Skip to main content
SpringerLink
Log in

Novel Approaches to Apoptosis-Inducing Therapies

  • Chapter
  • First Online:
Book cover Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 930))

Abstract

Induction of apoptotic programmed cell death is one of the underlying principles of most current cancer therapies. In this review, we discuss the limitations and drawbacks of this approach and identify three distinct, but overlapping strategies to avoid these difficulties and further enhance the efficacy of apoptosis-inducing therapies. We postulate that the application of multi-targeted small molecule inhibitor cocktails will reduce the risk of the cancer cell populations developing resistance towards therapy. Following from these considerations regarding population genetics and ecology, we advocate the reconsideration of therapeutic end points to maximise the benefits, in terms of quantity and quality of life, for the patients. Finally, combining both previous points, we also suggest an altered focus on the cellular and molecular targets of therapy, i.e. targeting the (cancer cells’) interaction with the tumour microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  3. Renehan AG, Booth C, Potten CS. What is apoptosis, and why is it important? BMJ. 2001;322(7301):1536–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Esserman LJ, Thompson Jr IM, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797–8.

    Article  CAS  PubMed  Google Scholar 

  5. Stroh S, Debatin K-M, Westhoff M-A. Darwinian principles in cancer therapy. Eur Oncol Haematol. 2014;10(2):116–120.

    Google Scholar 

  6. Westhoff MA, Brühl O, Nonnenmacher L, Karpel-Massler G, Debatin KM. Killing me softly-future challenges in apoptosis research. Int J Mol Sci. 2014;15(3):3746–67.

    Google Scholar 

  7. Fulda S, Debatin KM. Modulation of apoptosis signaling for cancer therapy. Arch Immunol Ther Exp (Warsz). 2006;54(3):173–5.

    Article  CAS  Google Scholar 

  8. Shivapurkar N, Toyooka S, Eby MT, Huang CX, Sathyanarayana UG, Cunningham HT, Reddy JL, Brambilla E, Takahashi T, Minna JD, Chaudhary PM, Gazdar AF. Differential inactivation of caspase-8 in lung cancers. Cancer Biol Ther. 2002;1(1):65–9.

    Article  CAS  PubMed  Google Scholar 

  9. Soung YH, Lee JW, Kim SY, Jang J, Park YG, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH. CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res. 2005;65(3):815–21.

    CAS  PubMed  Google Scholar 

  10. Soung YH, Lee JW, Kim SY, Sung YJ, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene. 2005;24(1):141–7.

    Article  CAS  PubMed  Google Scholar 

  11. Casciano I, De Ambrosis A, Croce M, Pagnan G, Di Vinci A, Allemanni G, Banelli B, Ponzoni M, Romani M, Ferrini S. Expression of the caspase-8 gene in neuroblastoma cells is regulated through an essential interferon-sensitive response element (ISRE). Cell Death Differ. 2004;11(1):131–4.

    Article  CAS  PubMed  Google Scholar 

  12. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.

    PubMed  PubMed Central  Google Scholar 

  14. Woods D, Turchi JJ. Chemotherapy induced DNA damage response: convergence of drugs and pathways. Cancer Biol Ther. 2013;14(5):379–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol. 2013;20(5):648–59.

    Article  CAS  PubMed  Google Scholar 

  16. Facchini LM, Penn LZ. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights. FASEB J. 1998;12(9):633–51.

    CAS  PubMed  Google Scholar 

  17. Pelengaris S, Khan M, Evan G. c-MYC: more than just a matter of life and death. Nat Rev Cancer. 2002;2(10):764–76.

    Article  CAS  PubMed  Google Scholar 

  18. Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. 2012;122(12):4621–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chesler L, Schlieve C, Goldenberg DD, Kenney A, Kim G, McMillan A, Matthay KK, Rowitch D, Weiss WA. Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res. 2006;66(16):8139–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4, e838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M, Wouters BG. PERK/eIF2alpha signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc Natl Acad Sci U S A. 2013;110(12):4622–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Burris III HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71(4):829–42.

    Article  CAS  PubMed  Google Scholar 

  23. Westhoff MA, Serrels B, Fincham VJ, Frame MC, Carragher NO. SRC-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol Cell Biol. 2004;24(18):8113–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Golubovskaya VM. Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci. 2014;19:687–706.

    Article  CAS  Google Scholar 

  25. Waters AM, Beierle EA. The interaction between FAK, MYCN, p53 and Mdm2 in neuroblastoma. Anticancer Agents Med Chem. 2014;14(1):46–51. pii: ACAMC-EPUB-55926.

    Article  CAS  PubMed  Google Scholar 

  26. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48.

    Article  CAS  PubMed  Google Scholar 

  27. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19(1):107–20.

    Article  CAS  PubMed  Google Scholar 

  28. Saha MN, Qiu L, Chang H. Targeting p53 by small molecules in hematological malignancies. J Hematol Oncol. 2013;6:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13(3):217–36.

    Article  CAS  PubMed  Google Scholar 

  30. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008;27(41):5443–53.

    Article  CAS  PubMed  Google Scholar 

  31. Fan QW, Weiss WA. Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol. 2010;347:279–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cancer-Genome-Atlas-Research-Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.

    Article  CAS  Google Scholar 

  33. Akhavan D, Cloughesy TF, Mischel PS. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro Oncol. 2010;12(8):882–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K pathway inhibitors in glioblastoma. Neuro Oncol. 2012;14(7):819–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 2010;12(3):233–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mendiburu-Elicabe M, Gil-Ranedo J, Izquierdo M. Efficacy of rapamycin against glioblastoma cancer stem cells. Clin Transl Oncol. 2014;16(5):495–502.

    Article  CAS  PubMed  Google Scholar 

  37. Westhoff M-A, Karpel-Massler G, Bruhl O, Enzenmuller S, La Ferla-Bruhl K, Siegelin M, Nonnenmacher L, Debatin K-M. A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy. Mol Cell Ther. 2014;2(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14(5):359–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol. 2014;89(5):547–56.

    Article  CAS  PubMed  Google Scholar 

  40. Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D’Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Valsecchi MG, Kim DW. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103(7):553–61.

    Article  CAS  PubMed  Google Scholar 

  41. An X, Tiwari AK, Sun Y, Ding PR, Ashby Jr CR, Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34(10):1255–68.

    Article  CAS  PubMed  Google Scholar 

  42. Mughal A, Aslam HM, Khan AM, Saleem S, Umah R, Saleem M. Bcr-Abl tyrosine kinase inhibitors- current status. Infect Agent Cancer. 2013;8(1):23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. DeVita Jr VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68(21):8643–53.

    Article  CAS  PubMed  Google Scholar 

  44. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, Shefler E, Sivachenko A, Sougnez C, Stewart C, Ally A, Birol I, Chiu R, Corbett RD, Hirst M, Jackman SD, Kamoh B, Khodabakshi AH, Krzywinski M, Lo A, Moore RA, Mungall KL, Qian J, Tam A, Thiessen N, Zhao Y, Cole KA, Diamond M, Diskin SJ, Mosse YP, Wood AC, Ji L, Sposto R, Badgett T, London WB, Moyer Y, Gastier-Foster JM, Smith MA, Guidry Auvil JM, Gerhard DS, Hogarty MD, Jones SJ, Lander ES, Gabriel SB, Getz G, Seeger RC, Khan J, Marra MA, Meyerson M, Maris JM. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45(3):279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR, Yates LR, Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Chapman MS, Teague J, Easton D, Langerod A, Lee MT, Shen CY, Tee BT, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin SF, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van’t Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SA, Salomon AV, Borresen-Dale AL, Richardson AL, Campbell PJ, Futreal PA, Stratton MR. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Klopocki E, Neumann LM, Tonnies H, Ropers HH, Mundlos S, Ullmann R. Ulnar-mammary syndrome with dysmorphic facies and mental retardation caused by a novel 1.28 Mb deletion encompassing the TBX3 gene. Eur J Hum Genet. 2006;14(12):1274–9.

    Article  CAS  PubMed  Google Scholar 

  48. Romiti A, Cox MC, Sarcina I, Di Rocco R, D’Antonio C, Barucca V, Marchetti P. Metronomic chemotherapy for cancer treatment: a decade of clinical studies. Cancer Chemother Pharmacol. 2013;72(1):13–33.

    Article  CAS  PubMed  Google Scholar 

  49. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell. 1994;76(4):665–76.

    Article  CAS  PubMed  Google Scholar 

  50. Leber B, Geng F, Kale J, Andrews DW. Drugs targeting Bcl-2 family members as an emerging strategy in cancer. Expert Rev Mol Med. 2010;12, e28.

    Article  PubMed  CAS  Google Scholar 

  51. Fischer U, Schulze-Osthoff K. Apoptosis-based therapies and drug targets. Cell Death Differ. 2005;12 Suppl 1:942–61.

    Article  CAS  PubMed  Google Scholar 

  52. Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG, Tsang BK, Cheng JQ. Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2004;279(7):5405–12.

    Article  CAS  PubMed  Google Scholar 

  53. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231–41.

    Article  CAS  PubMed  Google Scholar 

  54. Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem. 2004;279(20):21085–95.

    Article  CAS  PubMed  Google Scholar 

  55. Qi XJ, Wildey GM, Howe PH. Evidence that Ser87 of BimEL is phosphorylated by Akt and regulates BimEL apoptotic function. J Biol Chem. 2006;281(2):813–23.

    Article  CAS  PubMed  Google Scholar 

  56. Berthelet J, Dubrez L. Regulation of apoptosis by inhibitors of apoptosis (IAPs). Cells. 2013;2(1):163–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J, Rivard N. MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem. 2000;79(3):355–69.

    Article  CAS  PubMed  Google Scholar 

  58. Meier F, Schittek B, Busch S, Garbe C, Smalley K, Satyamoorthy K, Li G, Herlyn M. The RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma. Front Biosci. 2005;10:2986–3001.

    Article  CAS  PubMed  Google Scholar 

  59. Unni E, Koul D, Yung WK, Sinha R. Se-methylselenocysteine inhibits phosphatidylinositol 3-kinase activity of mouse mammary epithelial tumor cells in vitro. Breast Cancer Res. 2005;7(5):R699–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mortenson MM, Galante JG, Gilad O, Schlieman MG, Virudachalam S, Kung HJ, Bold RJ. BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer. J Cell Biochem. 2007;102(5):1171–9.

    Article  CAS  PubMed  Google Scholar 

  61. Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK. Invest Ophthalmol Vis Sci. 2010;51(1):421–9.

    Article  PubMed  Google Scholar 

  62. Shen J, Wu Y, Xu JY, Zhang J, Sinclair SH, Yanoff M, Xu G, Li W, Xu GT. ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Vis Sci. 2010;51(1):35–46.

    Article  PubMed  Google Scholar 

  63. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012;11(4):909–20.

    Article  CAS  PubMed  Google Scholar 

  64. Yamaguchi H, Hsu JL, Hung MC. Regulation of ubiquitination-mediated protein degradation by survival kinases in cancer. Front Oncol. 2012;2:15.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Suh DH, Kim MK, Kim HS, Chung HH, Song YS. Mitochondrial permeability transition pore as a selective target for anti-cancer therapy. Front Oncol. 2013;3:41.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Verhagen AM, Coulson EJ, Vaux DL. Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol. 2001;2(7):REVIEWS3009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 2010;10(8):561–74.

    Article  CAS  PubMed  Google Scholar 

  68. Owens TW, Gilmore AP, Streuli CH, Foster FM. Inhibitor of apoptosis proteins: promising targets for cancer therapy. J Carcinog Mutagen Suppl. 2013;14:S14.

    Google Scholar 

  69. Mannhold R, Fulda S, Carosati E. IAP antagonists: promising candidates for cancer therapy. Drug Discov Today. 2010;15(5-6):210–9.

    Article  CAS  PubMed  Google Scholar 

  70. Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808–15.

    CAS  PubMed  Google Scholar 

  71. Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006;244(2):164–71.

    Article  CAS  PubMed  Google Scholar 

  72. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000–5.

    Article  CAS  PubMed  Google Scholar 

  73. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004;23(16):2825–37.

    Article  CAS  PubMed  Google Scholar 

  74. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998;396(6711):580–4.

    Article  CAS  PubMed  Google Scholar 

  75. Fernandez JG, Rodriguez DA, Valenzuela M, Calderon C, Urzua U, Munroe D, Rosas C, Lemus D, Diaz N, Wright MC, Leyton L, Tapia JC, Quest AF. Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced beta-catenin/Tcf-Lef dependent transcription. Mol Cancer. 2014;13:209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Carvalho A, Carmena M, Sambade C, Earnshaw WC, Wheatley SP. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J Cell Sci. 2003;116(Pt 14):2987–98.

    Article  CAS  PubMed  Google Scholar 

  77. Lens SM, Wolthuis RM, Klompmaker R, Kauw J, Agami R, Brummelkamp T, Kops G, Medema RH. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J. 2003;22(12):2934–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Maskey D, Yousefi S, Schmid I, Zlobec I, Perren A, Friis R, Simon HU. ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nat Commun. 2013;4:2130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49–63.

    Article  CAS  PubMed  Google Scholar 

  80. Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther. 2013;12(9):1691–700.

    Article  CAS  PubMed  Google Scholar 

  81. Ni Chonghaile T, Letai A. Mimicking the BH3 domain to kill cancer cells. Oncogene. 2008;27 Suppl 1:S149–57.

    Article  PubMed  CAS  Google Scholar 

  82. Stamelos VA, Redman CW, Richardson A. Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine. J Mol Signal. 2012;7(1):12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Carico C, Nuno M, Mukherjee D, Elramsisy A, Dantis J, Hu J, Rudnick J, Yu JS, Black KL, Bannykh SI, Patil CG. Loss of PTEN is not associated with poor survival in newly diagnosed glioblastoma patients of the temozolomide era. PLoS One. 2012;7(3), e33684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shi Y, Paluch BE, Wang X, Jiang X. PTEN at a glance. J Cell Sci. 2012;125(Pt 20):4687–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Opel D, Westhoff MA, Bender A, Braun V, Debatin KM, Fulda S. Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res. 2008;68(15):6271–80.

    Article  CAS  PubMed  Google Scholar 

  86. Westhoff MA, Kandenwein JA, Karl S, Vellanki SH, Braun V, Eramo A, Antoniadis G, Debatin KM, Fulda S. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene. 2009;28(40):3586–96.

    Article  CAS  PubMed  Google Scholar 

  87. Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol. 2013;6(1):88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Mills GB, Younes A. Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol. 2006;132(4):503–11.

    CAS  PubMed  Google Scholar 

  89. Zhu Y, Shah K. Multiple lesions in receptor tyrosine kinase pathway determine glioblastoma response to pan-ERBB inhibitor PF-00299804 and PI3K/mTOR dual inhibitor PF-05212384. Cancer Biol Ther. 2014;15(6):815–22.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Ho R, Minturn JE, Hishiki T, Zhao H, Wang Q, Cnaan A, Maris J, Evans AE, Brodeur GM. Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Cancer Res. 2005;65(21):9868–75.

    Article  CAS  PubMed  Google Scholar 

  91. Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, Huang X, Monian P, Jiang X, de Stanchina E, Baselga J, Liu N, Chandarlapaty S, Rosen N. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. 2014;4(3):334–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773(8):1213–26.

    Article  CAS  PubMed  Google Scholar 

  94. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol. 2014;11(7):385–400.

    Article  CAS  PubMed  Google Scholar 

  96. Westhoff MA, Faham N, Marx D, Nonnenmacher L, Jennewein C, Enzenmuller S, Gonzalez P, Fulda S, Debatin KM. Sequential dosing in chemosensitization: targeting the PI3K/Akt/mTOR pathway in neuroblastoma. PLoS One. 2013;8(12), e83128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Kuger S, Graus D, Brendtke R, Gunther N, Katzer A, Lutyj P, Polat B, Chatterjee M, Sukhorukov VL, Flentje M, Djuzenova CS. Radiosensitization of glioblastoma cell lines by the dual PI3K and mTOR inhibitor NVP-BEZ235 depends on drug-irradiation schedule. Transl Oncol. 2013;6(2):169–79.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Mitchison TJ. The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell. 2012;23(1):1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Das G, Shravage BV, Baehrecke EH. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol. 2012;4(6):a008813.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, Kobayashi H, Sato F, Sato S, Ishikawa K, Imoto M, Hattori N. Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy. 2011;7(2):176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Castino R, Bellio N, Follo C, Murphy D, Isidoro C. Inhibition of PI3k class III-dependent autophagy prevents apoptosis and necrosis by oxidative stress in dopaminergic neuroblastoma cells. Toxicol Sci. 2010;117(1):152–62.

    Article  CAS  PubMed  Google Scholar 

  102. Nonnenmacher L, Westhoff MA, Fulda S, Karpel-Massler G, Halatsch ME, Engelke J, Simmet T, Corbacioglu S, Debatin KM. RIST: A potent new combination therapy for glioblastoma. Int J Cancer. 2015;136(4):E173–87.

    Article  CAS  PubMed  Google Scholar 

  103. Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell. 2012;149(4):780–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhou J, Bi C, Janakakumara JV, Liu SC, Chng WJ, Tay KG, Poon LF, Xie Z, Palaniyandi S, Yu H, Glaser KB, Albert DH, Davidsen SK, Chen CS. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood. 2009;113(17):4052–62.

    Article  CAS  PubMed  Google Scholar 

  105. Stolzel F, Steudel C, Oelschlagel U, Mohr B, Koch S, Ehninger G, Thiede C. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol. 2010;89(7):653–62.

    Article  PubMed  CAS  Google Scholar 

  106. Herrmann MD, Lennerz JK, Bullinger L, Bartholomae S, Holzmann K, Westhoff MA, Corbacioglu S, Debatin KM. Transitory dasatinib-resistant states in KITmut t(8;21) acute myeloid leukemia cells correlate with altered KIT expression. Exp Hematol. 2014;42:90–100.

    Article  CAS  PubMed  Google Scholar 

  107. Saito N, Ishihara S, Kaneko K. Baldwin effect under multipeaked fitness landscapes: phenotypic fluctuation accelerates evolutionary rate. Phys Rev E Stat Nonlin Soft Matter Phys. 2013;87(5):052701.

    Article  PubMed  CAS  Google Scholar 

  108. Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med. 2011;3(11):623–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014;5(18):8052–82.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Dougan M, Dranoff G. Immune therapy for cancer. Annu Rev Immunol. 2009;27:83–117.

    Article  CAS  PubMed  Google Scholar 

  111. Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J Immunother Cancer. 2013;1:12.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hall RD, Gray JE, Chiappori AA. Beyond the standard of care: a review of novel immunotherapy trials for the treatment of lung cancer. Cancer Control. 2013;20(1):22–31.

    PubMed  Google Scholar 

  113. Weber JS. Current perspectives on immunotherapy. Semin Oncol. 2014;41 Suppl 5:S14–29.

    Article  CAS  PubMed  Google Scholar 

  114. Okonogi N, Shirai K, Oike T, Murata K, Noda SE, Suzuki Y, Nakano T. Topics in chemotherapy, molecular-targeted therapy, and immunotherapy for newly-diagnosed glioblastoma multiforme. Anticancer Res. 2015;35(3):1229–35.

    CAS  PubMed  Google Scholar 

  115. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  117. Raval RR, Sharabi AB, Walker AJ, Drake CG, Sharma P. Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer. 2014;2:14.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol. 2014;4:325.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Campbell PJ, Pleasance ED, Stephens PJ, Dicks E, Rance R, Goodhead I, Follows GA, Green AR, Futreal PA, Stratton MR. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci U S A. 2008;105(35):13081–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gerecke C, Mascher C, Gottschalk U, Kleuser B, Scholtka B. Ultrasensitive detection of unknown colon cancer-initiating mutations using the example of the Adenomatous polyposis coli gene. Cancer Prev Res (Phila). 2013;6(9):898–907.

    Article  CAS  Google Scholar 

  122. Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15(8):453.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Cleary AS, Leonard TL, Gestl SA, Gunther EJ. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature. 2014;508(7494):113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014;514(7520):54–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gillies RJ, Verduzco D, Gatenby RA. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer. 2012;12(7):487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Choi S, Henderson MJ, Kwan E, Beesley AH, Sutton R, Bahar AY, Giles J, Venn NC, Pozza LD, Baker DL, Marshall GM, Kees UR, Haber M, Norris MD. Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone. Blood. 2007;110(2):632–9.

    Article  CAS  PubMed  Google Scholar 

  127. Kreso A, O’Brien CA, van Galen P, Gan OI, Notta F, Brown AM, Ng K, Ma J, Wienholds E, Dunant C, Pollett A, Gallinger S, McPherson J, Mullighan CG, Shibata D, Dick JE. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339(6119):543–8.

    Article  CAS  PubMed  Google Scholar 

  128. Gatenby RA, Brown J, Vincent T. Lessons from applied ecology: cancer control using an evolutionary double bind. Cancer Res. 2009;69(19):7499–502.

    Article  CAS  PubMed  Google Scholar 

  129. Westhoff MA, Bruhl O, Debatin KM. Cancer therapy: know your enemy? Mol Cell Pediatr. 2014;1(1):10.

    Google Scholar 

  130. Miller RG, Secrest AM, Sharma RK, Songer TJ, Orchard TJ. Improvements in the life expectancy of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications study cohort. Diabetes. 2012;61(11):2987–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84.

    Article  CAS  PubMed  Google Scholar 

  132. Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, Nonaka R, Yamamoto H, Ishii H, Mori M, Furuta K, Nakajima T, Hayashi H, Sugisaki H, Higashimoto H, Kato T, Takeshita F, Ochiya T. Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat Commun. 2014;5:3591.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Kaatsch P, Rickert CH, Kuhl J, Schuz J, Michaelis J. Population-based epidemiologic data on brain tumors in German children. Cancer. 2001;92(12):3155–64.

    Article  CAS  PubMed  Google Scholar 

  134. MacDonald TJ, Aguilera D, Kramm CM. Treatment of high-grade glioma in children and adolescents. Neuro Oncol. 2011;13(10):1049–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Karsy M, Huang T, Kleinman G, Karpel-Massler G. Molecular, histopathological, and genomic variants of glioblastoma. Front Biosci. 2014;19:1065–87.

    Article  CAS  Google Scholar 

  136. Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.

    CAS  PubMed  Google Scholar 

  138. Dolberg DS, Bissell MJ. Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature. 1984;309(5968):552–6.

    Article  CAS  PubMed  Google Scholar 

  139. Sevenich L, Bowman RL, Mason SD, Quail DF, Rapaport F, Elie BT, Brogi E, Brastianos PK, Hahn WC, Holsinger LJ, Massague J, Leslie CS, Joyce JA. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol. 2014;16(9):876–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32(3-4):449–64.

    Article  CAS  PubMed  Google Scholar 

  141. Steeg PS. Cancer biology: emissaries set up new sites. Nature. 2005;438(7069):750–1.

    Article  CAS  PubMed  Google Scholar 

  142. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46–54. doi:10.1038/35094059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sutherland RM, Durand RE. Cell contact as a possible contribution to radiation resistance of some tumours. Br J Radiol. 1972;45(538):788–9.

    Article  CAS  PubMed  Google Scholar 

  146. Durand RE, Sutherland RM. Radiation-resistant tumor cells may be more sensitive in vitro. Cancer Res. 1972;32(11):2587–8.

    CAS  PubMed  Google Scholar 

  147. Westhoff MA, Fulda S. Adhesion-mediated apoptosis resistance in cancer. Drug Resist Updat. 2009;12(4-5):127–36.

    Article  CAS  PubMed  Google Scholar 

  148. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood. 1999;93(5):1658–67.

    CAS  PubMed  Google Scholar 

  149. Hazlehurst LA, Argilagos RF, Emmons M, Boulware D, Beam CA, Sullivan DM, Dalton WS. Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. Cancer Res. 2006;66(4):2338–45.

    Article  CAS  PubMed  Google Scholar 

  150. Westhoff MA, Zhou S, Bachem MG, Debatin KM, Fulda S. Identification of a novel switch in the dominant forms of cell adhesion-mediated drug resistance in glioblastoma cells. Oncogene. 2008;27(39):5169–81.

    Article  CAS  PubMed  Google Scholar 

  151. Zhu B, Zhao L, Zhu L, Wang H, Sha Y, Yao J, Li Z, You Q, Guo Q. Oroxylin A reverses CAM-DR of HepG2 cells by suppressing Integrinbeta1 and its related pathway. Toxicol Appl Pharmacol. 2012;259(3):387–94.

    Article  CAS  PubMed  Google Scholar 

  152. Kiziltepe T, Ashley JD, Stefanick JF, Qi YM, Alves NJ, Handlogten MW, Suckow MA, Navari RM, Bilgicer B. Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo. Blood Cancer J. 2012;2(4), e64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cordes N, Meineke V. Cell adhesion-mediated radioresistance (CAM-RR). Extracellular matrix-dependent improvement of cell survival in human tumor and normal cells in vitro. Strahlenther Onkol. 2003;179(5):337–44.

    Article  PubMed  Google Scholar 

  154. Sandfort V, Koch U, Cordes N. Cell adhesion-mediated radioresistance revisited. Int J Radiat Biol. 2007;83(11-12):727–32.

    Article  CAS  PubMed  Google Scholar 

  155. Chiarugi P, Giannoni E. Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol. 2008;76(11):1352–64.

    Article  CAS  PubMed  Google Scholar 

  156. Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL. Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res. 1999;5(6):1587–94.

    CAS  PubMed  Google Scholar 

  157. Taylor ST, Hickman JA, Dive C. Epigenetic determinants of resistance to etoposide regulation of Bcl-X(L) and Bax by tumor microenvironmental factors. J Natl Cancer Inst. 2000;92(1):18–23.

    Article  CAS  PubMed  Google Scholar 

  158. Wang L, Li Z, Wang C, Yang Y, Sun L, Yao W, Cai X, Wu G, Zhou F, Zha X. E-cadherin decreased human breast cancer cells sensitivity to staurosporine by up-regulating Bcl-2 expression. Arch Biochem Biophys. 2009;481(1):116–22.

    Article  CAS  PubMed  Google Scholar 

  159. Lwin T, Hazlehurst LA, Li Z, Dessureault S, Sotomayor E, Moscinski LC, Dalton WS, Tao J. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia. 2007;21(7):1521–31.

    Article  CAS  PubMed  Google Scholar 

  160. Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene. 2001;20(36):4995–5004.

    Article  CAS  PubMed  Google Scholar 

  161. Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA. Isoform-selective phosphoinositide 3′-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009;113(22):5549–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Bourogaa E, Bertrand J, Despeaux M, Jarraya R, Fabre N, Payrastre L, Demur C, Fournie JJ, Damak M, Feki AE, Racaud-Sultan C. Hammada scoparia flavonoids and rutin kill adherent and chemoresistant leukemic cells. Leuk Res. 2011;35(8):1093–101.

    Article  CAS  PubMed  Google Scholar 

  163. Matsunaga T, Fukai F, Miura S, Nakane Y, Owaki T, Kodama H, Tanaka M, Nagaya T, Takimoto R, Takayama T, Niitsu Y. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia. 2008;22(2):353–60.

    Article  CAS  PubMed  Google Scholar 

  164. Wang X, Wang C, Qin YW, Yan SK, Gao YR. The association of up-regulation of X-linked inhibitor of apoptosis protein with cell adhesion-mediated drug resistance in U937 cells. Hematol Oncol. 2008;26(1):21–6.

    Article  PubMed  CAS  Google Scholar 

  165. Liu L, Zhang H, Sun L, Gao Y, Jin H, Liang S, Wang Y, Dong M, Shi Y, Li Z, Fan D. ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer. 2010;127(4):820–9.

    CAS  PubMed  Google Scholar 

  166. Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis—pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124(Pt 19):3189–97.

    Article  CAS  PubMed  Google Scholar 

  167. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.

    Article  CAS  PubMed  Google Scholar 

  168. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Westhoff MA, Zhou S, Nonnenmacher L, Karpel-Massler G, Jennewein C, Schneider M, Halatsch ME, Carragher NO, Baumann B, Krause A, Simmet T, Bachem MG, Wirtz CR, Debatin KM. Inhibition of NF-kappaB signaling ablates the invasive phenotype of glioblastoma. Mol Cancer Res. 2013;11(12):1611–23.

    Article  CAS  PubMed  Google Scholar 

  170. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158(5):1110–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lau D, Magill ST, Aghi MK. Molecularly targeted therapies for recurrent glioblastoma: current and future targets. Neurosurg Focus. 2014;37(6), E15.

    Article  PubMed  Google Scholar 

  174. Tjin Tham Sjin R, Lee K, Walter AO, Dubrovskiy A, Sheets M, Martin TS, Labenski MT, Zhu Z, Tester R, Karp R, Medikonda A, Chaturvedi P, Ren Y, Haringsma H, Etter J, Raponi M, Simmons AD, Harding TC, Niu D, Nacht M, Westlin WF, Petter RC, Allen A, Singh J. In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing. Mol Cancer Ther. 2014;13(6):1468–79.

    Article  PubMed  CAS  Google Scholar 

  175. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Eckstein N, Roper L, Haas B, Potthast H, Hermes U, Unkrig C, Naumann-Winter F, Enzmann H. Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective. J Exp Clin Cancer Res. 2014;33:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: multi-targeted or single-targeted? World J Clin Oncol. 2011;2(2):80–93.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Tomlinson I, Sasieni P, Bodmer W. How many mutations in a cancer? Am J Pathol. 2002;160(3):755–8.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hashmi JA, Baliki MN, Huang L, Baria AT, Torbey S, Hermann KM, Schnitzer TJ, Apkarian AV. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain. 2013;136(Pt 9):2751–68.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Marinelli S, Nazio F, Tinari A, Ciarlo L, D’Amelio M, Pieroni L, Vacca V, Urbani A, Cecconi F, Malorni W, Pavone F. Schwann cell autophagy counteracts the onset and chronification of neuropathic pain. Pain. 2014;155(1):93–107.

    Article  CAS  PubMed  Google Scholar 

  182. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014;8(2):143–51.

    PubMed  PubMed Central  Google Scholar 

  183. Miranda J, Lamana SM, Dias EV, Athie M, Parada CA, Tambeli CH. Effect of pain chronification and chronic pain on an endogenous pain modulation circuit in rats. Neuroscience. 2015;286:37–44.

    Article  CAS  PubMed  Google Scholar 

  184. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  CAS  PubMed  Google Scholar 

  185. Brock A, Chang H, Huang S. Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet. 2009;10(5):336–42.

    Article  CAS  PubMed  Google Scholar 

  186. Denison TA, Bae YH. Tumor heterogeneity and its implication for drug delivery. J Control Release. 2012;164(2):187–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Huang S. Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. Cancer Metastasis Rev. 2013;32(3-4):423–48.

    Article  PubMed  CAS  Google Scholar 

  188. Foo J, Leder K, Mumenthaler SM. Cancer as a moving target: understanding the composition and rebound growth kinetics of recurrent tumors. Evol Appl. 2013;6(1):54–69.

    Article  PubMed  Google Scholar 

  189. Durrett R. Population genetics of neutral mutations in exponentially growing cancer cell populations. Ann Appl Probab. 2013;23(1):230–50.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Lee SH, Sim SH, Kim JY, Cha S, Song A. Application of cancer genomics to solve unmet clinical needs. Genomics Inform. 2013;11(4):174–9.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Kim M, Lee KH, Yoon SW, Kim BS, Chun J, Yi H. Analytical tools and databases for metagenomics in the next-generation sequencing era. Genomics Inform. 2013;11(3):102–13.

    Article  PubMed  PubMed Central  Google Scholar 

  192. van Oostrum J, Calonder C, Rechsteiner D, Ehrat M, Mestan J, Fabbro D, Voshol H. Tracing pathway activities with kinase inhibitors and reverse phase protein arrays. Proteomics Clin Appl. 2009;3(4):412–22.

    Article  PubMed  CAS  Google Scholar 

  193. De Witt Hamer PC, Van Tilborg AA, Eijk PP, Sminia P, Troost D, Van Noorden CJ, Ylstra B, Leenstra S. The genomic profile of human malignant glioma is altered early in primary cell culture and preserved in spheroids. Oncogene. 2008;27(14):2091–6.

    Article  PubMed  CAS  Google Scholar 

  194. Li A, Walling J, Kotliarov Y, Center A, Steed ME, Ahn SJ, Rosenblum M, Mikkelsen T, Zenklusen JC, Fine HA. Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res. 2008;6(1):21–30.

    Google Scholar 

  195. Mak IW, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014;6(2):114–8.

    PubMed  PubMed Central  Google Scholar 

  196. Pennisi E. Biomedicine. Cancer therapies use a little help from microbial friends. Science. 2013;342(6161):921.

    Article  CAS  PubMed  Google Scholar 

  197. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70.

    Article  CAS  PubMed  Google Scholar 

  198. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Berard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Dore J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Keller R, Keist R, Wechsler A, Leist TP, van der Meide PH. Mechanisms of macrophage-mediated tumor cell killing: a comparative analysis of the roles of reactive nitrogen intermediates and tumor necrosis factor. Int J Cancer. 1990;46(4):682–6.

    Article  CAS  PubMed  Google Scholar 

  200. Jadus MR, Williams CC, Avina MD, Ly M, Kim S, Liu Y, Narasaki R, Lowell CA, Wepsic HT. Macrophages kill T9 glioma tumor cells bearing the membrane isoform of macrophage colony stimulating factor through a phagocytosis-dependent pathway. J Immunol. 1998;160(1):361–8.

    CAS  PubMed  Google Scholar 

  201. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164(12):6166–73.

    Article  CAS  PubMed  Google Scholar 

  202. Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H, Vogel I, Kruger U, Becker T, Ebsen M, Rocken C, Kabelitz D, Schafer H, Sebens S. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer. 2014;135(4):843–61.

    Article  CAS  PubMed  Google Scholar 

  203. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159(3):499–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R. Cancer exosomes perform cell-independent MicroRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26(5):707–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. E. Barry for critically reading early drafts of the manuscript and B. Welz as well as S. Glatzel for their many years of expert secretarial assistance.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany

    Mike-Andrew Westhoff, Nicolas Marschall & Klaus-Michael Debatin

Authors
  1. Mike-Andrew Westhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolas Marschall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaus-Michael Debatin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus-Michael Debatin .

Editor information

Editors and Affiliations

  1. MRC Centre for Inflammation Research, University of Edinburgh Queen’s Medical Research Institute, Edinburgh, United Kingdom

    Christopher D. Gregory

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Westhoff, MA., Marschall, N., Debatin, KM. (2016). Novel Approaches to Apoptosis-Inducing Therapies. In: Gregory, C. (eds) Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy. Advances in Experimental Medicine and Biology, vol 930. Springer, Cham. https://doi.org/10.1007/978-3-319-39406-0_8

Download citation

Publish with us

Policies and ethics

Search

Navigation