Table 2 Hypoxia and/or HIF-1-a activity and therapy in EwS
From: Hypoxia and HIFs in Ewing sarcoma: new perspectives on a multi-facetted relationship
Drug | Mode of action | Preclinical data in EwS | Clinical data in pediatric EwS patients | Reference(s) |
|---|---|---|---|---|
Salirasib | Ras inhibitor | In vitro and in vivo growth and migration inhibition Reduction of HIF-1-a levels in vivo | Not tested in pediatric patients | Hameiri-Grossman et al., 2015 |
Melatonin | Hydroxylation and inactivation of HIF-1-a | Induction of ROS and apoptosis in vitro, inhibition of glycolysis | Phase I study tested tolerability in pediatric patients with relapsed solid tumors, no EwS patients included | Sanchez-Sanchez et al., 2015 Johnston et al., 2019 |
Etinostat/ MS-275 | Inhibiton of HIF-1-a translation via inhibition of YB-1 binding to HIF-1-a mRNA | Reduction of metastasis in vivo | Phase I studies show tolerability in pediatric patients including EwS patients | El-Naggar et al., 2019 Bukowinski et al., 2021 Gore et al., 2008 |
Dasatinib | Src inhibitor | In vitro inhibition of migration and invasion, no inhibition of proliferation | Phase II study showed no efficiency as single agent in EwS Phase I/II study on combinational treatment in children with solid tumors ongoing | Bailey et al., 2016 Schuetze et al., 2016 NCT00788125 |
Plerixafor | CXCR4 inhibitor | In vitro inhibition of migration and invasion | Phase I/II study demonstrated tolerability in pediatric patients including EwS patients | Krook et al., 2014 Morland et al., 2020 |
Bevacizumab | VEGF monoclonal antibody | - | Tolerability and responses in EwS patients treated with a combination treatment including Bevacizumab | Kuo et al., 2017 Wagner et al., 2013 |
Irinotecan | DNA damaging agent | No data in EwS available Reduced HIF-1-a levels in glioma and colon cancer | Tolerability and efficacy of combined regimens including irinotecan in advanced EwS patients | Casey et al., 2009 Kurucu et al., 2015 Salah et al., 2021 Xu et al., 2021 |
Geldanamycin | Indirect inhibition of HIF-1-a | - | Phase I study demonstrated tolerability in pediatric patients including EwS patients | Bagatell et al., 2007 Bernauer et al., 2021 NCT00093821 |
Imatinib | Tyrosine-kinase inhibitor | In vitro reduction of HIF-1-a protein levels that were induced under hypoxia (± metformin) In vivo reduction of metastasis in combination treatment with metformin | Phase II studies demonstrated tolerability but no efficacy of imatinib as single agent therapy in relapsed EwS patients | Nan et al., 2020 Chugh et al., 2009 Bond et al., 2008 |