Background
Hypoxia-inducible transcription factors (HIFs)
Hypoxia definitions
Hypoxia in normal bone marrow
Hypoxia in the pathophysiology of haematological malignancies
Hypoxia in the pathophysiology of solid tumours
Angiogenesis and hypoxia
Treatment resistance
Clinical assessment of hypoxia
Method | Advantages | Disadvantages |
---|---|---|
Oxygen Electrodes | Around 100 measurements taken- good overview of area No major adverse effects | Surface lesions only Invasive No repeat measurements Cannot account for necrotic areas- will give discordant results Artifacts-excessive oxygen consumption Technically skilled user and inter-operator variability |
Phosphorescence quenching | Real time oxygenation information Readings are independent of tracer concentrations | Invasive technique Technically skilled user Early in development- limited availability |
Electron Paramagnetic Resonance oximetry | Implantable technology- repeated results. Can monitor effects of treatment Absolute pO2 readings | Invasive- needs a direct probe in situ Early in development- limited availability |
Endogenous markers | Not affected by the sampling time or microenvironment It can be correlated within the same sample against other markers of tumour hypoxia | Cell line specific Can be affected by metabolic factors that vary between cells |
Dynamic contrast-enhanced magnetic resonance imaging | Non-invasive Widely available Radiology departments familiar with method and equipped to perform and report imaging Can be repeated to monitor effects of treatment with relative accuracy | When administered IV mostly absorbed in liver/spleen. Amount in tumours often insufficient to get an accurate reading Cleared within days- limited time period for collecting data When administered into tumour can only read oxygen tension within that area of the tumour Readings significantly affected by temperature |
Blood-oxygen level dependent magnetic resonance imaging | Non-invasive Can detect changes in tumour hypoxia over time | Small movements can lead to poor images and artefact Not a direct measure of oxygenation and therefore independent variables can interfere with measurements |
Positron emission tomography imaging | Non-invasive Widely available Familiar method- clinicians and radiology departments used to dealing with images and results Repeated measurements possible Enables the visualization of the hypoxic status of the entire tumour in 3D image | Varying tracers used result in varying uptake levels and result in some discrimination between hypoxic levels Relatively short half life of tracer means it must be manufactured and imaged within several hours |
Pimonidazole | Non-invasive Good prognostic correlation | Limited availability Requires tumour biopsy after administration of Pimonidazole- tumour needs to be accessible Invasive |
Direct methods
Tissue based methods
Endogenous markers
Imaging techniques
Hypoxia targeting strategies
Hypoxia-activated Prodrugs (HAPs)
HIF Pathway Inhibitors
Clinical trials of hypoxia targeting strategies
Target | IMP | Treatment | Trial Phase | Patients Treated | Disease type | Findings | Reference |
---|---|---|---|---|---|---|---|
Hypoxia-activated Prodrugs | Evofosfamide (TH-302) | Pazopanib + Evofosfamide | I | 30 | All solid tumours | Partial response in 10%, stable disease in 57%, progressive disease in 23% of patients | (Riedel et al., 2017) [114] |
Evofosfamide monotherapy in relapsed/refractory leukaemia | I | 49 | Acute myeloid/lymphoid leukaemia | Reduced HIF1a/CAIX but only 6% overall response rate | (Badar et al., 2016) [115] | ||
Gemcitabine Vs Gemcitabine + Evofosfamide | II | 214 | Pancreatic | Extended progression-free survival (5.6 vs 3.6 months; p = 0.005), greater reduction in tumour burden (p = 0.04) and CA19.9 levels (p = 0.008) with addition of Evofosfamide. No significant difference in overall survival | (Borad et al., 2015) [116] | ||
Evofosfamide + Dexamethasone ± Bortezomib | I-II | 59 | Multiple myeloma | Stable disease (38/59) or better in 80% patients across all cohorts | (Laubach et al., 2019) | ||
Doxorubicin Vs Doxorubicin + Evofosfamide | III | 640 | Soft-tissue sarcoma | No survival benefit (18.4 months combination therapy Vs 19.0 months Doxorubicin monotherapy median overall survival) | (Tap et al., 2017) [117] | ||
Gemcitabine Vs Gemcitabine + Evofosfamide | III | 693 | Pancreatic | Overall survival endpoint not quite met (8.7 months combination therapy Vs 7.6 months Gemcitabine monotherapy; p = 0.059). Median progression-free survival 5.5 months combination therapy V 3.7 months Gemcitabine monotherapy (P = 0.004) | (Van Cutsem et al., 2016) [119] | ||
Tirapazamine (SR-4233) | Tirapazamine (TPZ) + Carboplatin + Paclitaxel | I | 42 | All solid tumours | 8% complete response, 5% partial response, 60% stable disease, 26% progression of disease | (Lara et al., 2003) [120] | |
Cisplatin + radiotherapy + Tirapazamine | I | 16 | Oesophageal adenocarcinoma | Three year overall survival 88%, but omission of Tirapazamine needed in latter cycles to avoid dose-limiting toxicity of neutropenia | (Rischin et al., 2001) [121] | ||
Arterial Embolisation + Tirapazamine | I | 27 | Hepatocellular carcinoma | 60% complete response, 84% objective response | (Abi-Jaoudeh et al., 2021) [122] | ||
Cisplatin + Etoposide + radiotherapy + Tirapazamine | II | 69 | Limited-stage small cell lung cancer | Median progression-free survival 11 months, median overall survival 21 months | (Le et al., 2009) [123] | ||
Paclitaxel + Carboplatin ± Tirapazamine | III | 367 | Non-small cell lung cancer | Overall survival end-points not reached, significantly more adverse events leading to treatment cessation when Tirapazamine added to combination therapy (p < 0.05), mostly due to myelosuppression | (Williamson et al., 2005) [124] | ||
PR-104 | PR-104 + Docetaxel or Gemcitabine | I | 42 | All solid tumours | 9.5% partial response overall, significant myelosuppression prevented further analysis of combo + Gemcitabine | (McKeage et al., 2012) [125] | |
PR-104 | I | 27 | All solid tumours | No objective responses were observed | (Jameson et al., 2010) [126] | ||
PR-104 | I-II | 50 | Acute myeloid/lymphoid leukaemia | Objective response in 32% AML and 20% ALL patients | (Konopleva et al., 2015) [127] | ||
HIF Signalling | Belzutifan | Belzutifan | I | 98 | Renal cell carcinoma | Objective response in 25%, median progression-free survival was 14.5 months | (Choueiri et al., 2021) [112] |
Belzutifan | II | VHL-associated tumours | Objective response in 49% renal cell carcinomas, 77% pancreatic lesions, 30% CNS haemangioblastomas, 100% retinal haemangioblastomas | (Jonasch et al., 2021) [111] | |||
PT2385 | PT2385 | I | 51 | Renal cell carcinoma | 2% complete response, 12% partial response, 52% stable disease | (Courtney et al., 2018) [113] | |
CRLX101 | CRLX101 + Bevacizumab | I-II | 22 | Renal cell carcinoma | 23% partial response, 55% achieving progression-free survival of more than four months | (Keefe et al., 2016) [109] | |
CRLX101 + Bevacizumab Vs standard of care (SOC) therapy | II | 111 | Renal cell carcinoma | No improvement in progression-free survival (3.7 months CRLX101 + Bevacizumab Vs 3.9 months SOC therapy; p = 0.831) or objective response (5% CRLX101 + Bevacizumab Vs 14% SOC therapy; p = 0.836) | (Voss et al., 2017) [110] | ||
PX-12 | PX-12 (thioredoxin-1 inhibitor) | I | 38 | All solid tumours | 18% stable disease, as best response observed | (Ramanathan et al., 2007) [128] | |
PX-12 | I | 14 | All solid tumours | 7% stable disease, as best response observed | (Ramanathan et al., 2012) [129] | ||
Tanespimycin | Tanespimycin + Bortezomib | I | 17 | All solid tumours | 6% stable disease, as best response observed | (Schenk et al., 2013) [102] | |
CXCR4 (haematological malignancies) | BL-8040 | BL-8040 + Ara-C | II | 42 | Acute myeloid leukaemia | 29% complete remission ± incomplete haematological recovery. Median overall survival 8.4 months | (Borthakur et al., 2021) [130] |
Plerixafor | Plerixafor + high-dose cytarabine + etoposide | I | 19 | Acute myeloid/lymphoid leukaemia, myelodysplastic syndrome | 16% objective response, exclusively in acute myeloid leukaemia | (Cooper et al., 2017) [131] | |
Plerixafor + Decitabine | I | 69 | Acute myeloid/lymphoid leukaemia, myelodysplastic syndrome | 43% objective response | (Roboz et al., 2018) [132] | ||
Plerixafor + FLAG-IDA | I-II | 41 | Acute myeloid leukaemia | Complete remission ± incomplete haematological recovery in 50% and 47% of primary refractory and early relapse groups respectively | (Martínez-Cuadrón et al., 2018) [133] | ||
Ulocuplumab | Ulocuplumab + MEC (mitoxantrone + etoposide + cytarabine) | I | 73 | Acute myeloid leukaemia | Complete remission ± incomplete haematological recovery in 51% combination therapy compared with 24–28% in those receiving MEC alone | (Becker et al., 2014) [134] |