Related Experiment Video
Updated: Dec 7, 2025
An Orthotopic Sciatic Nerve Xenograft for Neurofibromatosis Type 1 Neurofibromas
Published on: October 10, 2025
Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts
Erin Butler1, Blake Schwettmann1, Sophie Geboers2
1Department of Pediatrics Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
Background:
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date.
Procedure:
We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3'-deoxy-3'-[18 F]fluorothymidine (18 F-FLT) PET imaging followed by 18 F-FDG PET/CT imaging of MPNST xenografts coupled to short-term or longer-term treatment with selumetinib focusing on PET-based imaging as a biomarker of MEK inhibition.
Results:
Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by 18 F-FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib.
Conclusion:
The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by 18 F-FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell-cycle arrest.
Insights
Selumetinib prolonged survival in malignant peripheral nerve sheath tumor (MPNST) models by reducing cell proliferation. 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) PET imaging may serve as an early biomarker for MEK inhibitor response in MPNST.
Area of Science:
- Oncology
- Pharmacology
- Medical Imaging
Background:
- Malignant peripheral nerve sheath tumor (MPNST) is an aggressive pediatric soft-tissue sarcoma with poor survival rates, especially in metastatic cases.
- RAS pathway activation is frequent in MPNST, making MEK pathway inhibition a potential targeted therapy, though clinical outcomes have been limited.
- Existing therapies offer little hope for children with advanced MPNST.
Purpose of the Study:
- To evaluate the preclinical efficacy and pharmacodynamics of two MEK inhibitors, trametinib and selumetinib, in MPNST models.
- To investigate the utility of 3 -deoxy-3 -[18F]fluorothymidine (18F-FLT) and 18F-FDG PET/CT imaging as biomarkers for MEK inhibition response in MPNST.
Main Methods:
- Conducted pharmacokinetic and pharmacodynamic studies of trametinib and selumetinib in MPNST xenograft models.
- Analyzed intratumor drug levels, pERK and Ki67 expression, and animal survival.
- Utilized 18F-FLT PET/CT and 18F-FDG PET/CT imaging to assess tumor proliferation and response to selumetinib treatment.
Main Results:
- Trametinib reduced pERK but did not improve survival or decrease Ki67.
- Selumetinib significantly prolonged survival, correlating with decreased pERK and Ki67, and higher unbound drug fractions in responsive models.
- 18F-FLT uptake positively correlated with Ki67 expression and response to selumetinib.
Conclusions:
- MEK inhibitor efficacy in MPNST is not solely predicted by serum levels or pERK changes.
- 18F-FLT PET imaging shows promise as an early response biomarker for targeted therapies like MEK inhibitors, particularly for assessing cell-cycle arrest.
- Selumetinib demonstrates therapeutic potential in MPNST models, with 18F-FLT PET as a valuable tool for monitoring treatment response.
More Related Videos
07:10Orthotopic Xenografting of Human Luciferase-Tagged Malignant Peripheral Nerve Sheath Tumor Cells for in vivo Testing of Candidate Therapeutic Agents
Published on: March 7, 2011
10:04Radionuclide-fluorescence Reporter Gene Imaging to Track Tumor Progression in Rodent Tumor Models
Published on: March 13, 2018