Initial testing of topotecan by the pediatric preclinical testing program

Abstract

Background-Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the PPTP tumor panels as part of a validation process for these preclinical models.

Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition

“…Western blots for vinculin were used as protein loading controls. b Relative p-RET western blot band intensity (pRET/RET) was determined and plotted for each tested cell line Topotecan and temozolomide are chemotherapy agents shown to be effective against neuroblastoma tumors in preclinical models [52,53], and both agents are components of regimens commonly employed to treat children with relapsed neuroblastoma [36,[54][55][56][57]. The efficacy of cabozantinib in combination with topotecan and temozolomide provides an opportunity for testing in early-phase clinical trials for children with relapsed neuroblastoma to determine the safety and tolerability of these combinations.…”

Overview and recent advances in the treatment of neuroblastoma

“…Topotecan and irinotecan are topoisomerase inhibitors that are commonly used for treatment of relapsed neuroblastoma, and both have shown single agent activity in preclinical and clinical studies [99][100][101][102][103][104]. Topotecan is primarily used in combination with cyclophosphamide, and the initial phase II study using cycles of this combination (250 mg/m 2 /day cyclophosphamide and 0.75 mg/m 2 /day topotecan for 5 days each) achieved objective responses in 6 of 13 neuroblastoma patients [105].…”

Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL

“…On recovery, a frank discussion was held to consider palliation, topotecan-based or alternative chemotherapies. Topotecan-based therapy was offered based on the early xenograft response, supporting PPTP data 8 and activity in relapsed ALL. 10 The family agreed to topotecan treatment 10 which commenced 61 days after the 2nd relapse.…”

“…SAR3419 was effective in the PPTP ALL panel. 7 Topotecan and bortezomib were chosen primarily for their activity against the PPTP ALL panel 8,9 and relapsed ALL. 10,11 Mouse engraftment was detected 48 days after the 2nd relapse and 5 mouse PDX cohorts were treated with SAR3419, ATRA, topotecan, bortezomib or control injection vehicle, starting 53 days after relapse.…”

“…Our agent selection for PDX testing, topotecan and bortezomib, was biased towards agents tested in the PPTP ALL xenograft panel with supporting pediatric trial data. [8][9][10][11] We acknowledge that additional agents could have been tested if greater PDX numbers had been available. The PDX-validated topotecan activity, whereas bortezomib was less effective.…”