PMID- 36320041
OWN - NLM
STAT- MEDLINE
DCOM- 20221103
LR  - 20221105
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 41
IP  - 1
DP  - 2022 Nov 2
TI  - Targeting hypoxia in solid and haematological malignancies.
PG  - 318
LID - 10.1186/s13046-022-02522-y [doi]
LID - 318
AB  - Tumour hypoxia is a known and extensively researched phenomenon that occurs in 
      both solid and haematological malignancies. As cancer cells proliferate, demand 
      for oxygen can outstrip supply reducing tumour oxygenation. In solid tumours this 
      is contributed to by disorganized blood vessel development. Tumour hypoxia is 
      associated with resistance to treatment, more aggressive disease behaviour and an 
      increased likelihood of metastatic progression. It can be measured using both 
      invasive and non-invasive methods to varying degrees of accuracy. The presence of 
      hypoxia stimulates a complex cellular network of downstream factors including 
      Hypoxia Inducible Factor 1 (HIF1), C-X-C motif chemokine 4 (CXCR4) and 
      Hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) amongst many others. They 
      work by affecting different mechanisms including influencing angiogenesis, 
      treatment resistance, immune surveillance and the ability to metastasize all of 
      which contribute to a more aggressive disease pattern. Tumour hypoxia has been 
      correlated with poorer outcomes and worse prognosis in patients. The correlation 
      between hypoxic microenvironments and poor prognosis has led to an interest in 
      trying to therapeutically target this phenomenon. Various methods have been used 
      to target hypoxic microenvironments. Hypoxia-activated prodrugs (HAPs) are drugs 
      that are only activated within hypoxic environments and these agents have been 
      subject to investigation in several clinical trials. Drugs that target downstream 
      factors of hypoxic environments including HIF inhibitors, mammalian target of 
      rapamycin (mTOR) inhibitors and vascular endothelial growth factor (anti-VEGF) 
      therapies are also in development and being used in combination in clinical 
      trials. Despite promising pre-clinical data, clinical trials of hypoxia targeting 
      strategies have proven challenging. Further understanding of the effect of 
      hypoxia and related molecular mechanisms in human rather than animal models is 
      required to guide novel therapeutic strategies and future trial design. This 
      review will discuss the currently available methods of hypoxia targeting and 
      assessments that may be considered in planning future clinical trials. It will 
      also outline key trials to date in both the solid and haemato-oncology treatment 
      spheres and discuss the limitations that may have impacted on clinical success to 
      date.
CI  - (c) 2022. The Author(s).
FAU - Harris, Bill
AU  - Harris B
AD  - Experimental Cancer Medicine Team, Christie NHS Foundation Trust, Manchester, UK.
FAU - Saleem, Sana
AU  - Saleem S
AD  - Haematology Department, Christie NHS Foundation Trust, Manchester, UK.
FAU - Cook, Natalie
AU  - Cook N
AD  - Experimental Cancer Medicine Team, Christie NHS Foundation Trust, Manchester, UK.
AD  - Division of Cancer Sciences, University of Manchester, Manchester, UK.
FAU - Searle, Emma
AU  - Searle E
AUID- ORCID: 0000-0002-3942-3081
AD  - Haematology Department, Christie NHS Foundation Trust, Manchester, UK. 
      emma.searle9@nhs.net.
AD  - Division of Cancer Sciences, University of Manchester, Manchester, UK. 
      emma.searle9@nhs.net.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20221102
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Cell Hypoxia
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Hypoxia
MH  - *Neoplasms/pathology
MH  - *Hematologic Neoplasms
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Mammals/metabolism
MH  - Tumor Microenvironment
PMC - PMC9628170
OTO - NOTNLM
OT  - Cancer
OT  - Haematological
OT  - Hypoxia
OT  - Solid tumours
COIS- The authors declare no competing financial interests.
EDAT- 2022/11/03 06:00
MHDA- 2022/11/04 06:00
PMCR- 2022/11/02
CRDT- 2022/11/02 00:50
PHST- 2022/04/14 00:00 [received]
PHST- 2022/10/19 00:00 [accepted]
PHST- 2022/11/02 00:50 [entrez]
PHST- 2022/11/03 06:00 [pubmed]
PHST- 2022/11/04 06:00 [medline]
PHST- 2022/11/02 00:00 [pmc-release]
AID - 10.1186/s13046-022-02522-y [pii]
AID - 2522 [pii]
AID - 10.1186/s13046-022-02522-y [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2022 Nov 2;41(1):318. doi: 10.1186/s13046-022-02522-y.