The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

Abstract

PURPOSE:

PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS.

EXPERIMENTAL DESIGN:

Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models.

RESULTS:

Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis.

CONCLUSIONS:

We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.

• Authors: Katie E Hebron, Xiaolin Wan, Jacob S Roth, David J Liewehr, Nancy E Sealover, William J E Frye, Angela Kim, Stacey Stauffer, Olivia L Perkins, Wenyue Sun, Kristine A Isanogle, Christina M Robinson, Amy James, Parirokh Awasthi, Priya Shankarappa, Xiaoling Luo, Haiyan Lei, Donna Butcher, Roberta Smith, Elijah F Edmondson, Jin-Qiu Chen, Noemi Kedei, Cody J Peer, Jack F Shern, W Douglas Figg, Lu Chen, Matthew D Hall, Simone Difilippantonio, Frederic G Barr, Robert L Kortum, Robert W Robey, Angelina V Vaseva, Javed Khan, Marielle E Yohe
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 2 Pg. 472-487 (01 17 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 36322002 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• ganitumab
• trametinib
• Protein Kinase Inhibitors
• Mitogen-Activated Protein Kinase Kinases

Topics

• Humans
• Animals
• Mice
• Child
• Cell Line, Tumor
• Mice, SCID
• Rhabdomyosarcoma (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Mitogen-Activated Protein Kinase Kinases