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Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program
John M Maris1, Joshua Courtright, Peter J Houghton
1Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA. maris@chop.edu
Background:
Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT.
Procedures:
Sunitinib was tested at concentrations ranging from 0.1 nM to 1.0 microM against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 days by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies.
Results:
The leukemia cell line, Kasumi-1 (gain-of-function KIT(Asn822Lys) mutation) was the only line with an in vitro response to sunitinib (IC(50) 75.7 nM). Sunitinib significantly prolonged EFS in 19 of 35 (54%) of the solid tumor, and in 3 of 8 (38%) of the ALL xenografts analyzed. Using the PPTP time to event measure of efficacy, sunitinib had intermediate (13) and high (1) levels of activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 rhabdomyosarcoma, 4 of 5 Ewing tumor, and 2 of 3 rhabdoid tumor xenografts. Following cessation of treatment for the 14 solid tumor xenografts without tumor events by day 28, tumor growth rate increased in most. The only regression noted to sunitinib in the solid tumor panels was a complete response in a rhabdoid tumor xenograft.
Conclusions:
Sunitinib demonstrated significant tumor growth inhibition against most of the PPTP's solid tumor panels, but little activity against the neuroblastoma and ALL panel. Antitumor activity was manifested primarily as tumor growth delay, consistent with an anti-angiogenic effect for sunitinib against many of the pediatric preclinical models evaluated. Pediatr Blood Cancer 2008;51:42-48. (c) 2008 Wiley-Liss, Inc.
Insights
Sunitinib showed significant tumor growth inhibition in pediatric solid tumor models but limited effectiveness against neuroblastoma and ALL. Its anti-angiogenic effects primarily caused tumor growth delay in preclinical models.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Research
Background:
- Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor.
- It targets PDGF receptors, VEGF receptors, FLT3, and KIT.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of sunitinib in pediatric cancer models.
- To assess sunitinib's activity against various pediatric cancer histologies.
Main Methods:
- Sunitinib was tested in 23 pediatric cancer cell lines in vitro.
- Sunitinib efficacy was evaluated in 46 murine xenograft models across 9 pediatric cancer types.
- Drug administration was via oral gavage for 28 days.
Main Results:
- Kasumi-1 leukemia cell line with a KIT mutation showed in vitro response (IC50 75.7 nM).
- Sunitinib significantly prolonged event-free survival in 54% of solid tumor xenografts and 38% of ALL xenografts.
- Activity was observed against rhabdomyosarcoma, Ewing tumor, and rhabdoid tumor xenografts, with one complete response in a rhabdoid tumor.
Conclusions:
- Sunitinib demonstrated significant tumor growth inhibition in most pediatric solid tumor models.
- Activity was limited against neuroblastoma and ALL models.
- The primary antitumor effect was tumor growth delay, suggesting an anti-angiogenic mechanism.
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