Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies
Abstract
:1. Introduction
2. Human Papillomaviruses
2.1. HPV Life Cycle
2.2. HPV in Cancer Development
3. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) Signalling Pathways
3.1. Signal Transducer and Activator of Transcription (STAT) Family
3.2. Janus Kinases (JAKs)
3.3. Activation of JAK/STAT Signalling
4. JAK/STAT Signalling in the Immune Response
Interaction of HPV with STAT1/2 Signalling
5. STAT3 and STAT5 are Critical Drivers of HPV-Induced Malignancy
5.1. Interaction of HPV with STAT3 Signalling
5.2. Interaction of HPV with STAT5 Signalling
6. Targeting the JAK/STAT Pathway in HPV-Associated Cancers
6.1. Direct Targeting
6.1.1. Small Molecule Inhibitors
6.1.2. Nucleotide Therapeutics Targeting STAT3/STAT5
6.2. Indirect Targeting
6.2.1. Targeting IL-6 Signalling
6.2.2. Targeting Janus Kinases
7. Conclusions
Funding
Conflicts of Interest
References
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Therapeutic | Target/Mechanism | Indication | Regulatory Status | References |
---|---|---|---|---|
OPB-31121 | STAT3 dimerisation inhibitor | e.g., Advanced solid tumours | Phase I | [183] |
OPB-111077 | [184,185] | |||
IST5-002 | STAT5 dimerisation inhibitor | e.g., pancreatic cancer | Pre-clinical | [186] |
SD-36 | STAT3 [PROTAC] | e.g., leukaemias and lymphomas | Pre-clinical | [187] |
STAT3 decoy | STAT3 response element from FOS gene | HNSCC | Pre-clinical | [188] |
STAT5 decoy | STAT5 decoy oligonucleotide | e.g., leukaemias | Pre-clinical | [189] |
AZD9150 | STAT3 antisense oligonucleotide | e.g., solid tumours, metastatic HNSCC | Phase I/II | [188,190] |
T40214 | G-quartet oligodeoxynucleotides | e.g., HNSCC, liver cancer | Pre-clinical | [191] |
T40231 | e.g., HNSCC, prostate cancer | Pre-clinical | [192] | |
Siltuximab | Anti-IL-6 mAb | e.g., multiple myeloma, solid tumours | Phase I/II | [193,194,195] |
Olokizumab | e.g., RA | Phase II | [196] | |
Tocilizumab | Anti-IL-6R mAb | e.g., RA | FDA approved | [197,198] |
Sarilumab | [199] | |||
Olamkicept | Soluble gp130-Fc fusion protein | e.g., RA, IBD | Phase I/II | [200] |
Tofacitinib | JAK inhibitor | e.g., RA, psoriasis, myelofibrosis | FDA approved | [201] |
Ruxolitinib | FDA approved | [202,203] | ||
Pacritinib | Phase II | [204] |
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Morgan, E.L.; Macdonald, A. Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies. Viruses 2020, 12, 977. https://doi.org/10.3390/v12090977
Morgan EL, Macdonald A. Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies. Viruses. 2020; 12(9):977. https://doi.org/10.3390/v12090977
Chicago/Turabian StyleMorgan, Ethan L., and Andrew Macdonald. 2020. "Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies" Viruses 12, no. 9: 977. https://doi.org/10.3390/v12090977