Table 1.
Current and future TME targets for radiosensitisation
| Resistance mechanism | Drugs | Targets | Mode of action |
|---|---|---|---|
| Immune response | |||
| Ipilimumab | CTLA-4; | T-cell activation | |
| Imiquimod | TLR7; | DC activation | |
| Oncolytic viruses | Tumour cells | Activate immune response | |
| Future inhibitors | IL-6, IL-10 | T-cell activation | |
| PD-1, PD-L1, TIM3, LAG3; | Prevent T-cell exhaustion | ||
| Future agonists | GM-CSF, CXCL16, OX40, CD40L, CD80, CD137 (4-1BBL); | T-cell recruitment and activation | |
| CCL3, CCL5, IL-2, IL-4, IL-12, IRX-2; | Activate immune response | ||
| Hypoxia | |||
| Nitromidazole derivatives (i.e. Nimorazole) | Hypoxic cells | Reduce tumour hypoxia | |
| Bioreactive albumin-MnO2 nanoparticles | Hypoxic cells | Reduce tumour hypoxia | |
| Acriflavine, YC-1 | HIF-1α; | Reduce hypoxia response pathways | |
| Aflibercept | all VEGF molecules and PlGF; | Vessel normalisation | |
| AMG386 | ANG-1, ANG-2; | Inhibit pBMDC recruitment | |
| Endostar | VEGF, TGF-β, HIF-1α, bFGF; | Inhibit angiogenesis | |
| AMD3100 | CXCL12, CXCR4; | Inhibit BMDC recruitment and vasculogenesis | |
| Integrin inhibitors (i.e. Cilengitide, Vitaxin and Volociximab) | Integrins αvβ3, αvβ5, α5β1 | Inhibit angiogenesis | |
| Future inhibitors | Integrins α6β1, α6β4; | Reduce EC survival and inhibit angiogenesis | |
| Future inhibitors | PlGF, ANG-2; | Vessel normalisation and overcome resistance to anti-VEGF therapies | |
| Fibrotic processes | |||
| BIBF1000, BIBF1120 | PDGF, VEGF, bFGF receptors; | Reduce GF signalling and TME remodelling; fibrosis | |
| Imatinib, Nilotinib, Dasatanib | TGF-β, PDGF | GF signalling; collagen synthesis | |
| Vismodegib, Saredigb, Sonedegib | SMO; | Reduce HH signalling; fibrosis | |
| Suramin | PDGF, EGF, TGF-β, FGF-2 and IGF receptors and heparanase enzymes; | Reduce GF signalling and TME remodelling; fibrosis | |
| ST0001, PG545, M402, PI-88 | Heparanase; | Inhibit TME remodelling | |
| SD-208 | TGF-βRI; | Inhibit TGF-β signalling | |
| Simtuzumab | LOXL2; | Reduce TME remodelling; liver fibrosis | |
| 81C6, F16SIP | TN-C; | Reduce CAF-mediated TME remodelling | |
| Future inhibitors | HGF, CTGF, MMP-2, MMP-3, Integrins α11β1, αvβ6 and α3β1; | TME activation and remodeling; radiation-mediated fibrosis | |
Abbreviations: ANG-1/-2, angiopoetin 1 and 2; bFGF, basic fibroblast growth factor; BMDC, bone marrow-derived cells; CTGF, connective tissue growth factor; CTLA-4, cytotoxic T- lymphocyte associated protein 4; DC, dendritic cells; EGF, epithelial growth factor; FGF-2, fibroblast growth factor 2; GF, growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; HH, hedgehog; HIF-1α, hypoxia inducible factor 1α; IGF, insulin growth factor; IRX2, iroquois homeobox 2; LAG3, lymphocyte activation gene 3; LOXL2, lysyl oxidase-like 2; MMP-2/ -3, matrix metalloproteinase 2 and 3; pBMDC, perivascular bone marrow-derived cells; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PDGF, platelet-derived growth factor; PlGF, placental growth factor; SMO, smoothened; TGF-β, transforming growth factor β; TGF-βR1, transforming growth factor β receptor 1; TIM3, T-cell immunoglobulin mucin 3; TLR7, toll-like receptor 7; TME, tumour microenvironment; TN-C, tenascin C; VEGF, vascular endothelial growth factor