranial patient-derived xenografts (PDXs) treated with the EGFR-targeted monoclonal antibody drug conjugate, depatuxizumab mafodotin (ABT-414). Time-series bioluminescence imaging (BLI) data was used to develop a differential equation model of tumor growth for three PDX cell lines. Data from untreated PDXs, both in flank and intracranially, were used to parameterize tumor proliferation rates. Flank PDX data were used to parameterize individual sensitivity to ABT-414, whereas intracranial PDX data were used to determine the proportion of drug exposed to the tumor. RESULTS Each PDX line differed in response to the study drug ABT-414. As expected, such heterogeneous responses can primarily be attributed to differences in both drug sensitivity and the proportion of drug that reached the tumor. Notably, the estimated proportion of drug that reached the tumor was highest in the PDX line with the longest survival times, despite also having higher estimates of resistance. This suggests that PDXs with greater overall BBB breakdown may respond better to this agent. CONCLUSIONS Although more cell lines are needed to validate our approach, parameterizing this model for PDXs gives valuable insight into the extent of BBB breakdown in patient GBMs and may aid in determining optimal therapies for individual patients.