Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (36322002)
Authors Hebron KE, Wan X, Roth JS, Liewehr DJ, Sealover NE, Frye WJE, Kim A, Stauffer S, Perkins OL, Sun W, Isanogle KA, Robinson CM, James A, Awasthi P, Shankarappa P, Luo X, Lei H, Butcher D, Smith R, Edmondson EF, Chen JQ, Kedei N, Peer CJ, Shern JF, Figg WD, Chen L, Hall MD, Difilippantonio S, Barr FG, Kortum RL, Robey RW, Vaseva AV, Khan J, Yohe ME
Title The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 29 2 2023 Jan 17 472-487 Clin Cancer Res
URL
Abstract Text 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.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.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.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.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS Q61K rhabdomyosarcoma sensitive Ganitumab + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) synergistically inhibited growth of rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, and resulted in tumor regression and increased survival compared to either treatment alone in a cell line xenograft model (PMID: 36322002). 36322002
NRAS G13D rhabdomyosarcoma sensitive Ganitumab + Trametinib Preclinical - Pdx Actionable In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment resulted in tumor regression and increased progression-free survival in a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring NRAS G13D (PMID: 36322002). 36322002
HRAS G13R rhabdomyosarcoma sensitive Ganitumab + Trametinib Preclinical - Pdx Actionable In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment resulted in tumor regression and increased progression-free survival in a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring HRAS G13R (PMID: 36322002). 36322002
HRAS Q61K PTEN dec exp rhabdomyosarcoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, decreasing Pten expression through shRNA knockdown in a rhabdomyosarcoma cell line harboring HRAS Q61K conferred resistance to Mekinist (trametinib) treatment in culture (PMID: 36322002). 36322002
NRAS Q61H PTEN over exp rhabdomyosarcoma sensitive Ganitumab + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Ganitumab (AMG-479) sensitized a rhabdomyosarcoma cell line harboring NRAS Q61H and overexpressing PTEN to treatment with Mekinist (trametinib), resulting in reduced cell growth in culture (PMID: 36322002). 36322002
HRAS Q61K PTEN dec exp rhabdomyosarcoma sensitive Ganitumab + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Ganitumab (AMG-479) sensitized a rhabdomyosarcoma cell line harboring HRAS Q61K with low PTEN expression to treatment with Mekinist (trametinib), resulting in reduced cell growth in culture (PMID: 36322002). 36322002
NRAS G13R PIK3CA H1047R rhabdomyosarcoma resistant Ganitumab + Trametinib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring NRAS G13R and PIK3CA H1047R was resistant to the Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment (PMID: 36322002). 36322002
NRAS Q61H rhabdomyosarcoma predicted - sensitive Ganitumab + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Mekinist (trametinib) and Ganitumab (AMG-479) synergistically inhibited growth of a rhabdomyosarcoma cell line harboring NRAS Q61H in culture, but did not improve tumor suppression and survival compared to monotherapy in a cell line xenograft model (PMID: 36322002). 36322002