Abstract 37: A novel technique to preclinically assess the ability of targeted therapies to inhibit both primary and metastatic non small cell lung carcinoma

Abstract

Abstract Lung cancer remains a devastating cancer diagnosis around the world, resulting in 18% of all cancer-related deaths. Lung cancer often metastasizes to the brain, significantly reducing life expectancy. Up to 7% of patients with non-small cell lung cancer (NSCLC) already have brain metastasis when they are first diagnosed, and 20%-40% of patients with NSCLC will develop this complication during disease progression. Currently there are no targeted therapies specific for brain metastases, and the blood-brain barrier can pose a physiologic impediment to many cytotoxic drugs and antibody-based therapies. Here, we will discuss the development and use of xenograft models to address metastatic brain disease via a direct intracranial implant coupled with a subcutaneous “primary” tumor to effectively allow evaluation of the response to treatment at both locations. Treatment with targeted therapies could have significantly different penetration and absorption rates, which will alter pharmacokinetic and/or pharmacodynamic (PK/PD) assessment across either tissue. The dual implant technique can be a powerful tool to assess the simultaneous impact of treatment on established metastatic disease and primary tumor. We have characterized the dual disease induction parameters for two human NSCLC cell lines: NCI-H1975-Luc and PC-9-Luc. Both cell lines have been transfected with luciferase to allow for bioluminescence imaging (BLI) to monitor the intracranial disease progression. Both NCI-H1975-Luc and PC-9-Luc are of interest to the research community due to their unique mutational EGFR T790M status. Consistent with the historical and published data, the H1975-luc and PC-9-luc models behaved as expected, producing reliable tumor progression with minimal intragroup variability. In each case, subcutaneous tumors (primary site) reached an evaluation size of ~1000 mm3 in ~20 days, and intracranial tumors (metastatic site) exhibited a total flux doubling time of ~2 days by BLI. Treatment with Osimertinib, an approved first-line treatment for EGFR+ NSCLC patients, was effective against both the subcutaneous and intracranial tumors. Treatment with Osimertinib at 25 mg/kg, given orally, produced 100% complete regressions (CR) against the subcutaneous tumors, which never re-grew prior to study termination on Day 26 post implant and 100% partial regressions (PR) against the established intracranial tumors, which re-grew following the conclusion of treatment at the same rate as the control brain tumors. These data show a difference between the responsive nature of subcutaneous and intracranial NSCLC tumors representing the difference in responsiveness of primary tumors and brain metastases. Utilizing this in vivo dual implant technique can be effective in comparing and assessing the ability of targeted therapies to inhibit both primary and metastatic diseases. Citation Format: Erin Trachet, Scott Wise. A novel technique to preclinically assess the ability of targeted therapies to inhibit both primary and metastatic non small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 37.