Positioning of proteasome inhibitors in therapy of solid malignancies

1.

Wijdeven RH, Pang B, Assaraf YG, Neefjes J (2016) Old drugs, novel ways out: drug resistance toward cytotoxic chemotherapeutics. Drug Resist Updat 28:65–81. https://doi.org/10.1016/j.drup.2016.07.001 PubMedCrossRef

2.

Dou QP, Zonder JA (2014) Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr Cancer Drug Targets 14:517–536. https://doi.org/10.2174/1568009614666140804154511 PubMedPubMedCentralCrossRef

3.

Hochstrasser M (1995) Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 7:215–223. https://doi.org/10.1016/0955-0674(95)80031-X PubMedCrossRef

4.

Dou QP, Li B (1999) Proteasome inhibitors as potential novel anticancer agents. Drug Resist Updat 2:215–223. https://doi.org/10.1054/drup.1999.0095 PubMedCrossRef

5.

Anderson KC (2012) The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol 30:445–452. https://doi.org/10.1200/JCO.2011.37.8919 PubMedPubMedCentralCrossRef

6.

San-Miguel JF, Mateos MV (2011) Can multiple myeloma become a curable disease? Haematologica 96:1246–1248. https://doi.org/10.3324/haematol.2011.051169 PubMedPubMedCentralCrossRef

7.

Cloos J, Roeten MSF, Franke NE et al (2017) (Immuno) proteasomes as therapeutic target in acute leukemia. Cancer Metastasis Rev. https://doi.org/10.1007/s10555-017-9699-4 PubMedPubMedCentral

8.

Niewerth D, Jansen G, Assaraf YG et al (2015) Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat 18:18–35. https://doi.org/10.1016/j.drup.2014.12.001 PubMedCrossRef

9.

Huber EM, Heinemeyer W, Groll M (2015) Bortezomib-resistant mutant proteasomes: Structural and biochemical evaluation with carfilzomib and ONX 0914. Structure 23:407–417. https://doi.org/10.1016/j.str.2014.11.019 PubMedCrossRef

10.

Niewerth D, Jansen G, Riethoff LF et al (2014) Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor salinosporamide A (Marizomib). Mol Pharmacol 86:12–19. https://doi.org/10.1124/mol.114.092114 PubMedPubMedCentralCrossRef

11.

Corso A, Mangiacavalli S, Varettoni M et al (2010) Bortezomib-induced peripheral neuropathy in multiple myeloma: a comparison between previously treated and untreated patients. Leuk Res 34:471–474. https://doi.org/10.1016/j.leukres.2009.07.022 PubMedCrossRef

12.

Cavaletti G, Jakubowiak AJ (2010) Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies. Leuk Lymphoma 51:1178–1187. https://doi.org/10.3109/10428194.2010.483303 PubMedCrossRef

13.

Huang Z, Wu Y, Zhou X et al (2014) Efficacy of therapy with bortezomib in solid tumors: a review based on 32 clinical trials. Future Oncol 10:1795–1807. https://doi.org/10.2217/fon.14.30 PubMedCrossRef

14.

Ri M (2016) Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol 104:273–280. https://doi.org/10.1007/s12185-016-2016-0 PubMedCrossRef

15.

Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79:13–21PubMedCrossRef

16.

Demarchi F, Brancolini C (2005) Altering protein turnover in tumor cells: New opportunities for anti-cancer therapies. Drug Resist Updat 8:359–368. https://doi.org/10.1016/j.drup.2005.12.001 PubMedCrossRef

17.

Komander D, Clague MJ, Urbé S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563. https://doi.org/10.1038/nrm2731 PubMedCrossRef

18.

Streich FC, Lima CD (2014) Structural and functional insights to ubiquitin-like protein conjugation. Annu Rev Biophys 43:357–379. https://doi.org/10.1146/annurev-biophys-051013-022958 PubMedPubMedCentralCrossRef

19.

Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360. https://doi.org/10.1038/nrc1361 PubMedCrossRef

20.

Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428. https://doi.org/10.1152/physrev.00027.2001 PubMedCrossRef

21.

Moiseeva TN, Bottrill A, Melino G, Barlev NA (2013) DNA damage-induced ubiquitylation of proteasome controls its proteolytic activity. Oncotarget 44:1338–1348. https://doi.org/10.18632/oncotarget.1060

22.

Hitzerd SM, Verbrugge SE, Ossenkoppele G et al (2014) Positioning of aminopeptidase inhibitors in next generation cancer therapy. Amino Acids 46:793–808. https://doi.org/10.1007/s00726-013-1648-0 PubMedCrossRef

23.

Reits E, Griekspoor A, Neijssen J et al (2003) Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18:97–108. https://doi.org/10.1016/S1074-7613(02)00511-3 PubMedCrossRef

24.

Rock K, York I, Saric T, Goldberg A (2002) Protein degradation and the generation of MHC class I-presented peptides. Adv Immunol 80:1–70PubMedCrossRef

25.

Chen D, Frezza M, Schmitt S et al (2011) Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 11:239–253. https://doi.org/10.2174/156800911794519752 PubMedPubMedCentralCrossRef

26.

Almond JB, Cohen GM (2002) The proteasome: a novel target for cancer chemotherapy. Leukemia 16:433–443PubMedCrossRef

27.

Manasanch EE, Orlowski RZ (2017) Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 14:417–433. https://doi.org/10.1007/s12079-011-0121-7 PubMedCrossRef

28.

Groettrup M, Kirk CJ, Basler M (2010) Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol 10:73–78. https://doi.org/10.1038/nri2687 PubMedCrossRef

29.

de Wilt LH, Jansen G, Assaraf YG et al (2012) Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer. Biochem Pharmacol 83:207–217. https://doi.org/10.1016/j.bcp.2011.10.009 PubMedCrossRef

30.

Busse A, Kraus M, Na IK et al (2008) Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits. Cancer 112:659–670. https://doi.org/10.1002/cncr.23224 PubMedCrossRef

31.

Obeng EA, Carlson LM, Gutman DM et al (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107:4907–4917. https://doi.org/10.1182/blood-2005-08-3531 PubMedPubMedCentralCrossRef

32.

Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389–1398. https://doi.org/10.1172/JCI200216886 PubMedPubMedCentralCrossRef

33.

Ron D (2002) Translational control in the endoplasmic reticulum stress response. J Clin Invest 110:1383–1388. https://doi.org/10.1172/JCI200216784 PubMedPubMedCentralCrossRef

34.

Shimizu Y, Hendershot LM (2009) Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species. Antioxid Redox Signal 11:2317–2331. https://doi.org/10.1089/ars.2009.2501 PubMedPubMedCentralCrossRef

35.

Fribley A, Zeng Q, Wang C (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 24:9695–9704. https://doi.org/10.1128/MCB.24.22.9695 PubMedPubMedCentralCrossRef

36.

Pérez-Galán P, Roue G, Villamor N et al (2006) The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 107:257–264. https://doi.org/10.1182/blood-2005-05-2091 PubMedCrossRef

37.

Paramore A, Frantz S (2003) Bortezomib. Nat Rev Drug Discov 2:611–612. https://doi.org/10.1038/nrd1159 PubMedCrossRef

38.

Hideshima T, Ikeda H, Chauhan D et al (2009) Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 114:1046–1052. https://doi.org/10.1182/blood-2009-01-199604 PubMedPubMedCentralCrossRef

39.

McConkey DJ, Zhu K (2008) Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist 11:164–179. https://doi.org/10.1016/j.drup.2008.08.002 CrossRef

40.

Chaturvedi MM, Sung B, Yadav VR et al (2011) NFkB addiction and its role in cancer : “one size does not fit all.” Oncogene 30:1615–1630. https://doi.org/10.1038/onc.2010.566 PubMedCrossRef

41.

Nencioni A, Grünebach F, Patrone F et al (2007) Proteasome inhibitors: antitumor effects and beyond. Leukemia 21:30–36. https://doi.org/10.1038/sj.leu.2404444 PubMedCrossRef

42.

Gatti L, Zuco V, Zaffaroni N, Perego P (2013) Drug combinations with proteasome inhibitors in antitumor therapy. Curr Pharm Des 19:4094–4114. https://doi.org/10.2174/1381612811319220015 PubMedCrossRef

43.

Rastogi N, Duggal S, Singh SK et al (2015) Proteasome inhibition mediates p53 reactivation and anti- cancer activity of 6-Gingerol in cervical cancer cells. Oncotarget 6:43310–43325. https://doi.org/10.18632/oncotarget.6383 PubMedPubMedCentralCrossRef

44.

Li C, Li R, Grandis JR, Johnson DE (2008) Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells. Mol Cancer Ther 7:1647–1656. https://doi.org/10.1158/1535-7163.MCT-07-2444 PubMedPubMedCentralCrossRef

45.

Tan T, Degenhardt K, Nelson DA et al (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238. https://doi.org/10.1016/j.ccr.2005.02.008 PubMedCrossRef

46.

Wirth M, Stojanovic N, Christian J et al (2014) MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib. Nucleic Acids Res 42:10433–10447. https://doi.org/10.1093/nar/gku763 PubMedPubMedCentralCrossRef

47.

Fennell DA, Chacko A, Mutti L (2008) BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 27:1189–1197. https://doi.org/10.1038/sj.onc.1210744 PubMedCrossRef

48.

Ding W-X, Ni H-M, Gao W et al (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171:513–524. https://doi.org/10.2353/ajpath.2007.070188 PubMedPubMedCentralCrossRef

49.

Ding WX, Ni HM, Gao W et al (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282:4702–4710. https://doi.org/10.1074/jbc.M609267200 PubMedCrossRef

50.

Nawrocki ST, Carew JS, Pino MS et al (2006) Aggresome disruption: a novel strategy to enhance bortezomib- induced apoptosis in pancreatic cancer cells. Cancer Res 1:3773–3782. https://doi.org/10.1158/0008-5472.CAN-05-2961 CrossRef

51.

Simms-waldrip T, Rodriguez-gonzalez A, Lin T et al (2008) The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 94:283–286. https://doi.org/10.1016/j.ymgme.2008.03.012 PubMedPubMedCentralCrossRef

52.

Pandey UB, Nie Z, Batlevi Y et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:860–864. https://doi.org/10.1038/nature05853 CrossRef

53.

Tallóczy Z, Jiang W, Virgin HW et al (2002) Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci USA 99:190–195. https://doi.org/10.1073/pnas.012485299 PubMedCrossRef

54.

Carew JS, Medina EC, Esquivel JA et al (2010) Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med 14:2448–2459. https://doi.org/10.1111/j.1582-4934.2009.00832.x PubMedCrossRef

55.

Harousseau JL, Attal M, Avet-Loiseau H et al (2010) Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005–01 phase III trial. J Clin Oncol 28:4621–4629. https://doi.org/10.1200/JCO.2009.27.9158 PubMedCrossRef

56.

Jagannath S, Durie BGM, Wolf J et al (2005) Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776–783. https://doi.org/10.1111/j.1365-2141.2005.05540.x PubMedCrossRef

57.

Jagannath S, Durie BGM, Wolf JL et al (2009) Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma. Br J Haematol 146:619–626. https://doi.org/10.1111/j.1365-2141.2009.07803.x PubMedCrossRef

58.

Arastu-Kapur S, Anderl JL, Kraus M et al (2011) Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 17:2734–2743. https://doi.org/10.1158/1078-0432.CCR-10-1950 PubMedCrossRef

59.

Voortman J, Giaccone G (2007) Clinical application of proteasome inhibitor bortezomib : characterization of neurotoxicity. Ubiquitin proteasome Syst. Cent. Nerv. Syst. from Physiol. to Pathol. pp 1037–1054

60.

Allegra A, Alonci A, Gerace D et al (2014) New orally active proteasome inhibitors in multiple myeloma. Leuk Res 38:1–9. https://doi.org/10.1016/j.leukres.2013.10.018 PubMedCrossRef

61.

Moreau P, Richardson PG, Cavo M et al (2015) Review article Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120:947–960. https://doi.org/10.1182/blood-2012-04-403733 CrossRef

62.

Kortuem KM, Stewart AK (2013) Carfilzomib Blood 121:893–897. https://doi.org/10.1182/blood-2012-10-459883 PubMedCrossRef

63.

Siegel D, Martin T, Nooka A et al (2013) Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica 98:1753–1761. https://doi.org/10.3324/haematol.2013.089334 PubMedPubMedCentralCrossRef

64.

Ruschak AM, Slassi M, Kay LE, Schimmer AD (2011) Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst 103:1007–1017. https://doi.org/10.1093/jnci/djr160 PubMedCrossRef

65.

Demo SD, Kirk CJ, Aujay MA et al (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67:6383–6391. https://doi.org/10.1158/0008-5472.CAN-06-4086 PubMedCrossRef

66.

Kuhn DJ, Chen Q, Voorhees PM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110:3281–3290. https://doi.org/10.1182/blood-2007-01-065888 PubMedPubMedCentralCrossRef

67.

Potts C, Albitar BX, Anderson MC K, et al (2011) Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets 11:254–284. https://doi.org/10.2174/156800911794519716 PubMedPubMedCentralCrossRef

68.

Kisselev AF, Van Der Linden WA, Overkleeft HS (2012) Proteasome inhibitors: An expanding army attacking a unique target. Chem Biol 19:99–115. https://doi.org/10.1016/j.chembiol.2012.01.003 PubMedPubMedCentralCrossRef

69.

Obaidat A, Weiss J, Wahlgren B et al (2011) Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs. J Pharmacol Exp Ther 337:479–486. https://doi.org/10.1124/jpet.110.177824.is PubMedPubMedCentralCrossRef

70.

Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 15:243–249. https://doi.org/10.1016/j.drudis.2010.01.008 PubMedCrossRef

71.

Buac D, Shen M, Schmitt S et al (2013) From bortezomib to other inhibitors of the proteasome and beyond. Curr Pharm Des 19:4025–4038. https://doi.org/10.2174/1381612811319220012 PubMedPubMedCentralCrossRef

72.

Piva R, Ruggeri B, Williams M et al (2008) CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111:2765–2775. https://doi.org/10.1182/blood-2007-07-100651 PubMedCrossRef

73.

Berkers CR, Leestemaker Y, Schuurman KG et al (2012) Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Mol Pharm 9:1126–1135. https://doi.org/10.1021/mp2004143 PubMedCrossRef

74.

Kouroukis CT, Fernandez LA, Crump M et al (2011) A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172). Leuk Lymphoma 52:394–399. https://doi.org/10.3109/10428194.2010.546015 PubMedCrossRef

75.

Chauhan D, Tian Z, Zhou B et al (2011) In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 17:5311–5321. https://doi.org/10.1158/1078-0432.CCR-11-0476 PubMedPubMedCentralCrossRef

76.

Chauhan D, Singh AV, Aujay M et al (2010) A novel orally active proteasome inhibitor ONX 0912 trigger in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116:4906–4915. https://doi.org/10.1182/blood-2010-04-276626 PubMedPubMedCentralCrossRef

77.

Nooka A, Gleason C, Casbourne D, Lonial S (2013) Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib. Biol Targets Ther 7:13–32. https://doi.org/10.2147/BTT.S24580

78.

Thompson JL (2013) Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Ann Pharmacother 47:56–62. https://doi.org/10.1345/aph.1R561 PubMedCrossRef

79.

Voortman J, Checińska A, Giaccone G (2007) The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells. Mol Cancer 6:73. https://doi.org/10.1186/1476-4598-6-73 PubMedPubMedCentralCrossRef

80.

Fanucchi MP, Fossella FV, Belt R et al (2006) Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol 24:5025–5033. https://doi.org/10.1200/JCO.2006.06.1853 PubMedCrossRef

81.

Williamson MJ, Silva MD, Terkelsen J et al (2009) The relationship among tumor architecture, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in mouse xenograft models. Mol Cancer Ther 8:3234–3243. https://doi.org/10.1158/1535-7163.MCT-09-0239 PubMedCrossRef

82.

Zhao Y, Foster NR, Meyers JP et al (2015) A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer. J Thorac Oncol 10:172–180. https://doi.org/10.1097/JTO.0000000000000383 PubMedPubMedCentralCrossRef

83.

Jones DR, Moskaluk CA, Gillenwater HH et al (2012) Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer. J Thorac Oncol 7:1683–1690. https://doi.org/10.1097/JTO.0b013e318267928d PubMedPubMedCentralCrossRef

84.

Arnold SM, Chansky K, Leggas M et al (2017) Phase 1b trial of proteasome inhibitor carfilzomib with irinotecan in lung cancer and other irinotecan-sensitive malignancies that have progressed on prior therapy (Onyx IST reference number: CAR-IST-553). Invest New Drugs 35:608–615. https://doi.org/10.1007/s10637-017-0441-4 PubMedPubMedCentralCrossRef

85.

Zhu W, Liu J, Nie J et al (2015) MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo. Oncol Rep 34:2083–2089. https://doi.org/10.3892/or.2015.4169 PubMedCrossRef

86.

Kontopodis E, Kotsakis A, Kentepozidis N et al (2016) A phase II, open-label trial of bortezomib (VELCADE®) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer. Cancer Chemother Pharmacol 77:949–956. https://doi.org/10.1007/s00280-016-2997-7 PubMedCrossRef

87.

Voortman J, Smit EF, Honeywell R et al (2007) A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clin Cancer Res 13:3642–3652. https://doi.org/10.1158/1078-0432.CCR-07-0061 PubMedCrossRef

88.

Baker AF, Hanke NT, Sands BJ et al (2014) Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models. J Exp Clin Cancer Res 33:111. https://doi.org/10.1186/s13046-014-0111-8 PubMedPubMedCentralCrossRef

89.

Ceresa C, Giovannetti E, Voortman J et al (2009) Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells. Mol Cancer Ther 8:1026–1037. https://doi.org/10.1158/1535-7163.MCT-08-0700 PubMedCrossRef

90.

de Wilt LHAM., Kroon J, Jansen G et al (2013) Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells? Crit Rev Oncol Hematol 85:363–372. https://doi.org/10.1016/j.critrevonc.2012.08.001 PubMedCrossRef

91.

Cron KR, Zhu K, Kushwaha DS et al (2013) Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer. PLoS One 8:e73710. https://doi.org/10.1371/journal.pone.0073710 PubMedPubMedCentralCrossRef

92.

Mortenson MM, Schlieman MG, Virudachalam S et al (2005) Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer. Lung Cancer 49:163–170. https://doi.org/10.1016/j.lungcan.2005.01.006 PubMedCrossRef

93.

Shen J, Song G, An M et al (2014) The use of hollow mesoporous silica nanospheres to encapsulate bortezomib and improve efficacy for non-small cell lung cancer therapy. Biomaterials 35:316–326. https://doi.org/10.1016/j.biomaterials.2013.09.098 PubMedCrossRef

94.

Ao L, Reichel D, Hu D et al (2015) Polymer micelle formulations of proteasome inhibitor farfilzomib for improved metabolic stability and anticancer efficacy in human multiple myeloma and ung cancer cell lines. J Pharmacol Exp Ther 355:168–173. https://doi.org/10.1124/jpet.115.226993 PubMedPubMedCentralCrossRef

95.

Li C, Hu J, Li W et al (2017) Combined bortezomib-based chemotherapy and p53 gene therapy using hollow mesoporous silica nanospheres for p53 mutant non-small cell lung cancer treatment. Biomater Sci 5:77–88. https://doi.org/10.1039/C6BM00449K CrossRef

96.

Huang C, Yokomise H, Miyatake A (2007) Clinical significance of the p53 pathway and associated gene therapy in non-small cell lung cancers. Future Oncol 3:83–93. https://doi.org/10.2217/14796694.3.1.83 PubMedCrossRef

97.

Neukirchen J, Meier A, Rohrbeck A et al (2007) The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells. Cancer Gene Ther 14:431–439. https://doi.org/10.1038/sj.cgt.7701029 PubMedCrossRef

98.

Nawrocki ST, Carew JS, Dunner K et al (2005) Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells. Cancer Res 65:11510–11520. https://doi.org/10.1158/0008-5472.CAN-05-2394 PubMedCrossRef

99.

Chiu HW, Lin SW, Lin LC et al (2015) Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett 365:229–239. https://doi.org/10.1016/j.canlet.2015.05.025 PubMedCrossRef

100.

Fang J, Rhyasen G, Bolanos L et al (2012) Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood 120:858–867. https://doi.org/10.1182/blood-2012-02-407999.The PubMedPubMedCentralCrossRef

101.

Min H, Xu M, Chen ZR et al (2014) Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemother Pharmacol 74:167–176. https://doi.org/10.1007/s00280-014-2451-7 PubMedCrossRef

102.

Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9:1004–1010. https://doi.org/10.1038/nrm2529 PubMedPubMedCentralCrossRef

103.

Yu L, Wan F, Dutta S et al (2006) Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 103:4952–4957 https://doi.org/10.1073/pnas.0511288103 PubMedPubMedCentralCrossRef

104.

Naumann K, Schmich K, Jaeger C et al (2012) Noxa/Mcl-1 balance influences the effect of the proteasome inhibitor MG-132 in combination with anticancer agents in pancreatic cancer cell lines. Anticancer Drugs 23:614–626. https://doi.org/10.1097/CAD.0b013e3283504e53 PubMedCrossRef

105.

Gong L, Yang B, Xu M et al (2014) Bortezomib-induced apoptosis in cultured pancreatic cancer cells is associated with ceramide production. Cancer Chemother Pharmacol 73:69–77. https://doi.org/10.1007/s00280-013-2318-3 PubMedCrossRef

106.

Millward M, Price T, Townsend A et al (2012) Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs 30:2303–2317. https://doi.org/10.1007/s10637-011-9766-6 PubMedCrossRef

107.

Coelho SC, Almeida GM, Santos-Silva F et al (2016) Enhancing the efficiency of bortezomib conjugated to pegylated gold nanoparticles: an in vitro study on human pancreatic cancer cells and adenocarcinoma human lung alveolar basal epithelial cells. Expert Opin Drug Deliv 13:1075–1083. https://doi.org/10.1080/17425247.2016.1178234 PubMedCrossRef

108.

Tseng LM, Liu CY, Chang KC et al (2012) CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res 14:R68. https://doi.org/10.1186/bcr3175 PubMedPubMedCentralCrossRef

109.

Chen YJ, Yeh MH, Yu MC et al (2013) Lapatinib-induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors. Breast Cancer Res 15:R108–R108. https://doi.org/10.1186/bcr3575 PubMedPubMedCentralCrossRef

110.

Chang H, Huang T, Chen N et al (2014) Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. Cell Death Dis 5:e1540. https://doi.org/10.1038/cddis.2014.504 PubMedPubMedCentralCrossRef

111.

Gu Y, Bouwman P, Greco D et al (2014) Suppression of BRCA1 sensitizes cells to proteasome inhibitors. Cell Death Dis 5:e1580. https://doi.org/10.1038/cddis.2014.537 PubMedPubMedCentralCrossRef

112.

Komatsu S, Miyazawa K, Moriya S et al (2012) Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. Int J Oncol 1029–1039. https://doi.org/10.3892/ijo.2011.1317

113.

Miyahara K, Kazama H, Kokuba H et al (2016) Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. Int J Oncol 49:1848–1858. https://doi.org/10.3892/ijo.2016.3673 PubMedPubMedCentralCrossRef

114.

Shi Y, Yu Y, Wang Z et al (2016) Second-generation proteasome inhibitor carfilzomib enhances doxorubicin-induced cytotoxicity and apoptosis in breast cancer cells. Oncotarget 7:73697–73710. https://doi.org/10.18632/oncotarget.12048 PubMedPubMedCentral

115.

Wang H, Yu Y, Jiang Z et al (2016) Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis. Sci Rep 6:26456. https://doi.org/10.1038/srep26456 PubMedPubMedCentralCrossRef

116.

Maynadier M, Basile I, Gallud A et al (2016) Combination treatment with proteasome inhibitors and antiestrogens has a synergistic effect mediated by p21WAF1 in estrogen receptor-positive breast cancer. Oncol Rep 36:1127–1134. https://doi.org/10.3892/or.2016.4873 PubMedCrossRef

117.

Lin Y-C, Chen K-C, Chen C-C et al (2012) CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol 48:585–593. https://doi.org/10.1016/j.oraloncology.2012.01.012 PubMedCrossRef

118.

Li C, Johnson DE (2013) Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle 12:923–934. https://doi.org/10.4161/cc.23882 PubMedPubMedCentralCrossRef

119.

Zang Y, Thomas SM, Chan ET et al (2012) Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy. Clin Cancer Res 18:5639–5649. https://doi.org/10.1158/1078-0432.CCR-12-1213 PubMedPubMedCentralCrossRef

120.

Gilbert J, Lee JW, Argiris A et al (2012) Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma. Head Neck 341:942–948. https://doi.org/10.1002/HED

121.

Sung ES, Park KJ, Choi HJ et al (2012) The proteasome inhibitor MG132 potentiates TRAIL receptor agonist-induced apoptosis by stabilizing tBid and Bik in human head and neck squamous cell carcinoma cells. Exp Cell Res 318:1564–1576. https://doi.org/10.1016/j.yexcr.2012.04.003 PubMedCrossRef

122.

Chang I, Wang CY (2016) Inhibition of HDAC6 protein enhances bortezomib-induced apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by reducing autophagy. J Biol Chem 291:18199–18209. https://doi.org/10.1074/jbc.M116.717793 PubMedPubMedCentralCrossRef

123.

Yim JH, Yun HS, Lee SJ et al (2016) Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells. Biochem Biophys Res Commun 469:94–100. https://doi.org/10.1016/j.bbrc.2015.11.077 PubMedCrossRef

124.

Mehta A, Zhang L, Boufraqech M et al (2015) Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer. Endocr Relat Cancer 22:319–329. https://doi.org/10.1530/ERC-14-0510 PubMedCrossRef

125.

Altmann A, Markert A, Askoxylakis V et al (2012) Antitumor effects of proteasome inhibition in anaplastic thyroid carcinoma. J Nucl Med 53:1764–1771. https://doi.org/10.2967/jnumed.111.101295 PubMedCrossRef

126.

Zhang L, Boufraqech M, Lake R, Kebebew E (2016) Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer. Oncotarget 7:16517–16528. https://doi.org/10.18632/oncotarget.7760 PubMedPubMedCentral

127.

Qiang W, Sui F, Ma J et al (2017) Proteasome inhibitor MG132 induces thyroid cancer cell apoptosis by modulating the activity of transcription factor FOXO3a. Endocrine 56:98–108. https://doi.org/10.1007/s12020-017-1256-y PubMedCrossRef

128.

Zhang HY, Du ZX, Meng X et al (2013) Beclin 1 enhances proteasome inhibition-mediated cytotoxicity of thyroid cancer cells in macroautophagy-independent manner. J Clin Endocrinol Metab 98:217–226. https://doi.org/10.1210/jc.2012-2679 CrossRef

129.

Chen YJ, Wu H, Shen XZ (2016) The ubiquitin-proteasome system and its potential application in hepatocellular carcinoma therapy. Cancer Lett 379:245–252. https://doi.org/10.1016/j.canlet.2015.06.023 PubMedCrossRef

130.

Vandewynckel Y, Coucke C, Laukens D et al (2016) Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma. Oncotarget 7:34988–35000. https://doi.org/10.18632/oncotarget.9222 PubMedPubMedCentralCrossRef

131.

Baiz D, Dapas B, Farra R et al (2014) Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines. World J Gastroenterol 20:795–803. https://doi.org/10.3748/wjg.v20.i3.795 PubMedPubMedCentralCrossRef

132.

Witort E, Lulli M, Carloni V, Capaccioli S (2013) Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells. J Chemother 25:292–297. https://doi.org/10.1179/1973947813Y.0000000087 PubMedCrossRef

133.

Chen H, Yang H, Pan L et al (2016) The molecular mechanisms of XBP-1 gene silencing on IRE1α-TRAF2-ASK1-JNK pathways in oral squamous cell carcinoma under endoplasmic reticulum stress. Biomed Pharmacother 77:108–113. https://doi.org/10.1016/j.biopha.2015.12.010 PubMedCrossRef

134.

Liu D, Gao M, Yang Y et al (2015) Inhibition of autophagy promotes cell apoptosis induced by the proteasome inhibitor MG-132 in human esophageal squamous cell carcinoma EC9706 cells. Oncol Lett 9:2278–2282. https://doi.org/10.3892/ol.2015.3047 PubMedPubMedCentralCrossRef

135.

Dang L, Wen F, Yang Y et al (2014) Proteasome inhibitor MG132 inhibits the proliferation and promotes the cisplatin-induced apoptosis of human esophageal squamous cell carcinoma cells. Int J Mol Med 33:1083–1088. https://doi.org/10.3892/ijmm.2014.1678 PubMedPubMedCentralCrossRef

136.

Yang X (2012) Proteasome inhibitor bortezomi-induced the apoptosis of laryngeal squamous cell carcinoma Hep-2 cell line via disrupting redox equilibrium. Biomed Pharmacother 66:607–611. https://doi.org/10.1016/j.biopha.2012.08.010 PubMedCrossRef

137.

Li D, Lu Y, Sun P et al (2015) Inhibition on proteasome B1 subunit might contribute to the anti-cancer effects of fangchinoline in human prostate cancer cells. PLoS One 10:e0141681. https://doi.org/10.1371/journal.pone.0141681 PubMedPubMedCentralCrossRef

138.

Modernelli A, Naponelli V, Giovanna Troglio M et al (2015) EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism. Sci Rep 5:15270. https://doi.org/10.1038/srep15270 PubMedPubMedCentralCrossRef

139.

Chattopadhyay N, Berger AJ, Koenig E et al (2015) KRAS genotype correlates with proteasome inhibitor ixazomib activity in preclinical in vivo models of colon and non-small cell lung cancer: Potential role of tumor metabolism. PLoS One 10:e0144825. https://doi.org/10.1371/journal.pone.0144825 PubMedPubMedCentralCrossRef

140.

Krȩtowski R, Borzym-Kluczyk M, Cechowska-Pasko M (2014) Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line. Mol Cell Biochem 389:177–185. https://doi.org/10.1007/s11010-013-1939-5 PubMedPubMedCentralCrossRef

141.

Singha B, Gatla HR, Phyo S, Patel A (2015) IKK Inhibition Increases Bortezomib Effectiveness in Ovarian Cancer. Oncotarget 6:26347–26358. https://doi.org/10.18632/oncotarget.4613 PubMedPubMedCentralCrossRef

142.

Denlinger CS, Meropol NJ, Li T et al (2014) A phase II trial of the proteasome inhibitor bortezomib in patients with advanced biliary tract cancers. Cancer Res 13:81–86. https://doi.org/10.1016/j.clcc.2013.12.005

143.

Ito K, Kobayashi M, Kuroki S et al (2013) The proteasome inhibitor bortezomib inhibits the growth of canine malignant melanoma cells in vitro and in vivo. Vet J 198:577–582. https://doi.org/10.1016/j.tvjl.2013.08.003 PubMedCrossRef

144.

Selimovic D, Porzig BBOW., El-Khattouti A et al (2013) Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells. Cell Signal 25:308–318. https://doi.org/10.1016/j.cellsig.2012.10.004 PubMedCrossRef

145.

Franke NE, Niewerth D, Assaraf YG et al (2012) Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26:757–768. https://doi.org/10.1038/leu.2011.256 PubMedCrossRef

146.

Niewerth D, Kaspers GJL, Assaraf YG et al (2014) Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines. J Hematol Oncol 7:7. https://doi.org/10.1186/1756-8722-7-7 PubMedPubMedCentralCrossRef

147.

Niewerth D, van Meerloo J, Jansen G et al (2014) Anti-leukemic activity and mechanisms underlying resistance to the novel immunoproteasome inhibitor PR-924. Biochem Pharmacol 89:43–51. https://doi.org/10.1016/j.bcp.2014.02.005 PubMedCrossRef

148.

Suzuki E, Demo S, Deu E et al (2011) Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6:e27996. https://doi.org/10.1371/journal.pone.0027996 PubMedPubMedCentralCrossRef

149.

Weyburne ES, Wilkins OM, Sha Z et al (2017) Inhibition of the proteasome β2 site sensitizes triple-negative breast cancer cells to β5 inhibitors and suppresses Nrf1 activation. Cell Chem Biol 24:218–230. https://doi.org/10.1016/j.chembiol.2016.12.016 PubMedCrossRef

150.

Niewerth D, Franke NE, Jansen G et al (2013) Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica 98:1896–1904. https://doi.org/10.3324/haematol.2013.092411 PubMedPubMedCentralCrossRef

151.

Nguyen M, Marcellus RC, Roulston A et al (2007) Small molecule obatoclax (GX15–070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci 104:19512–19517. https://doi.org/10.1073/pnas.0709443104 PubMedPubMedCentralCrossRef

152.

Miyamoto Y, Hosotani R, Wada M et al (1999) Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology 56:73–82. https://doi.org/10.1159/000011933 PubMedCrossRef

153.

Zang Y, Kirk CJ, Johnson DE (2014) Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Cancer Biol Ther 15:1142–1152. https://doi.org/10.4161/cbt.29452 PubMedPubMedCentralCrossRef

154.

Ao L, Wu Y, Kim D et al (2012) Development of peptide-based reversing agents for P-glycoprotein-mediated resistance to carfilzomib. Mol Pharm 9:2197–2205. https://doi.org/10.1021/mp300044b PubMedPubMedCentralCrossRef

155.

Verbrugge SE, Assaraf YG, Dijkmans BA et al (2012) Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with. J Pharmacol Exp Ther 341:174–182. https://doi.org/10.1124/jpet.111.187542 PubMedCrossRef

156.

Oerlemans R, Franke NE, Assaraf YG et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112:2489–2499. https://doi.org/10.1182/blood-2007-08-104950 PubMedCrossRef

157.

de Bruin G, Xin BT, Kraus M et al (2016) A set of activity-based probes to visualize human (immuno) proteasome activities. Angew Chem Int Ed Engl 55:4199–4203. https://doi.org/10.1002/anie.201509092 PubMedCrossRef

158.

Lee SJ, Levitsky K, Parlati F et al (2016) Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits : application of a novel pharmacodynamic assay. Br J Cancer 173:884–895. https://doi.org/10.1111/bjh.14014

159.

Seifert U, Bialy LP, Ebstein F et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142:613–624. https://doi.org/10.1016/j.cell.2010.07.036 PubMedCrossRef

160.

Yun YS, Kim KH, Tschida B et al (2016) mTORC1 coordinates protein synthesis and immunoproteasome formation via PRAS40 to prevent accumulation of protein stress. Mol Cell 61:625–639. https://doi.org/10.1016/j.molcel.2016.01.013 PubMedPubMedCentralCrossRef

161.

Muchamuel T, Basler M, Aujay MA et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15:781–787. https://doi.org/10.1038/nm.1978 PubMedCrossRef

162.

Raz S, Sheban D, Gonen N et al (2014) Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis 5:e1067. https://doi.org/10.1038/cddis.2014.39 PubMedPubMedCentralCrossRef

163.

Franke NE, Kaspers GL, Assaraf YG et al (2016) Exocytosis of polyubiquitinated proteins in bortezomib-resistant leukemia cells: a role for MARCKS in acquired resistance to proteasome inhibitors. Oncotarget 7:74779–74796. https://doi.org/10.18632/oncotarget.11340 PubMedPubMedCentralCrossRef

164.

Green TD, Crews AL, Park J et al (2011) Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein? Biochim Biophys Acta 1810:1110–1113. https://doi.org/10.1016/j.bbagen.2011.01.009 PubMedPubMedCentralCrossRef

165.

Chen CH, Thai P, Yoneda K et al (2014) A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis. Oncogene 33:3696–3706. https://doi.org/10.1038/onc.2013.336 PubMedCrossRef

166.

Micallef J, Dharsee M, Chen J et al (2010) Applying mass spectrometry based proteomic technology to advance the understanding of multiple myeloma. J Hematol Oncol 3:13. https://doi.org/10.1186/1756-8722-3-13 PubMedPubMedCentralCrossRef

167.

Zaal EA, Wu W, Jansen G et al (2017) Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer Metab 5:7. https://doi.org/10.1186/s40170-017-0169-9 PubMedPubMedCentralCrossRef

168.

Li X, Wood TE, Sprangers R et al (2010) Effect of noncompetitive proteasome inhibition on bortezomib resistance. J Natl Cancer Inst 102:1069–1082. https://doi.org/10.1093/jnci/djq198 PubMedCrossRef

169.

Arcy PD, Brnjic S, Olofsson MH et al (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17:1636–1640. https://doi.org/10.1038/nm.2536 PubMedCrossRef

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Positioning of proteasome inhibitors in therapy of solid malignancies

Abstract

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma

The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer

A pilot study of daunorubicin-augmented hyper-CVAD induction chemotherapy for adults with acute lymphoblastic leukemia

A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting

Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer