DDEL-18. High throughput screening driven personalized chemotherapy for brain metastases enabled by laser interstitial thermotherapy

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Abstract BACKGROUND Treatment of malignant brain tumors is limited in part because most chemotherapeutic agents do not cross the blood-brain barrier (BBB). Laser interstitial thermotherapy (LITT) transiently disrupts the BBB, potentially enhancing drug delivery. High-throughput screening (HTS) of tumor tissue enables identification of effective, patient-specific drugs, many of which are not traditionally BBB-permeable. OBJECTIVE To evaluate the therapeutic potential of combining LITT with HTS-identified, non-BBB-penetrant chemotherapeutics in a personalized treatment strategy for malignant brain tumors. METHODS Intracranial KR158-luc glioma model and treated with LITT on day 14 post-implantation. Mice received temozolomide (cross BBB) or carboplatin (does not cross BBB) following LITT. Brain drug concentration was quantified via ICP-MS. Further, freshly resected human melanoma brain-mets samples were used to generate 3D organoids and patient derived xenograft (PDX) models. HTS was conducted using a 179-drug oncologic panel. A study was conducted using carfilzomib (HTS-identified drug) combined with LITT in a PDX model (FCBTR-2716-10309). Plasma drug concentration was assessed using LC-MS. RESULTS LITT significantly enhanced intra-tumoral concentration of TMZ at 1 hour (39 µg/g) compared to TMZ control only (18.2 µg/g). LITT+carboplatin at 1 hour (p=0.0054) demonstrated significantly increased intra-tumoral carboplatin concentration (1252 ng/g) as compared with carboplatin only (352 ng/g). Survival was improved in glioma bearing mice treated with LITT plus carboplatin (p=0.0218) versus LITT monotherapy (p=0.0098). Organoids formed from patient samples demonstrated differential drug sensitivity in HTS, validating the screening platform. In the human melanoma PDX model, one of the top drugs identifed via HTS, carfilzomib, was combined with LITT resulted in reduced plasma levels and suggesting increased brain tumor penetration. CONCLUSION Combining LITT with HTS-guided chemotherapy enables effective delivery of drugs otherwise excluded by the BBB. Survival with LITT + carfilzomib in preclinical brain-mets models is underway. Further studies will refine the timing of drug delivery (neoadjuvant vs. adjuvant).

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