Related Experiment Video
Updated: Dec 31, 2025
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
Prospective use of the single-mouse experimental design for the evaluation of PLX038A
Samson Ghilu1, Qilin Li1, Shaun D Fontaine2
1Greehey Children's Cancer Research Institute, UT Health San Antonio, 8403 Floyd Curl Drive, San Antonio, TX, 78229, USA.
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 ten 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 with EFS (r2 = 0.238), but sensitivity to PLX038A was better correlated with response to irinotecan when one tumor hypersensitive to PLX038A was omitted (r2 = 0.6844). Mutations in 53BP1 were observed in three of six sensitive tumor models compared to none in resistant models (n = 6).
Conclusions:
This study demonstrates the feasibility of using a single-mouse design for assessing the antitumor activity of an agent, while encompassing greater genetic diversity representative of childhood cancers. PLX038A was highly active in most xenograft models, and tumor sensitivity to PLX038A was correlated with sensitivity to irinotecan, validating the single-mouse design in identifying agents with the same mechanism of action. Biomarkers that correlated with model sensitivity included wild-type TP53, or mutant TP53 but with a mutation in 53BP1, thus a defect in DNA damage response. These results support the value of the single-mouse experimental design.
Insights
A novel single-mouse design effectively evaluated drug activity in diverse pediatric cancer models, showing pegylated-SN38 (PLX038A) is highly active and its sensitivity correlates with irinotecan response. This approach enhances preclinical cancer research efficiency.
Area of Science:
- Oncology
- Preclinical Drug Development
- Cancer Genomics
Background:
- Robust preclinical criteria are essential for efficient drug activity assessment.
- Evaluating novel agents across diverse cancer models improves translational relevance.
- Identifying biomarkers of drug sensitivity aids personalized medicine.
Purpose of the Study:
- To assess the feasibility and efficacy of a single-mouse experimental design for evaluating preclinical drug activity.
- To determine the antitumor activity of pegylated-SN38 (PLX038A) in a diverse panel of pediatric cancer xenografts.
- To identify potential biomarkers correlating with drug sensitivity.
Main Methods:
- A single-mouse design was employed to test 32 pediatric xenograft models with pegylated-SN38 (PLX038A).
- Endpoints included tumor regression and event-free survival (EFS).
- Responses were compared to irinotecan treatment in a traditional 10-mouse/group design; genetic mutations were analyzed.
Main Results:
- Pegylated-SN38 (PLX038A) showed significant activity, inducing >50% volume regressions in 78% of evaluable models.
- Sensitivity to PLX038A correlated with irinotecan response (r²=0.6844, excluding one outlier).
- Mutations in 53BP1 were found in sensitive models, suggesting a role in DNA damage response.
Conclusions:
- The single-mouse design is a feasible and efficient method for evaluating drug efficacy across diverse cancer models.
- Pegylated-SN38 (PLX038A) demonstrates broad activity in pediatric xenografts.
- Biomarkers such as wild-type TP53 or specific 53BP1 mutations may predict sensitivity to DNA damage response-targeting agents.
