Prospective use of the single-mouse experimental design for the evaluation of PLX038A

Abstract

Purpose-Defining robust criteria for drug activity in preclinical studies allows for fewer animals per treatment group, and potentially allows for inclusion of additional cancer models that more accurately represent genetic diversity and, potentially, allows for tumor sensitivity biomarker identification.Methods-Using a single mouse design, 32 pediatric xenograft tumor models representing diverse pediatric cancer types (Ewing sarcoma [9], brain [4], rhabdomyosarcoma [10], Wilms tumor [4], and non-CNS rhabdoid tumors [5]) were evaluated for response to a single administration of pegylated-SN38 (PLX038A), a controlled-release PEGylated formulation of SN-38. Endpoints measured were percent tumor regression, and Event Free Survival (EFS). The correlation between response to PLX038A was compared to that for 10 models treated with irinotecan (2.5 mg/kg × 5 days × 2 cycles), using a traditional design (10 mice/group). Correlations between tumor sensitivity, genetic mutations and gene expression were sought. Models showing no disease at week 20 were categorized as 'extreme responders' to PLX038A, whereas those with EFS less than 5 weeks were categorized as 'resistant'.Results-The activity of PLX038A was evaluable in 31/32 models. PLX038A induced >50% volume regressions in 25 models (78%). Initial tumor volume regression correlated only modestly Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

“…Taken together, heterogeneity at different levels strongly argues for a functional precision medicine approach and might be taken into account in screening programs using a fixed number of models 38 . Importantly, experimental-designs using one mouse per tumor have been proposed as approach to test a large number of different tumors in vivo in parallel 39 .…”

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

“…Connecting molecular model characterization and drug response data is an essential avenue in moving towards precision oncology in pediatrics [ 172 ]. Recent reports applying this concept by conducting single-mouse-design studies highlight the feasibility and translational relevance of this approach [ 33 , 174 , 175 ]. Approaches to use PDX models as avatars for individual patients that are parallelly being treated in the clinic are possible in principle, but typically hampered by time-consuming model establishment and variable engraftment rates [ 176 ].…”

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

“…In comparison to irinotecan, PLX038 leads to the sustained release of SN-38, which may result in improved efficacy over conventional topoisomerase I inhibitors due to the accumulation of the drug within tumors [ 91 ]. This agent was evaluated in 32 xenograft models of pediatric cancers, including RMS [ 92 ]. PLX038 was highly active, with 78% of the xenografts experiencing more than a 50% reduction in tumor size after one dose [ 92 ].…”

“…This agent was evaluated in 32 xenograft models of pediatric cancers, including RMS [ 92 ]. PLX038 was highly active, with 78% of the xenografts experiencing more than a 50% reduction in tumor size after one dose [ 92 ]. Additionally, PLX038 showed equal or slightly improved responses in the same study when compared to irinotecan.…”