Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

Abstract

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

Keywords: Chemotherapy; Combination therapy; HIF-1; HIF-2; Hypoxia; Immunotherapy; Metabolic therapy; Radiotherapy; Target therapy; Therapeutic resistance.

Fig. 1

Targeting HIF in conjunction with current therapies. Resistance to chemotherapy, radiotherapy and immunotherapy is associated with the activation of HIF and its downstream. To improve anti-tumor effect and diminish treatment resistance, HIF inhibitors together with cancer therapies would be a good solution for patients with resistant cancer. Abbreviations: HIF = hypoxia inducible factor

Fig. 2

HIF-1a and HIF-2a upstream and downstream pathways promoting cancer. HIF-1a expression varies with oxygen level in the cellular environment while HIF-2a is constitutively expressed and has some known oncogenic effects. Under normal oxygen conditions, both HIF-1a and HIF-2a are degraded through ubiquitination pathway by proteasome. Under hypoxia (low oxygen) conditions, HIF-1a translocates into the nucleus and forms HIF complex with HIF-1b and p300, leading to many cancer-promoting outcomes, including metabolic adaptation, cell survival, invasion and metastasis, angiogenesis and vascular tone, cellular proliferation, and apoptosis. Abbreviations: ADM = adrenomedullin; ALD = adrenoleukodystrophy protein; ANF = atrial natriuretic factor; Ang2 = Angiopoietin 2; ANGPT = Angiopoietin-related protein; ANP = Atrial natriuretic peptide; BCL-2 = B-cell lymphoma 2; BNIP3 = BCL2/adenovirus E1B 19 kDa interacting protein 3; CATHD = Cathepsin D; c-MET = mesenchymal-epithelial transition factor; C-MYC = Cellular myelocytomatosis oncogene; COS4 = ; EDN1 = Endothelin 1 gene; EGF = Epidermal growth factor; EG-VEGF = endocrine gland derived vascular endothelial growth factor; ENG = Endoglin; ENO = Enolase; EPO = Erythropoietin; ET1 = Endothelin 1; Flt-1 = Fms Related Receptor Tyrosine Kinase 1; FN1 = soluble plasma fibronectin; GAPDH = Glyceraldehyde 3-phosphate dehydrogenase; GPI = Glycosylphosphatidylinositol; HIF = hypoxia inducible factor; HK = Hexokinase; HRE = Hypoxia-response element; HSP90 = Heat shock protein 90; ID2 = Inhibitor Of DNA binding 2; IGF2 = Insulin like growth factor 2; IGF-BP = Insulin-like growth factor-binding protein; iNOS = Inducible nitric oxide synthases; KL = Klotho; KRT = Keratin; LDH-A = Lactate Dehydrogenase A; LEP = Leptin; LRP = Low-density lipoprotein (LDL)-related protein; MMPs = Matrix metalloproteinases; mTORC = mechanistic target of rapamycin complex; NOS = nitric oxide synthases; OH = Hydroxyl group; P4HS = Prolyl 4-hydroxylase; PDGF-B = platelet derived growth factor; PDK1 = Pyruvate Dehydrogenase Kinase 1; PFK2 = Phosphofructokinase 2; PFKFB3 = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PFKL = ATP-dependent 6-phosphofructokinase, liver type; PGF = Placenta growth factor; PGK1 = Phosphoglycerate Kinase 1; PGM = phosphoglucomutase; PHD = HIF prolyl hydroxylase; PKM2 = Pyruvate kinase isozymes M2; POK1 = Phragmoplast orienting kinesin 1; pVHL = Von Hippel–Lindau tumor suppressor; RTP801 = HIF responsive protein; S6K1 = Ribosomal protein S6 kinase beta-1; TGF = Transforming growth factor; TIMP = Tissue Inhibitor of Metalloproteinase; TPI = Triosephosphate isomerase; Ub = Ubiquitin; uPAR = urokinase plasminogen activator surface receptor; PAI-1 = plasminogen activator inhibitor 1; PI3K = Phosphoinositide-3-kinase; VEGF = Vascular endothelial growth factor; VEGFR2 = Vascular endothelial growth factor receptor 2; VIM = Vimentin; WAF-1 = Wild type p53 activated protein-1

Fig. 3

Inhibition of HIF-1α and HIF-2α in combination with chemotherapy, radiotherapy, and targeted therapy. Chemotherapy such as Cisplatin and 5-FU can cause DNA damage and cancer cell apoptosis. Radiotherapy can increase the level of ROS and lead to cancer cell apoptosis. However, during hypoxia, tumor cell HIF-1 pathway will be activated and result in therapy resistance. For chemotherapy resistance induced by HIF pathway, cancer cell can promote chemo-drug pump out, undergo DNA repairment, inhibit cell apoptosis and shift cell metabolism. And radiotherapy resistance is made by angiogenesis and more blood supply which promote cancer cell survival. Therefore, many synergistic effects by the combination therapy of HIF inhibitor and chemo, radio and targeted therapy through reversing the resistance by HIF pathway. The effects are seen in vivo and in vitro of varied cancer cell type. • Chemotherapy includes cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, irinotecan. • HIF-1 pathway inhibitor includes erlotinib (EGFR inhibitor); HS-173 (PI3K inhibitor); everolimus/sirolimus (m-TOR inhibitor); Panobinostat (HDAC inhibitor); EZN-2698, PX-478, 2ME2, Camptothecin (HIF-1α translation inhibitor); Acriflavine (HIF-1α dimerization inhibitor); Echinomycin and Anthracycline (HIF-1α DNA-binding inhibitor). • HIF-2 pathway inhibitor includes PT-2385 and PT-2977. • The impact of cancer therapy (White words with blue background). • The effect of activated HIF-1 pathway (White words with green background). If given HIF inhibitor, the downstream mechanism of HIF would decrease (Dotted lines). Abbreviations: PI3K = Phosphoinositide-3-kinase; Akt = protein kinase B; mTOR = mechanistic target of rapamycin VEGF = Vascular endothelial growth factor; VEGFR = Vascular endothelial growth factor receptor; EGF = Epidermal growth factor; IGF-1 = Insulin like growth factor-1; GLUT = Glucose transporter; BCL-2 = B-cell lymphoma 2; EPO = Erythropoietin; HIF = hypoxia inducible factor; HRE = Hypoxia-response element; HSP90 = Heat shock protein 90; ROS = Reactive oxygen species; TOP1 = Topoisomerase1

Fig. 4

Combination therapy with immunotherapy or metabolic therapy. Combining blockage of HIF-1α or HIF-2α with immunotherapy (left). PD-1/PD-L1/CTLA-4, the immune checkpoint proteins on T cells which often transmit “immune switch off” signal, is correlated with HIF pathway, and tumor hypoxic status usually leads to the failure of immunotherapy. Therefore, by combining HIF/hypoxia inhibitors with PD-1/PD-L1/CTLA-4 inhibitors, it has been proved to significantly raise T cell immune activity, reducing the amount and malignant potential of tumors. • Immunotherapies: PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor. • HIF-1 pathway inhibitors: POG, X4-136, POM-1, ARL67156, Ganetespib. • HIF-2 pathway inhibitors: PT2385, PT2399. Combining blockage of HIF-1α or HIF-2α with metabolic therapy (right). Pyruvate flux through TCA cycle is downregulated in cancer cells. Glycolysis sustains the high proliferative rate of cancer cells. Targeting of HIF-1α may be a prerequisite for cancer metabolism targeted therapy. • Metabolic therapies: D-allose, dichloroacetate and vitamin C. • HIF-1 pathway inhibitors: polydatin, LY294002 and BAY872243. • Metabolic and HIF-1 pathway inhibitors: 2-DG, cardamonin and metformin. Abbreviation: IGF-1 = Insulin like growth factor-1; PI3K = Phosphoinositide-3-kinase; Akt = protein kinase B; mTOR = mechanistic target of rapamycin; mTORC2 = Mammalian Target of Rapamycin Complex 2; HIF = hypoxia inducible factor; HRE = Hypoxia-response element; PHD2 = prolyl hydroxylase domain protein 2; PP2A = Protein phosphatase 2A; HSP90 = Heat shock protein 90; CXCR4 = chemokine receptor type 4; COX2 = Cyclooxygenase-2; PGE2 = prostaglandin E2; MAPK = mitogen-activated protein kinase; ENTPD2 = Ectonucleoside Triphosphate Diphosphohydrolase 2; MDSC = Myeloid Derived Suppressor Cell; PD-1 = Programmed death-1; PD-L1 = Programmed death-ligand 1; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; CD80/86 = Cluster of differentiation 80/86; APC = Antigen-presenting cell; LDHA = Lactate dehydrogenase A; TCA = tricarboxylic acid