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Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers

Nature Reviews Gastroenterology & Hepatology volume 17, pages 298–313 (2020)Cite this article

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Abstract

Radiotherapy is used in the treatment of approximately 50% of all malignancies including gastrointestinal cancers. Radiation can be given prior to surgery (neoadjuvant radiotherapy) to shrink the tumour or after surgery to kill any remaining cancer cells. Radiotherapy aims to maximize damage to cancer cells, while minimizing damage to healthy cells. However, only 10–30% of patients with rectal cancer or oesophageal cancer have a pathological complete response to neoadjuvant chemoradiation therapy, with the rest suffering the negative consequences of toxicities and delays to surgery with no clinical benefit. Furthermore, in pancreatic cancer, neoadjuvant chemoradiation therapy results in a pathological complete response in only 4% of patients and a partial pathological response in only 31%. Resistance to radiation therapy is polymodal and associated with a number of biological alterations both within the tumour itself and in the surrounding microenvironment including the following: altered cell cycle; repopulation by cancer stem cells; hypoxia; altered management of oxidative stress; evasion of apoptosis; altered DNA damage response and enhanced DNA repair; inflammation; and altered mitochondrial function and cellular energetics. Radiosensitizers are needed to improve treatment response to radiation, which will directly influence patient outcomes in gastrointestinal cancers. This article reviews the literature to identify strategies — including DNA-targeting agents, antimetabolic agents, antiangiogenics and novel immunotherapies — being used to enhance radiosensitivity in gastrointestinal cancers according to the hallmarks of cancer. Evidence from radiosensitizers from in vitro and in vivo models is documented and the action of radiosensitizers through clinical trial data is assessed.

Key points

  • Resistance to radiation therapy in gastrointestinal cancer occurs in 70–96% of patients depending on the specific cancer type.

  • Currently, no agents that can function as radiosensitizers are approved for use in gastrointestinal cancers in the clinic.

  • Resistance to radiation therapy is polymodal and associated with changes in DNA repair, cellular energetics, growth signalling pathways, inflammation, angiogenesis and oxygen tension.

  • Targeting the hallmarks of cancer in vitro and in vivo, and in patients enrolled in clinical trials, has been shown to enhance radioresponse in gastrointestinal cancers.

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Fig. 1: Molecular mechanisms contributing to a radioresistant phenotype.
Fig. 2: Potential therapeutics to enhance radiosensitivity in gastrointestinal cancers.

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References

  1. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Siegel, R. L., Kimberly, D. M. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  3. Donohoe, C. L. & Reynolds, J. V. Neoadjuvant treatment of locally advanced esophageal and junctional cancer: the evidence-base, current key questions and clinical trials. J. Thorac. Dis. 9, S697–S704 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schmidt, B. et al. Combining bevacizumab with radiation or chemoradiation for solid tumors: a review of the scientific rationale, and clinical trials. Curr. Angiogenesis 1, 169–179 (2012).

    Article  CAS  Google Scholar 

  5. Geh, J. I., Crellin, A. M. & Glynne-Jones, R. Preoperative (neoadjuvant) chemoradiotherapy in oesophageal cancer. Br. J. Surg. 88, 338–356 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Hoendervangers, S. et al. Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer. Eur. J. Surg. Oncol. 44, 1013–1017 (2018).

    Article  PubMed  Google Scholar 

  7. Siegel, R. et al. Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014).

    Article  PubMed  Google Scholar 

  8. Gillen, S. et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLOS Med. 7, e1000267 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wang, H. et al. Cancer radiosensitizers. Trends Pharmacol. Sci. 39, 24–48 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Maity, A., McKenna, W. G. & Muschel, R. J. The molecular basis for cell cycle delays following ionizing radiation: a review. Radiother. Oncol. 31, 1–13 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Yoshida, G. J. & Saya, H. Therapeutic strategies targeting cancer stem cells. Cancer Sci. 107, 5–11 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Skvortsova, I. et al. Radiation resistance: cancer stem cells (CSCs) and their enigmatic pro-survival signaling. Semin. Cancer Biol. 35, 39–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Igney, F. H. & Krammer, P. H. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2, 277–288 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Lynam-Lennon, N. et al. Alterations in DNA repair efficiency are involved in the radioresistance of esophageal adenocarcinoma. Radiat. Res. 174, 703–711 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Kim, W. et al. Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. Apoptosis 20, 1242–1252 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Dewhirst, M. W., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat. Rev. Cancer 8, 425–437 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lynam-Lennon, N. et al. Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma. PLOS ONE 9, e100738 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yard, B. D. et al. A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat. Commun. 7, 11428 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mierzwa, M. L. et al. Recent advances in combined modality therapy. Oncologist 15, 372–381 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chakravarty, T. et al. Intensity-modulated radiation therapy with concurrent chemotherapy as preoperative treatment for localized gastric adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 83, 581–586 (2012).

    Article  PubMed  Google Scholar 

  22. Gerard, J. P. et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J. Clin. Oncol. 24, 4620–4625 (2006).

    Article  PubMed  Google Scholar 

  23. Cunningham, D. et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N. Engl. J. Med. 355, 11–20 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Schaue, D. & McBride, W. H. Counteracting tumor radioresistance by targeting DNA repair. Mol. Cancer Ther. 4, 1548–1550 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Helleday, T. et al. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 8, 193–204 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Pires, I. M. et al. Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br. J. Cancer 107, 291–299 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leszczynska, K. B. et al. Preclinical testing of an ATR inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiother. Oncol. 121, 232–238 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fokas, E. et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 3, e441 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dillon, M. T. et al. PATRIOT: a phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours. Clin. Transl. Radiat. Oncol. 12, 16–20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin, C. et al. Combination of quercetin with radiotherapy enhances tumor radiosensitivity in vitro and in vivo. Radiother. Oncol. 104, 395–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Javle, M. & Curtin, N. J. The role of PARP in DNA repair and its therapeutic exploitation. Br. J. Cancer 105, 1114–1122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Beck, C. et al. Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp. Cell Res. 329, 18–25 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Poggio, F. et al. Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis. ESMO Open 3, e000361 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Haince, J. F. et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J. Biol. Chem. 283, 1197–1208 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Guillot, C. et al. PARP inhibition and the radiosensitizing effects of the PARP inhibitor ABT-888 in in vitro hepatocellular carcinoma models. BMC Cancer 14, 603 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Miura, K. et al. The combination of olaparib and camptothecin for effective radiosensitization. Radiat. Oncol. 7, 62 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Komaki, R. et al. Phase I study of irinotecan and concurrent radiation therapy for upper GI tumors. Oncology 14 (12 Suppl. 14), 34–37 (2000).

    CAS  PubMed  Google Scholar 

  41. Porcelli, L. et al. Optimize radiochemotherapy in pancreatic cancer: PARP inhibitors a new therapeutic opportunity. Mol. Oncol. 7, 308–322 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Lohse, I. et al. Effects of combined treatment with ionizing radiation and the PARP inhibitor olaparib in BRCA mutant and wild type patient-derived pancreatic cancer xenografts. PLOS ONE 11, e0167272 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01460888 (2013).

  44. Bang, Y. J. et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1637–1651 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Collis, S. J. et al. The life and death of DNA-PK. Oncogene 24, 949–961 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Li, Y. H. et al. Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response. PLOS ONE 7, e39588 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sun, X. et al. Identification and characterization of a small inhibitory peptide that can target DNA-PKcs autophosphorylation and increase tumor radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys. 84, 1212–1219 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Zhao, Y. et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354–5362 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Van Triest, B. et al. A phase Ia/Ib trial of the DNA-PK inhibitor M3814 in combination with radiotherapy (RT) in patients (pts) with advanced solid tumors: dose-escalation results [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 2518 (2018).

    Article  Google Scholar 

  50. Stachelek, G. C. et al. YU238259 is a novel inhibitor of homology-dependent DNA repair that exhibits synthetic lethality and radiosensitization in repair-deficient tumors. Mol. Cancer Res. 13, 1389–1397 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Estrada-Bernal, A. et al. MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways. Cell Cycle 14, 3713–3724 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shoji, M. et al. Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma. Int. J. Oncol. 40, 2140–2146 (2012).

    CAS  PubMed  Google Scholar 

  53. Makita, N. et al. Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells. Oncol. Rep. 34, 1185–1192 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Williams, T. M. et al. A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for locally-advanced rectal adenocarcinoma [abstract]. Cancer Res. 77, CT088 (2017).

    Google Scholar 

  55. Banks, M. et al. Cardiovascular effects of the MEK inhibitor, trametinib: a case report, literature review, and consideration of mechanism. Cardiovasc. Toxicol. 17, 487–493 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kleiman, L. B., Krebs, A. M., Kim, S. Y., Hong, T. S. & Haigis, K. M. Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers. PLOS ONE 8, e82982 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Tao, Y. et al. Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints. Cell Cycle 8, 1196–1205 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Morgan, M. A. et al. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 70, 4972–4981 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mitchell, J. B. et al. In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin. Cancer Res. 16, 2076–2084 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kausar, T. et al. Sensitization of pancreatic cancers to gemcitabine chemoradiation by WEE1 kinase inhibition depends on homologous recombination repair. Neoplasia 17, 757–766 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02037230 (2019).

  62. Karnak, D. et al. Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer. Clin. Cancer Res 20, 5085–5096 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lu, W., Zhang, Y., Liu, D., Songyang, Z. & Wan, M. Telomeres — structure, function, and regulation. Exp. Cell Res. 319, 133–141 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Goytisolo, F. A. et al. Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J. Exp. Med. 192, 1625–1636 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wong, K. K. et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat. Genet. 26, 85–88 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Chen, X. et al. Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines. Oncol. Rep. 36, 239–246 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Leeansyah, E. et al. Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging. J. Infect. Dis. 207, 1157–1165 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Wu, X. et al. Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma. Oncotarget 8, 13600–13619 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Wang, Y. et al. Radiosensitization to X-ray radiation by telomerase inhibitor MST-312 in human hepatoma HepG2 cells. Life Sci. 123, 43–50 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. Hauguel, T. & Bunz, F. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. Cancer Biol. Ther. 2, 679–684 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01342224 (2018).

  72. Toulany, M. & Rodemann, H. P. Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation. Semin. Cancer Biol. 35, 180–190 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Park, J. H. et al. Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer. Oncotarget 8, 112893–112906 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Pal, I. et al. Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma. Tumor Biol. 37, 6389–6402 (2016).

    Article  CAS  Google Scholar 

  75. Machiels, J. P. et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann. Oncol. 18, 738–744 (2007).

    Article  PubMed  Google Scholar 

  76. Mardjuadi, F. I. et al. Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer. Target. Oncol. 10, 375–383 (2015).

    Article  PubMed  Google Scholar 

  77. Helbling, D. et al. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann. Oncol. 24, 718–725 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Rödel, C. et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 1081–1086 (2008).

    Article  PubMed  CAS  Google Scholar 

  79. Janjigian, Y. Y. et al. KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJC): a double-blind, randomized, placebo-controlled phase 3 study [abstract]. J. Clin. Oncol. 37 (Suppl. 15), TPS4146 (2019).

    Article  Google Scholar 

  80. Ciric, E. & Sersa, G. Radiotherapy in combination with vascular-targeted therapies. Radiol. Oncol. 44, 67–78 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhu, H. et al. Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia. Sci. Rep. 5, 14503 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hoang, T. et al. Enhancement of radiation response with bevacizumab. J. Exp. Clin. Cancer Res. 31, 37–37 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Teicher, B. A. et al. Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents. Int. J. Cancer 57, 920–925 (1994).

    Article  CAS  PubMed  Google Scholar 

  84. Park, H. J. et al. Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat. Res. 177, 311–327 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Lv, J. et al. Randomized phase II study of recombinant human endostatin combined with definitive chemoradiotherapy in locally advanced esophageal squamous cell carcinoma [abstract]. J. Clin. Oncol. 33 (Suppl. 15), 4035 (2015).

    Article  Google Scholar 

  86. Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565–5570 (2000).

    CAS  PubMed  Google Scholar 

  87. Cao, N. et al. Monitoring the effects of anti-angiogenesis on the radiation sensitivity of pancreatic cancer xenografts using dynamic contrast-enhanced CT. Int. J. Radiat. Oncol. Biol. Phys. 88, 412–418 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Koukourakis, M. I. et al. Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: vasculature-independent radiosensitizing effect of bevacizumab. Clin. Cancer Res. 15, 7069–7076 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Koukourakis, M. I. et al. Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a phase II study. Int. J. Radiat. Oncol. Biol. Phys. 80, 492–498 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Wen, X. et al. Down-regulation of XIAP enhances the radiosensitivity of esophageal cancer cells in vivo and in vitro. Biosci. Rep. 37, BSR20170711 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Park, M. et al. MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin. Sci. Rep. 7, 10932 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Morales, D. R. & Morris, A. D. Metformin in cancer treatment and prevention. Annu. Rev. Med. 66, 17–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Feng, T. et al. Metformin enhances radiation response of ECa109 cells through activation of ATM and AMPK. Biomed. Pharmacother. 69, 260–266 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Jeong, Y. K. et al. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLOS ONE 10, e0143596 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Jin, H. et al. Re-sensitization of radiation resistant colorectal cancer cells to radiation through inhibition of AMPK pathway. Oncol. Lett. 11, 3197–3201 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fasih, A. et al. Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway. Radiat. Res. 182, 50–59 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liu, J. et al. Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair. Oncol. Rep. 28, 1406–1412 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Cheng, G. et al. Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res. 76, 3904–3915 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Elbaz, H. A. et al. Epicatechin stimulates mitochondrial activity and selectively sensitizes cancer cells to radiation. PLOS ONE 9, e88322 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Zannella, V. E. et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin. Cancer Res. 19, 6741–6750 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Liu, S.-C. et al. Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance. J. Clin. Invest. 123, 5269–5283 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vella, V., Milluzzo, A., Scalisi, N. M., Vigneri, P. & Sciacca, L. Insulin receptor isoforms in cancer. Int. J. Mol. Sci. 19, 3615 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  103. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02153450 (2019).

  104. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02473094 (2017).

  105. Benej, M. et al. Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc. Natl Acad. Sci. USA 115, 10756–10761 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Buckley, A. M. et al. Pyrazinib (P3), [(E)-2-(2-pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma. Cancer Lett. 447, 115–129 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Coleman, M. C. et al. 2-Deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic. Biol. Med. 44, 322–331 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Multhoff, G. & Radons, J. Radiation, inflammation, and immune responses in cancer. Front. Oncol. 2, 58 (2012).

    PubMed  PubMed Central  Google Scholar 

  109. Maher, S. G. et al. Serum proteomic profiling reveals that pretreatment complement protein levels are predictive of esophageal cancer patient response to neoadjuvant chemoradiation. Ann. Surg. 254, 809–816 (2011).

    Article  PubMed  Google Scholar 

  110. Picardo, S. L. et al. Barrett’s to oesophageal cancer sequence: a model of inflammatory-driven upper gastrointestinal cancer. Dig. Surg. 29, 251–260 (2012).

    Article  PubMed  Google Scholar 

  111. Buckley, A. M. et al. Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma. Oncotarget 9, 33634 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Chen, M.-F. et al. IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol. Cancer 12, 26–26 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02767557 (2019).

  114. Brown, J. M. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol. Med. Today 6, 157–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Yasui, H. et al. Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo. Br. J. Cancer 99, 1442–1452 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wardman, P. Chemical radiosensitizers for use in radiotherapy. Clin. Oncol. 19, 397–417 (2007).

    Article  CAS  Google Scholar 

  117. Bonnet, M. et al. Next-generation hypoxic cell radiosensitizers: nitroimidazole alkylsulfonamides. J. Med. Chem. 61, 1241–1254 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01880359 (2019).

  119. Schwartz, D. L. et al. Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Mol. Cancer Ther. 9, 2057–2067 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00522652 (2018).

  121. Seyfried, T. N. & Huysentruyt, L. C. On the origin of cancer metastasis. Crit. Rev. Oncog. 18, 43–73 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Hay, E. D. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn. 233, 706–720 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Josson, S. et al. Tumor-stromal interactions influence radiation sensitivity in epithelial- versus mesenchymal-like prostate cancer cells. J. Oncol. 2010, 232831 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Choi, Y.-J. et al. Smad2/3-regulated expression of DLX2 is associated with radiation-induced epithelial-mesenchymal transition and radioresistance of A549 and MDA-MB-231 human cancer cell lines. PLOS ONE 11, e0147343 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Su, H. et al. FH535 increases the radiosensitivity and reverses epithelial-to-mesenchymal transition of radioresistant esophageal cancer cell line KYSE-150R. J. Transl. Med. 13, 104 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Fernandez, Y. et al. Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines resistance. Cell Death Differ. 7, 350–359 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Yang, J. et al. Adenovirus-mediated siRNA targeting Bcl-xL inhibits proliferation, reduces invasion and enhances radiosensitivity of human colorectal cancer cells. World J. Surg. Oncol. 9, 117 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  128. O’Steen, S. et al. Venetoclax synergizes with radiotherapy for treatment of B-cell lymphomas. Cancer Res. 77, 3885–3893 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tang, C. et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol. Res. 2, 831–838 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Azad, A. et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol. Med. 9, 167–180 (2017).

    Article  CAS  PubMed  Google Scholar 

  131. Tabernero, J. et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study [abstract]. J. Clin. Oncol. 37 (Suppl. 18), LBA4007 (2019).

    Article  Google Scholar 

  132. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02494583 (2019).

  133. Kim, K. W. et al. Direct injection of immature dendritic cells into irradiated tumor induces efficient antitumor immunity. Int. J. Cancer 109, 685–690 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Son, C. H. et al. CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. J. Immunother. 37, 1–7 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Dewan, M. Z. et al. Fractionated but not single dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Welsh, J. W. et al. Phase 2 5-arm trial of ipilimumab plus lung or liver stereotactic radiation for patients with advanced malignancies [abstract LBA-5]. Int. J. Radiat. Oncol. Biol. Phys. 99, 1315 (2017).

    Article  Google Scholar 

  137. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01691664 (2019).

  138. Kirsch, D. G. et al. The future of radiobiology. J. Natl. Cancer Inst. 110, 329–340 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. O’Neil, B. H. et al. A phase I study of bortezomib in combination with standard 5-fluorouracil and external-beam radiation therapy for the treatment of locally advanced or metastatic rectal cancer. Clin. Colorectal Cancer 9, 119–125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02223923 (2019).

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02010567 (2019).

  142. Sanoff, H. K. et al. Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer. Nanomedicine 18, 189–195 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Van Triest, B. et al. A phase Ia/Ib trial of the DNA-PK inhibitor M3814 in combination with radiotherapy (RT) in patients (pts) with advanced solid tumors: dose-escalation results. J. Clin. Oncol. 36, 2518–2518 (2018).

    Article  Google Scholar 

  144. Merx, K. et al. Panitumumab in combination with preoperative radiation therapy in patients with locally advanced RAS wild-type rectal cancer: results of the multicenter explorative single-arm phase 2 study NEORIT. Int. J. Radiat. Oncol. Biol. Phys. 99, 867–875 (2017).

    Article  CAS  PubMed  Google Scholar 

  145. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01691625 (2019).

  146. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02642809 (2019).

  147. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02830594 (2019).

  148. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02735239 (2019).

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Authors and Affiliations

  1. Department of Surgery, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland

    Amy M. Buckley, Niamh Lynam-Lennon, Hazel O’Neill & Jacintha O’Sullivan

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  1. Amy M. Buckley
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  2. Niamh Lynam-Lennon
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  3. Hazel O’Neill
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  4. Jacintha O’Sullivan
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All authors researched data for the article, A.M.B., N.L.-L. and H.O’N. wrote the article, and J.O’S. and A.M.B. reviewed/edited the manuscript before submission.

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Correspondence to Jacintha O’Sullivan.

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Nature Reviews Gastroenterology & Hepatology thanks N. Cordes, J. Torres-Roca and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Buckley, A.M., Lynam-Lennon, N., O’Neill, H. et al. Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers. Nat Rev Gastroenterol Hepatol 17, 298–313 (2020). https://doi.org/10.1038/s41575-019-0247-2

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