TRTH-18. Combined Topotecan and Carboplatin Therapy for Dipg Suppresses Cell Growth in Vitro and Is Well Tolerated When Delivered by Convection Enhanced Delivery in Vivo

Abstract

NEURO-ONCOLOGY • JUNE 2017 confer resistance. RESULTS: Altered expression of the anti-apoptosis pathway, cell cycle activation and PI3-kinase signaling, in addition to several lineage-specific transcription factors, rescued MYC-amplified cells from BET-bromodomain inhibition. Cell-lines that had acquired resistance to BET-bromodomain inhibitors exhibited altered cell-state and increased expression of candidate resistance proteins. These lines were resistant to structurally distinct BET-bromodomain inhibitors, and whole-exome sequencing did not reveal mutations in BRD2, BRD3 or BRD4. Resistant cell-lines were sensitive to inhibitors targeting candidate resistance drivers. CONCLUSIONS: MYC-amplified medulloblastoma cell-lines evolve to increase expression of candidate resistant pathways to acquire resistance to BET-bromodomain inhibition. These represent potential therapeutic targets for combination therapies to increase the clinical efficacy of BET-bromodomain inhibitors for children with MYCamplified medulloblastoma. TRTH-16.

Combinatorial Intracellular Delivery Screening of Anticancer Drugs

“…28, 51, 52, 66, 87, 92, 95, 125, 133, 136, 141-143, 174, 176, 178-180, 183-185, 189, 193, 194, 207, 208, 211, 212, 215, 219, 221, 223, 227-229, 231, 241, 244, 245 POs Polymersomes. 64,66,69,76,[79][80][81][82][83][84][85][86][87] PTM Post-translational modification. 92 PTX Paclitaxel.…”

“…Although this strategy has not shown improvement in paediatric patients' survival, new strategies combining alkylating agents with other pharmacological agents presenting distinct mechanisms of action has been explored in the recent therapeutic studies for pHGG. An example is the use of carboplatin (alkylating agent) combined with sodium valproate (HDAC inhibitor) [63] or topotecan (topoisomerase inhibitor) [64]. For both studies, the horizontal inhibition approach resulted in an enhanced effect on DIPG cell viability in vitro.…”