BSLM-09 Identification of Drugs With Selective Activity Against Melanoma-Associated Leptomeningeal Disease Using Patient-Derived Circulating Tumor Cells

Abstract BACKGROUND Melanoma associated leptomeningeal disease (M-LMD) occurs in ~5% of late stage melanoma patients and the prognosis is dismal without effective treatments. The difficulty in obtaining enough patient-derived cerebral spinal fluid-circulating tumor cells (PD-CSF-CTCs) and the absence of model systems to study the biology of M-LMD have posed challenges in assessing novel therapeutics. To address this, we have made considerable progress in routinely collecting CSF and tissue specimens (in clinic and at rapid autopsy). Recently, we successfully propagated CSF-CTCs from patients in vitro and in murine xenograft models. With these tools and -omics techniques we found unique M-LMD-specific biological pathways. In the current preliminary study, we identified clinical compounds that could target these biological pathways and have efficacy against PD-CSF-CTCs in vitro and in vivo. METHODS PD-CSF-CTCs were derived and propagated from individual M-LMD patients. Next, a 384-well high throughput cell-based process was developed to screen a library of more than 1,400 FDA-approved small molecule compounds to identify pharmaceutics that inhibit cell proliferation. Clinical compounds with the highest sensitivity were selected for validation of efficacy in vivo via intrathecal (IT) delivery of patient-derived cell lines to establish M-LMD xenografts. RESULTS Of the 1,436 FDA-approved small molecule compounds, 57 (~3.9%) exerted 95% proliferation inhibition and 20 (~1.4%) had 100% killing effect in PD-CSF-CTCs and murine melanoma cell lines. The compounds with the highest sensitivity include ponatinib (EC50: 1.85 – 4.06e-06), sorafenib (EC50: 9.57 – 9.77e-06), ceritinib (EC50: 1.84 – 2.05e-06) and homoharringtonine (HHT) (3.63 – 4.11e-08). In a randomized murine M-LMD efficacy study, we selected the HHT compound which was given by systemic or intrathecal (IT) injections and found M-LMD mice that received a daily IT dose of 14.5ng HHT resulted prolonged median survival (control vs. HHT, P value: 0.0006; Mantel Cox test). CONCLUSION This is the first demonstration of an approach that allows for the rational development of therapeutics in M-LMD, which may help identify drug candidates for future trials.