ATCT-14CHEMOSENSITIVITY OF PRIMARY AND METASTATIC CNS TUMORS TO 4-DEMETHYL-4-CHOLESTERYLOXYCARBONYLPENCLOMEDINE (DM-CHOC-PEN) AND TEMOZOLOMIDE

BACKGROUND: The efficacy of TMZ in the treatment of high-grade astrocytomas is limited by drug-resistance mediated by O6-methylguanine-DNA methyltransferase (MGMT). Brain metastases are difficult to treat and currently no standard chemotherapeutic therapies exist. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate whose mechanism of action is via alkylation of DNA at N7-guanine. This agent has had early therapeutic success in treating both primary and metastatic CNS malignancies in Phase I and Phase II clinical trials. METHODS: To better understand the sensitivity and mechanisms of resistance in primary and metastatic CNS tumors, we collected tissue from subjects (n = 38) enrolled between March 2014 - January 2015 for chemosensitivity studies. These included high-grade astrocytomas (9), metastatic brain tumors (6) meningiomas (6), and other more benign tumors such as pituitary adenomas (4), hemangioblastoma (1), and chondrosarcoma (1). Using viable tumor cell explants from surgery, cells were grown under standard conditions (RPMI/FBS, 5%CO2, 37°C), in vitro chemosensitivity profiles were obtained comparing DM-CHOC-PEN vs. TMZ and other commonly used anti-cancer agents. RESULTS: Tumor cells exhibited higher susceptibility to DM-CHOC-PEN than to TMZ (RR = 3.19, p = 0.0029, 95% confidence interval [CI], 1.3-7.8 vs. TMZ). In a subgroup analysis of high-grade astrocytomas, atypical meningiomas, and secondary metastases in this cohort, an association was noted between TMZ-resistance (µIC50 = 3.3, S.D. = 0.46) and DM-CHOC-PEN-sensitivity (µIC50 = 1.0, S.D = 0.26) using two-sample independent, Student's t-test with Fisher's exact P-value (p = 0.0001, t(23.72) = 4.5, df = 27.17). CONCLUSIONS: These preliminary results suggest that DM-CHOC-PEN may promote cell death in tumors possessing acquired MGMT-mediated drug-resistance. Furthermore, it supports roles for this promising new agent in the treatment of primary and metastatic brain tumors and in treatment of high-grade astrocytomas, either in combination with TMZ or alone in cases of TMZ-resistance.