Table 2 Preclinical and clinical strategies for targeting hypoxia in newly diagnosed and recurrent GBM and their limitations upon the clinical translation.
From: Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme
Strategies to target hypoxia in GBM | Molecules | Mode of action | Limitations |
|---|---|---|---|
Hypoxia signaling pathways | OKN-007, 103D5R, KC7F2, Cardiac glycosides, PX-478, Vorinostat, Panobinostat, Topotecane, Icaritin, Acriflavine, Echinomycin, KCN1 | Inhibit HIF-1α | Risks of unintended adverse side effects linked to the ubiquitous expression of HIF-1α in non-tumor tissue [8] |
PT2385 | Inhibits HIF-2α | - PT2385, presented anti-tumoral activity in a phase I trial (NCT02293980) in patients with clear renal cell carcinoma, but no responses were demonstrated in a phase II (NCT03216499) trial with recurrent GBM patients - Limited activity in first recurrent GBM, acidic lesions were correlated with treatment duration (NCT03216499) | |
Reoxygenation | Trans-sodium crocetinate | Enhances oxygen diffusion by organizing the water matrix | Diffusion, stability, and bioavailability issues [62] |
Myo-inositol trispyrophosphate | Enhances oxygen release from RBCs and stabilizes tumor vascularization | No sufficient data and no clinical trials on GBM models | |
Hyperbaric oxygen therapy | Elevates atmospheric pressure (>1 ATA) with 100% O2 | No sham group was used to assess the efficacy of HBOT and the timespan between HBOT and RT seemed unreasoned [59] | |
Carbogen and nicotinamide | - Increase dissolved oxygen - Increase the uniformity of tumor blood perfusion and reduce the intermittent closure of blood vessels | Tolerance issues and increased toxicities [60] | |
Dodecafluoropentane emulsion | - Carries large amounts of oxygen - Enhances oxygen deposit | - Radionecrosis [64] - No sufficient data on OS in GBM | |
Anti-angiogenesis | Bevacizumab | Neutralizes the biological activity of VEGF-A | - Beneficial effects on the PFS [74] - No positive impact on the OS outcome [68, 72] - Grade 3–4 complications including cerebrovascular events and embolism [70] |
SU1498 | Selectively inhibits VEGFR2 | No clinical trials available on GBM | |
Cilengitide | Selectively inhibits the activation of αvβ3 and αvβ5 integrins | Did not improve the OS of GBM patients upon combination with TMZ [84] | |
Si306 | Antagonizes c-SRC | No clinical trials available on GBM | |
Cediranib, vandetanib | Inhibit VEGF receptor tyrosine kinase | Did not improve the PFS or OS of GBM patients upon combination with TMZ and RT [85] | |
Galunisertib | Inhibits TGF-β | No clinical data results available on GBM | |
Celastrol | Inhibits PI3K/Akt/mTOR pathway | No clinical trials available on GBM | |
Isolinderalactone | Suppresses the expression of VEGF | No clinical trials available on GBM | |
Cellular oxygen consumption | Atovaquone, Doramectin, Ivermectin, Mefloquine, Chloroquine, and Quinacrine | - Anti-parasitic drugs - Inhibit the mitochondrial respiration | Only chloroquine have been assessed in GBM clinical trials with no published results so far |
Metformin | -Anti-diabetic drug (type II diabetes) - Reprograms oxygen metabolism | Did not improve the OS of patients upon combination with low-dose TMZ in refractory and recurrent GBM [86] |
