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Updated: May 18, 2026
Orthotopic Xenografting of Human Luciferase-Tagged Malignant Peripheral Nerve Sheath Tumor Cells for in vivo Testing of Candidate Therapeutic Agents
Published on: March 7, 2011
Initial testing (stage 1) of the phosphatidylinositol 3' kinase inhibitor, SAR245408 (XL147) by the pediatric
C Patrick Reynolds1, Min H Kang, Hernan Carol
1Cancer Center, Cancer Center, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6450, USA. patrick.reynolds@ttuhsc.edu
Background:
Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts.
Procedures:
SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14.
Results:
In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7-24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts.
Conclusions:
Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered.
Insights
This study evaluated SAR245408, a PI3K inhibitor, in pediatric cancer models. SAR245408 showed modest activity, suggesting potential for combination therapies in childhood cancers.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The PI3K pathway is crucial in adult cancers but less understood in pediatric malignancies.
- This pathway influences tumor cell proliferation, survival, and treatment resistance.
Purpose of the Study:
- To evaluate SAR245408, a novel PI3K inhibitor, against pediatric cancer cell lines and xenografts.
- To assess the preclinical efficacy of SAR245408 in childhood cancers.
Main Methods:
- SAR245408 was tested in vitro against a panel of pediatric cancer cell lines (10–100 µM).
- In vivo efficacy was assessed using pediatric cancer xenograft models at 100 mg/kg daily for 14 days.
Main Results:
- SAR245408 exhibited cytotoxic activity in vitro (median relative IC50: 10.9 µM).
- In vivo, SAR245408 showed significant efficacy in 79% of solid tumor xenografts and 29% of ALL xenografts.
- Modest tumor growth inhibition was observed, but objective responses were not seen.
Conclusions:
- SAR245408 demonstrated modest single-agent preclinical activity in pediatric cancer models.
- Combination strategies with SAR245408 and other agents warrant further investigation.
