Medu-14. Genomic analysis of ETMR guides efficacious DFMO drug combinations

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By bhadmin February 2, 2021

Embryonal tumor with multilayered rosettes (ETMR), formerly termed ETANTR, is a rare pediatric tumor carrying a poor prognosis and occurring primarily in patients less than 4 years of age. The median overall survival of <1 year for patients diagnosed with these primitive neuroectodermal (PNET)-like tumors demands the development of novel treatment regimens. Recent clinical and experimental data shows treatment with the highly tolerated drug DFMO (α-difluoromethylornithine) improves overall survival in neuroblastoma patients; and ETMR patients currently receiving DFMO on our expanded use trial have displayed clinical benefit. In neuroblastoma, DFMO reduces tumor burden through G1 cell cycle arrest, induction of senescence, and targeted cytotoxicity towards cancer stem cells. The effect of DFMO on tumors is mediated through polyamine depletion leading to disruption of the Lin28/Let-7 axis. We hypothesize that; ETMR, characterized by particularly high Lin28 expression, will be responsive to DFMO treatment. We have shown that DFMO treatment of the BT-183 and BIO-296-08 ETMR cell lines leads to a reduced number of viable cells, reducing viable cell number by 50% at 144 hours of exposure (CellTiter Glo). This reduction in viable cells is coupled with a simultaneous reduction in the overall expression of Lin28 as well as a reduction in the proportion and viability of the cancer stem cell subpopulation (flow cytometry). High throughput drug testing of BT-183 and RNA sequencing of six individual ETMR tumors identified temozolomide and the HDAC inhibitor panobinostat as ideal combination agents in treating ETMR cells. Treatment with temozolomide (IC50 2–6µM) and panobinostat (IC50 2-6nM), even in the presence of DFMO, resulted in a potent reduction in ETMR cell viability (CellTiter Glo). These data warrant further work elucidating the mechanism of this therapy and provides rationale for the development of clinical trials incorporating the use of DFMO in this lethal disease.

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