Perspectives on Hypoxia Signaling in Tumor Stroma
Abstract
Simple Summary
Abstract
1. Introduction
2. Hypoxic Response of Tumor Vasculature
3. Hypoxic Response of ECM and CAFs
4. The Effect of Hypoxia on T Cells
4.1. CD4+ T Helper Cells and Regulatory T Cells
4.2. CD8+ Effector T Cells
5. The Effect of Hypoxia on Myeloid Cells
5.1. Tumor-Associated Macrophages
5.2. Myeloid-Derived Suppressor Cells (MDSCs)
5.3. Dendritic Cells
6. Targeting Hypoxia and HIFs in Cancer
6.1. Hypoxia Activated Prodrugs (HAPs)
6.2. Inhibitors of HIF
6.3. Combination with Immune Checkpoint Inhibitors
6.4. Combination with Anti-Angiogenesis Therapy
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinical Trial | Trial Phase | Drug | Mechanism | Disease | References |
---|---|---|---|---|---|
Hypoxia activated prodrug | |||||
NCT03224182 | III | Apaziquone | Indolequinone | Non-muscle invasive bladder cancer | Clinicaltrials.gov |
NCT02174549 | I/II | Tirapazamine + transarterial embolization | Aromatic n-oxide | Liver cancer | Clinicaltrials.gov |
NCT01880359 NCT02661152 | III | Nimorazole + chemoradiotherapy | 5-nitroimidazoles, radiosensitizer | Locally advanced head and neck squamous cell cancer | Clinicaltrials.gov |
HIF inhibitors | |||||
NCT03531827 | II | NLG207 + enzalutamide | HIF-1α/topoisomerase I inhibitor + antiandrogen | Metastatic prostate cancer | [158] |
NCT02769962 NCT04669002 | I/II | EP0057 + olaparib | HIF-1α/topoisomerase I inhibitor + PARP inhibitor | Relapsed/refractory small cell lung cancer Ovarian cancer | Clinicaltrials.gov |
NCT03108066 NCT03216499 | II | PT2385 | HIF-2α inhibitor | Von Hippel-Lindau associated clear cell renal carcinoma Glioblastoma | Clinicaltrials.gov |
NCT02974738 | I | Belzutifan (PT2977) | HIF-2α inhibitor | Advanced solid tumors | Clinicaltrials.gov |
NCT04195750 | III | Belzutifan (MK-6482) | HIF-2α inhibitor | Advanced renal cell carcinoma | Clinicaltrials.gov |
Targeting Associated pathways | |||||
NCT01101438 NCT01864096 NCT01697566 NCT03685409 | III | Metformin | Decreases HIF-1α accumulation | Early-stage breast cancer Low risk prostate cancer Chemoprevention study in endometrial and oral cancer | [149] |
NCT02614339 | III | Metformin + traditional chemotherapy | Decreases HIF-1α accumulation | Recurrent colorectal cancer | [149] |
NCT04275713 | II | Metformin + cisplatin | Decreases HIF-1α accumulation | Locally advanced cervical cancer | [179] Clinicaltrials.gov |
NCT03117920 | II | Minnelide | HSP70, p300 inhibitors | Refractory pancreatic cancer | [149] |
NCT03450018 | I/II | SLC0111+ gemcitabine | CAIX | Metastatic pancreatic cancer | [180] |
NCT04648033 NCT02628080 | I | Atovaquone + chemoradiotherapy | Antimalarial drug; Hypoxia modifier via inhibition of mitochondrial complex III | Locally advanced non-small cell lung cancer | [180] Clinicaltrials.gov |
Combination with immunotherapy or anti-angiogenesis therapy | |||||
NCT03098160 | I | TH-302 + ipilimumab | HAP + anti-CTLA4 Ab | Advanced solid malignancies | [170] |
NCT01652079 | II | NLG207 + bevacizumab | HIF-1α/topoisomerase I inhibitor + anti-VEGF Ab | Ovarian/peritoneal cancer | [158] |
NCT03634540 | II | Belzutifan (PT2977) + cabozantinib | HIF-2α + VEGFR2 inhibitors | Advanced clear cell renal carcinoma | Clinicaltrials.gov |
NCT04895748 | I/Ib | DFF332 + everolimus + spartalizumab | HIF-2α inhibitor + mTOR inhibitor + anti-PD-1 Ab | Relapsed renal cell carcinoma, advanced malignancies with HIF stabilizing mutations | Clinicaltrials.gov |
NCT04114136 | II | Metformin or rosiglitazone + nivolumab or pembrolizumab | Decreases HIF-1α accumulation | Advanced solid tumor malignancies | Clinicaltrials.gov |
Assessment of hypoxia | |||||
NCT03003637 | IB/II | 18F-FDG PET-CT | Pre and post nivolumab +/- ipilimumab | Advanced/recurrent head and neck carcinoma | [171] |
NCT03373994 | 18F-FDG PET-CT | Evaluate tumor perfusion and hypoxia | Solid tumors | Clinicaltrials.gov | |
NCT03646747 | Oxygen enhanced MRI measurement | Pre and post radiotherapy | Head and neck cancer | Clinicaltrials.gov | |
NCT04309552 | FMISO, FLT PET | Compare FMISO, FLT PET vs. molecular biomarkers of hypoxia and cell proliferation | High grade glioma | Clinicaltrials.gov | |
NCT02095249 | Pimonidazole followed by prostatectomy | Measure tumor hypoxia via immunohistochemical staining | Prostate cancer | Clinicaltrials.gov | |
NCT04001023 | 18F-EF5 PET-CT and targeted tumor sampling | Identify molecular differences between hypoxic and non-hypoxic tumors | Advanced ovarian cancer | Clinicaltrials.gov | |
NCT00568490 | Osteopontin, lysyl oxidase, macrophage inhibiting factor and proteomic technology | Identify hypoxic biomarkers in blood and tumors | Head and neck cancer Lung cancer | Clinicaltrials.gov | |
NCT03054792 | 18F-FAZA/BOLD PET-MRI | Measure hypoxia between start and completion of treatment | Pediatric sarcomas | Clinicaltrials.gov | |
Hypoxia assessment + radiotherapy | |||||
NCT04846309 | I | FMISO PET + radiation | Hypoxic tumors receive higher dose of radiation | Esophageal cancer | Clinicaltrials.gov |
NCT02352792 | II | FMISO PET + radiation | Hypoxic tumors receive 10% higher dose of radiation | Head and neck squamous cell carcinoma | Clinicaltrials.gov |
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Zhang, Y.; Coleman, M.; Brekken, R.A. Perspectives on Hypoxia Signaling in Tumor Stroma. Cancers 2021, 13, 3070. https://doi.org/10.3390/cancers13123070
Zhang Y, Coleman M, Brekken RA. Perspectives on Hypoxia Signaling in Tumor Stroma. Cancers. 2021; 13(12):3070. https://doi.org/10.3390/cancers13123070
Chicago/Turabian StyleZhang, Yuqing, Morgan Coleman, and Rolf A. Brekken. 2021. "Perspectives on Hypoxia Signaling in Tumor Stroma" Cancers 13, no. 12: 3070. https://doi.org/10.3390/cancers13123070
APA StyleZhang, Y., Coleman, M., & Brekken, R. A. (2021). Perspectives on Hypoxia Signaling in Tumor Stroma. Cancers, 13(12), 3070. https://doi.org/10.3390/cancers13123070