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Table 1 Therapies targeting hypoxia or hypoxic downstream effects in pancreatic adenocarcinoma

From: Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Category Mechanism Drug(s) Clinical trials in pancreatic adenocarcinoma
Simulates increased oxygen levels Electron affinity increases free radical formation Misonidazole Pre-clinical, non-pancreatic cancers
  Promote oxygen dissociation from hemoglobin OXY111A NCT02528526 (unknown)
  Small molecule enzyme mimetic that converts superoxide to hydrogen peroxide and oxygen GC4419 NCT03340974 (recruiting)
Hypoxia-activated pro-drug Converted to active cytotoxic drug via cellular reductases Evofosfamide (TH-302)—Mustard
Apaziquone (E09)—Mitomycin C
Tirapazamine—Free radical
NCT01746979 (completed), NCT02402062 (active), NCT00743379 (completed), NCT02047500 (terminated)
  Hypoxia activated topoisomerase Banoxantrone/AQ4N NCT00090727 (unknown)
Hypoxia-targeting fusion protein Protein-transduction domain, oxygen dependent degradation domain similar to HIF-1α, and cleaved caspase 3 pro-enzyme or other cytotoxic element POP33 Pre-clinical
Gene-Directed Enzymatic Pro-drug Therapy (GDEPT) Viral vectors transfer heterologous gene to tumor cells and hypoxia response element in promoter causes increased transcription of target gene in hypoxia to convert pro-drug to active form Vectors (retroviruses) containing suicide genes such as Herpes simplex virus thymidine kinase, cytosine deaminase, or cytochrome P450 Pre-clinical
Direct HIF inhibition Binds to HIF-1α and/or HIF-2α and inhibits dimerization and transcription Acriflavine
PT2385
Pre-clinical, Non-pancreatic cancers
  Inhibits HSP 90 leading to HIF-1α degradation XL888
Geldanamycin/tanespimycin
Luminespib (AUY922)
NCT03095781 (recruiting)
NCT00577889 (completed)
NCT01484860 (terminated)
Inhibition of major pathways influenced by HIF STAT3 inhibitor Napabucasin (BBI608)—small molecule
AZD9150—antisense oligonucleotide
NCT02231723 (active)
NCT02983578 (recruiting)
  Notch inhibition via gamma-secretase inhibitor MK-0752
Demcizumab
RO4929097
NCT01098344 (completed), NCT02289898 (completed), NCT01145456 (completed), NCT01131234 (completed), NCT01232829 (completed)
  Notch inhibition via binding delta-like ligand 4 TGR-1202 NCT02574663 (active)
  Notch inhibition via antibody targeting Notch 2/3 receptors Tarextumab (OMP-59R5) NCT01647828 (completed)
  PI3K inhibition via small molecule binding Alpelisib (BYL719)
Buparlisib (BKM120)
Rigosertib (ON 01910.Na)
Gedatolisib
LY3023414
Dactolisib (BEZ235)
NCT02077933 (active), NCT02155088 (active)
NCT01571024 (completed), NCT01360853 (completed), NCT03065062 (recruiting), NCT02981342 (active)
NCT01658436 (completed), NCT01155453 (completed), NCT01337765 (completed)
  Hedgehog signaling pathway inhibition via signal transducer smoothened inhibition by small molecule Sonidegib (LDE-225)
Vismodegib (GCD-0449)
Saridegib (IPI-926)
NCT01487785 (completed), NCT01195415 (completed), NCT01064622 (completed), NCT00878163 (active), NCT01537107 (suspended), NCT01383538 (completed)
Inhibition of metabolic changes associated with hypoxia Shifts cell metabolism from glycolysis to oxidate phosphorylation BPM31510—liposomal CoQ10 NCT02650804 (recruiting)
  Indolamine 2,3 dioxygenase-1 inhibitor to prevent trypthophan depletion Epacadostat NCT03006302 (recruiting), NCT03432676 (withdrawn)
  Inhibition of CD73 to prevent adenosine accumulation CPI-006—anti-CD73 humanized antibody
Oleclumab (MEDI9447)—anti-CD73 monoclonal antibody
NCT03454451 (recruiting)
NCT03611556 (recruiting)
  Inhibition of A2A adenosine receptor to prevent adenosine binding on lymphocytes NIR178—small molecule
CPI-444—small molecule
NCT03207867 (recruiting)
NCT03454451 (recruiting)
  Interference with MMP-9 upregulation Zoledronic acid—decrease MMP-9 production by myeloid derived cells
Andecaliximab—Anti-MMP-9 monoclonal antibody
NCT00892242 (terminated)
NCT01803282 (active)
Inhibition of cytokines upregulated by hypoxia TGF-β inhibition via prevention of binding to receptor or signal transduction Galunisertib—TGFbR1
Vactosertib—binds TGFbR1
M7824—fusion protein binds TGFbR2
NIS793—monoclonal antibody to TGFb
NCT02734160 (active), NCT02154646 (completed), NCT01373164 (completed), NCT03666832 (not yet recruiting), NCT03451773 (suspended), NCT02947165 (recruiting)
  TGF-β inhibition via TGF-β2 antisense oligonucleotide AP 12009 NCT00844064 (completed)
  IL-6 inhibition Tocilizumab—anti-IL-6 receptor
Siltuximab—anti-IL-6
NCT02767557 (recruiting)
NCT00841191 (completed)
Inhibition of chemokines upregulated by hypoxia Prevention of PD-1/PD-L1 checkpoint inhibition via anti- PD-L1 antibodies Durvalumab
Avelumab
M7824
LY3300054
Atezolizumab
NCT03257761 (recruiting), NCT03376659 (recruiting), NCT02403271 (completed), NCT03245541 (recruiting), NCT03572400 (recruiting), NCT02868632 (recruiting), NCT02639026 (recruiting), NCT02734160 (active), NCT03344172 (recruiting), NCT03637491 (recruiting), NCT03829501 (recruiting)
  Inhibition of Treg migration via CCR2/CCR5 antagonist BMS-813160—small molecule NCT03184870 (recruiting), NCT03767582 (not yet recruiting)
  Inhibition of MDSC and Treg recruitment via decreased CXCR4 inhibition BL-8040—small molecule
Plerixafor—small molecule
NCT02907099 (recruiting), NCT02826486 (unknown), NCT03277209 (active), NCT02179970 (completed)
  Inhibition of MDSC and Treg recruitment via decreased CXCL12(SDF-1) inhibition Olaptesed—small molecule NCT03168139 (active)
  1. HIF, hypoxia-inducible factor; STAT, signal transducer and activator of transcription; PI3K, phosphoinositide 3-kinase; HSP, heat shock protein; MMP, matrix metalloproteinases; TGF, transforming growth factor; PD, programmed cell death; MDSC, myeloid derived suppressor cell; Treg, regulatory T cell; SDF, stromal-derived factor