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 |
| Â | Promote oxygen dissociation from hemoglobin | OXY111A | NCT02528526 (unknown) |
| Â | 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) |
| Â | 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) |
| Â | Notch inhibition via gamma-secretase inhibitor | MK-0752 Demcizumab RO4929097 | NCT01098344 (completed), NCT02289898 (completed), NCT01145456 (completed), NCT01131234 (completed), NCT01232829 (completed) |
| Â | Notch inhibition via binding delta-like ligand 4 | TGR-1202 | NCT02574663 (active) |
| Â | Notch inhibition via antibody targeting Notch 2/3 receptors | Tarextumab (OMP-59R5) | NCT01647828 (completed) |
| Â | 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) |
| Â | 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) |
| Â | 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) |