Abstract PO-024: Catastrophic ATP loss underlines a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

摘要: MYCN-amplified neuroblastoma is responsible for ~10% of all cancer-related deaths in the pediatric population. MYCN drives numerous effects cell, including metabolic changes that are critical oncogenesis. The understanding both compensatory pathways and intrinsic redundancy cell systems exists implies use combination therapies effective durable responses necessary. Additionally, most targeted exploit an “Achilles’ heels” tailored to genetics cancer under study. We performed unbiased screen on select therapy combinations correlated sensitivity with over 20 subsets cancer. found hypersensitive AZD3965, inhibitor lactate transporter MCT1, phenformin, complex I mitochondrion. Our data demonstrate MCT4 highly resistance AZD3965 phenformin through screen, heavily methylated, lowly expressed neuroblastoma. Low combines high expression MCT2 MCT1 chaperone CD147 neuroblastoma, altogether conferring combination. Metabolomic analysis showed result simultaneous disruption glycolysis oxidative phosphorylation, resulting dramatic adenosine triphosphate (ATP) production, endoplasmic reticulum (ER) stress, apoptosis, which was seen viability assays protein analysis. In mouse models tolerable at concentrations where it shrank tumors did not increase white blood toxicity compared single-drugs. Therefore, we a can identify vulnerabilities put forth demonstrates efficacy tolerability vivo. Citation Format: Krista M. Powell, Timonthy L. Lochmann, Konstantinos V. Floros, Marissa Calbert, Richard Kurupi, Giovanna T. Stein, Joseph McClanaghan, Ellen Murchie, Regina K. Egan, Patricia Greninger, Mikhail Dozmorov, Sivapriya Ramamoorthy, Madhavi Puchalapalli, Bin Hu, Lisa Shock, Jennifer Koblisnski, John Glod, Sosipatros A. Boikos, Cyril H. Benes, Anthony C. Faber. Catastrophic ATP loss underlines [abstract]. In: Abstracts: AACR Special Virtual Conference Epigenetics Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-024.