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Множественные механизмы действия эрибулина мезилата: новые данные и клинические аспекты
Множественные механизмы действия эрибулина мезилата: новые данные и клинические аспекты
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Аннотация
Эрибулина мезилат (эрибулин) является синтетическим аналогом натурального вещества галихондрина B, получаемого из морской губки. Эрибулин проявляет выраженную антипролиферативную активность в отношении опухолевых клеток многих видов раком молочной железы или липосаркомой, рефрактерных к терапии другими химиопрепаратами. Антипролиферативный эффект эрибулина долгое время связывали с его антимитотической активностью. В отличие от других таргетных препаратов, действие которых направлено на микротрубочки, эрибулин подавляет полимеризацию микротрубочек путем присоединения к специфическим плюс-концам, нарушая тем самым динамическую нестабильность микротрубочек. В лабораторных условиях были установлены также немитотические эффекты эрибулина, такие как ремоделирование кровеносных сосудов опухоли, уменьшение гипоксии и фенотипические изменения, включающие реверс эпителиально-мезенхимального перехода (ЭМП), что приводит к снижению способности к миграции, инвазии и диссеминации метастазов в легкие в экспериментальных моделях. Результаты доклинических исследований подтверждают, что увеличение перфузии, обусловленное терапией эрибулином, улучшает доставку препаратов при последующей терапии. Доказательства немитотических эффектов эрибулина, полученные в условиях клиники, включают повышенное насыщение опухоли кислородом, уменьшение гипоксии, изменение фенотипа, соответствующее реверсу ЭМП, и изменение генотипа, соответствующее сдвигу от гормононезависимого люминального В типа к гормонзависимому люминальному А типу рака молочной железы. И наконец, были выявлены потенциальные биомаркеры для ответа эрибулина, основанные на профилях опухолевого фенотипа и экспрессии генов. Таким образом, доклинические и клинические данные подтверждают наличие у эрибулина как антимитотических, так и немитотических механизмов действия, которые могут лежать в основе улучшения общей выживаемости, наблюдаемой в различных клинических исследованиях.
Ключевые слова: эрибулин, антимитотический препарат, микроокружение опухоли, преимущество в общей выживаемости, эпителиально-мезенхимальный переход, метастатический рак молочной железы.
Key words: eribulin, antimitotic, tumor microenvironment, survival benefit, epithelial-to-mesenchymal transition, metastatic breast cancer.
Ключевые слова: эрибулин, антимитотический препарат, микроокружение опухоли, преимущество в общей выживаемости, эпителиально-мезенхимальный переход, метастатический рак молочной железы.
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Key words: eribulin, antimitotic, tumor microenvironment, survival benefit, epithelial-to-mesenchymal transition, metastatic breast cancer.
Полный текст
Список литературы
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2. Schöffski P, Chawla S, Maki RG et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016; 387: 1629–37.
3. Halaven (eribulin mesylate) injection [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; 2016.
4. Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Hertfordshire, UK: Eisai Europe Limited.
5. Towle MJ, Nomoto K, Asano M et al. Broad spectrum preclinical antitumor activity of eribulin (HalavenR): optimal effectiveness under intermittent dosing conditions. Anticancer Res 2012; 32: 1611–9.
6. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res 2016; 36: 1553–61.
7. Towle MJ, Salvato KA, Budrow J et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001; 61: 1013–21.
8. Kolb EA, Gorlick R, Reynolds CP et al. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 2013; 60: 1325–32.
9. Hirata Y, Uemura D. Halichondrins – antitumor polyether macrolides from a marine sponge. Pure Appl Chem 1986; 58: 701–10.
10. Bai RL, Paull KD, Herald CL et al. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem 1991; 266: 15882–9.
11. Ludueña RF, Roach MC, Prasad V, Pettit GR. Interaction of halichondrin B and homohalichondrin B with bovine brain tubulin. Biochem Pharmacol 1993; 45: 421–7.
12. Jordan MA, Kamath K, Manna T et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005; 4: 1086–95.
13. Doodhi H, Prota AE, Rodríguez-García R et al. Termination of protofilament elongation by eribulin induces lattice defects that promote microtubule catastrophes. Curr Biol 2016; 26: 1713–21.
14. Funahashi Y, Okamoto K, Adachi Y et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 2014; 105: 1334–42.
15. Yoshida T, Ozawa Y, Kimura T et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer 2014; 110: 1497–505.
16. Kuznetsov G, Towle MJ, Cheng H et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 2004; 64: 5760–6.
17. Okouneva T, Azarenko O, Wilson L et al. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008; 7: 2003–11.
18. Smith JA, Wilson L, Azarenko O et al. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 2010; 49: 1331–7.
19. Towle MJ, Salvato KA, Wels BF et al. Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 2011; 71: 496–505.
20. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic effect and complex of nonmitotic effect on tumor biology of eribulin mesilate in soft tissue sarcoma models. Presented at: Japanese Cancer Association, October 6–8, 2016, Yokohama, Japan.
21. Ozawa Y, Okamoto K, Adachi M et al. Supression of metastasis and improvement of drug distribution by eribulin mesylate. Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 18–21, 2014, Spain, Barcelona.
22. Kanthou C, Tozer GM. Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies. Int J Exp Pathol 2009; 90: 284–94.
23. Kruczynski A, Poli M, Dossi R et al. Antiangiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development. Eur J Cancer 2006; 42: 2821–32.
24. Hill SA, Lonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: anti-vascular effects in a murine tumour. Eur J Cancer 1993; 29A: 1320–4.
25. Agoulnik SI, Kawano S, Taylor N et al. Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericytedriven capillary network in vitro. Vasc Cell 2014; 6: 3.
26. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97–110.
27. Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des 2015; 21: 1279–91.
28. Dongre A, Rashidian M, Reinhardt F et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 2017; 77: 3982–9.
29. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res 2015; 21: 962–8.
30. Dezső Z, Oestreicher J, Weaver A et al. Gene expression profiling reveals epithelial mesenchymal transition (EMT) genes can selectively differentiate eribulin sensitive breast cancer cells. PLoS One 2014; 9: e106131.
31. Yang Q, Huang J, Wu Q et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer 2014; 110: 1958–67.
32. Kaul R, Risinger AL, Mooberry S. Eribulin differentially disrupts TGF-b signaling pathway in BT-549 and HCC1937 breast cancer cell lines. Presented at: San Antonio Breast Cancer Symposium, December 5–9, 2017, San Antonio, TX, USA. Poster P5-04-04.
33. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin. Oncotarget 2018; 9: 5545–61.
34. Kitahara H, Hirai M, Kato K et al. Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition. Oncol Rep 2016; 36: 3139–44.
35. Asano M, Matsui J, Towle MJ et al. Broadspectrum preclinical antitumor activity of eribulin (HalavenR): combination with anticancer agents of differing mechanisms. Anticancer Res 2018; 38: 3375–85.
36. Wu Y, Sarkissyan M, Vadgama JV. Epithelial-mesenchymal transition and breast cancer. J Clin Med 2016; 5 (2). https://doi.org/ 10.3390/jcm5020013. pii: E13.
37. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004; 4: 448–56.
38. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73.
39. Suzuki H, Hirata Y, Suzuki N et al. Characterization of a new small bowel adenocarcinoma cell line and screening of anti-cancer drug against small bowel adenocarcinoma. Am J Pathol 2015; 185: 550–62.
40. Jang GB, Kim JY, Cho SD et al. Blockade of Wnt/bcatenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 2015; 5: 12465.
41. Kurebayashi J, Kanomata N, Yamashita T et al. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. Breast Cancer 2016; 23: 425–36.
42. Dong C, Li Z, Alvarez Jr. R, Feng XH, Goldschmidt-Clermont PJ. Microtubule binding to Smads may regulate TGFb activity. Mol Cell 2000; 5: 27–34.
43. Dai P, Nakagami T, Tanaka H et al. Cx43 mediates TGF-b signaling through competitive Smads binding to microtubules. Mol Biol Cell 2007; 18: 2264–73.
44. Sánchez-Tilló E, Liu Y, de Barrios O et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 2012; 69: 3429–56.
45. Kevenaar JT, Hoogenraad CC. The axonal cytoskeleton: from organization to function. Front Mol Neurosci 2015; 8: 44.
46. Wozniak KM, Nomoto K, Lapidus RG et al. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 2011; 71: 3952–62.
47. Wozniak KM, Wu Y, Farah MH et al. Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res 2013; 24: 338–44.
48. LaPointe NE, Morfini G, Brady ST et al. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 2013; 37: 231–9.
49. Vahdat LT, Garcia AA, Vogel C et al. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 2013; 140: 341–51.
50. Vahdat LT, Pruitt B, Fabian CJ et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2009; 27: 2954–61.
51. Ueda S, Saeki T, Takeuchi H et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer 2016; 114: 1212–8.
52. Ueda S, Saeki T, Yamane T, Kuji I. Assessing oxygenation response to eribulin in a patient with recurrent breast cancer after resistance to endocrine therapy. OMICS J Radiol 2017; 6: 250. https://doi.org/ 10.4172/2167-7964.1000250
53. Yardley DA, Chandra P, Hart L et al. A phase II randomized study with eribulin/cyclophosphamide (ErC) or docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer: Final efficacy analysis and results of correlative studies. Presented at: San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX, USA.
54. Goto W, Kashiwagi S, Asano Y et al. Clinical verification of antitumor autoimmune response in eribulin chemotherapy for breast cancer. Presented at: Annual Meeting of the American Association for Cancer Research, April 16–20, 2016, New Orleans, LA, USA.
55. Kashiwagi S, Asano Y, Goto W et al. Mesenchymal-epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. Anticancer Res 2018; 38: 401–10.
56. Chen L, Gibbons DL, Goswami S et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5: 5241.
57. Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol 2017; 11: 805–23.
58. Demetri GD, Schöffski P, Grignani G et al. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol 2017; 35: 3433–9.
59. Yang J, Eddy JA, Pan Y et al. Integrated proteomics and genomics analysis reveals a novel mesenchymal to epithelial reverting transition in leiomyosarcoma through regulation of slug. Mol Cell Proteomics 2010; 9: 2405–13.
60. Cioffi A, Reichert S, Antonescu CR, Maki RG. Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am 2013; 27: 975–88.
61. Prat A, Ortega V, Pare L et al. Efficacy and gene expression results from eribulin SOLTI1007 neoadjuvant study. Presented at: San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX, USA.
62. Parker JS, Mullins M, Cheang MC et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009; 27: 1160–7.
63. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014; 5: 412–24.
64. Kobayashi K, Ito Y, Shibayama T, Fukada I et al. Eribulin mesylate may improve the sensitivity of endocrine therapy in metastatic breast cancer. Presented at: European Society for Medical Oncology, October 7–11, 2016, Copenhagan, Denmark.
65. Jiang WG, Sanders AJ, Katoh M et al. Tissue invasion and metastasis: molecular, biological and clinical perspectives. Semin Cancer Biol 2015; 35 (Suppl.): S244–75.
66. Pernas S, Martin M, Kaufman PA et al. Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. Lancet Oncol 2018; 19: 812–24.
67. U.S. FDA grants Fast Track designation for Polyphor's innovative immuno-oncology candidate balixafortide in combination with eribulin as third line therapy for metastatic breast cancer [press release]. 19 April 2018. https://www.polyphor.com/news/corporate-news-details/?newsid= 1689641
68. ClinicalTrials.gov. https://clinicaltrials.gov/
69. Wiemer EAC, Wozniak A, Burger H et al. Identification of microRNA biomarkers for response of advanced soft tissue sarcomas to eribulin: Translational results of the EORTC 62052 trial. Eur J Cancer 2017; 75: 33–40.
70. Schöffski P, Ray-Coquard IL, Cioffi A et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 2011; 12: 1045–52.
71. Mao Y, Qu Q, Zhang Y et al. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One 2014; 9: e115103.
72. Kashiwagi S, Asano Y, Goto W et al. Use of tumorinfiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One 2017; 12: e0170634.
2. Schöffski P, Chawla S, Maki RG et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016; 387: 1629–37.
3. Halaven (eribulin mesylate) injection [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; 2016.
4. Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Hertfordshire, UK: Eisai Europe Limited.
5. Towle MJ, Nomoto K, Asano M et al. Broad spectrum preclinical antitumor activity of eribulin (HalavenR): optimal effectiveness under intermittent dosing conditions. Anticancer Res 2012; 32: 1611–9.
6. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res 2016; 36: 1553–61.
7. Towle MJ, Salvato KA, Budrow J et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001; 61: 1013–21.
8. Kolb EA, Gorlick R, Reynolds CP et al. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 2013; 60: 1325–32.
9. Hirata Y, Uemura D. Halichondrins – antitumor polyether macrolides from a marine sponge. Pure Appl Chem 1986; 58: 701–10.
10. Bai RL, Paull KD, Herald CL et al. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem 1991; 266: 15882–9.
11. Ludueña RF, Roach MC, Prasad V, Pettit GR. Interaction of halichondrin B and homohalichondrin B with bovine brain tubulin. Biochem Pharmacol 1993; 45: 421–7.
12. Jordan MA, Kamath K, Manna T et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005; 4: 1086–95.
13. Doodhi H, Prota AE, Rodríguez-García R et al. Termination of protofilament elongation by eribulin induces lattice defects that promote microtubule catastrophes. Curr Biol 2016; 26: 1713–21.
14. Funahashi Y, Okamoto K, Adachi Y et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 2014; 105: 1334–42.
15. Yoshida T, Ozawa Y, Kimura T et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer 2014; 110: 1497–505.
16. Kuznetsov G, Towle MJ, Cheng H et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 2004; 64: 5760–6.
17. Okouneva T, Azarenko O, Wilson L et al. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008; 7: 2003–11.
18. Smith JA, Wilson L, Azarenko O et al. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 2010; 49: 1331–7.
19. Towle MJ, Salvato KA, Wels BF et al. Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 2011; 71: 496–505.
20. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic effect and complex of nonmitotic effect on tumor biology of eribulin mesilate in soft tissue sarcoma models. Presented at: Japanese Cancer Association, October 6–8, 2016, Yokohama, Japan.
21. Ozawa Y, Okamoto K, Adachi M et al. Supression of metastasis and improvement of drug distribution by eribulin mesylate. Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 18–21, 2014, Spain, Barcelona.
22. Kanthou C, Tozer GM. Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies. Int J Exp Pathol 2009; 90: 284–94.
23. Kruczynski A, Poli M, Dossi R et al. Antiangiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development. Eur J Cancer 2006; 42: 2821–32.
24. Hill SA, Lonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: anti-vascular effects in a murine tumour. Eur J Cancer 1993; 29A: 1320–4.
25. Agoulnik SI, Kawano S, Taylor N et al. Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericytedriven capillary network in vitro. Vasc Cell 2014; 6: 3.
26. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97–110.
27. Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des 2015; 21: 1279–91.
28. Dongre A, Rashidian M, Reinhardt F et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 2017; 77: 3982–9.
29. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res 2015; 21: 962–8.
30. Dezső Z, Oestreicher J, Weaver A et al. Gene expression profiling reveals epithelial mesenchymal transition (EMT) genes can selectively differentiate eribulin sensitive breast cancer cells. PLoS One 2014; 9: e106131.
31. Yang Q, Huang J, Wu Q et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer 2014; 110: 1958–67.
32. Kaul R, Risinger AL, Mooberry S. Eribulin differentially disrupts TGF-b signaling pathway in BT-549 and HCC1937 breast cancer cell lines. Presented at: San Antonio Breast Cancer Symposium, December 5–9, 2017, San Antonio, TX, USA. Poster P5-04-04.
33. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin. Oncotarget 2018; 9: 5545–61.
34. Kitahara H, Hirai M, Kato K et al. Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition. Oncol Rep 2016; 36: 3139–44.
35. Asano M, Matsui J, Towle MJ et al. Broadspectrum preclinical antitumor activity of eribulin (HalavenR): combination with anticancer agents of differing mechanisms. Anticancer Res 2018; 38: 3375–85.
36. Wu Y, Sarkissyan M, Vadgama JV. Epithelial-mesenchymal transition and breast cancer. J Clin Med 2016; 5 (2). https://doi.org/ 10.3390/jcm5020013. pii: E13.
37. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004; 4: 448–56.
38. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73.
39. Suzuki H, Hirata Y, Suzuki N et al. Characterization of a new small bowel adenocarcinoma cell line and screening of anti-cancer drug against small bowel adenocarcinoma. Am J Pathol 2015; 185: 550–62.
40. Jang GB, Kim JY, Cho SD et al. Blockade of Wnt/bcatenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 2015; 5: 12465.
41. Kurebayashi J, Kanomata N, Yamashita T et al. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. Breast Cancer 2016; 23: 425–36.
42. Dong C, Li Z, Alvarez Jr. R, Feng XH, Goldschmidt-Clermont PJ. Microtubule binding to Smads may regulate TGFb activity. Mol Cell 2000; 5: 27–34.
43. Dai P, Nakagami T, Tanaka H et al. Cx43 mediates TGF-b signaling through competitive Smads binding to microtubules. Mol Biol Cell 2007; 18: 2264–73.
44. Sánchez-Tilló E, Liu Y, de Barrios O et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 2012; 69: 3429–56.
45. Kevenaar JT, Hoogenraad CC. The axonal cytoskeleton: from organization to function. Front Mol Neurosci 2015; 8: 44.
46. Wozniak KM, Nomoto K, Lapidus RG et al. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 2011; 71: 3952–62.
47. Wozniak KM, Wu Y, Farah MH et al. Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res 2013; 24: 338–44.
48. LaPointe NE, Morfini G, Brady ST et al. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 2013; 37: 231–9.
49. Vahdat LT, Garcia AA, Vogel C et al. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 2013; 140: 341–51.
50. Vahdat LT, Pruitt B, Fabian CJ et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2009; 27: 2954–61.
51. Ueda S, Saeki T, Takeuchi H et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer 2016; 114: 1212–8.
52. Ueda S, Saeki T, Yamane T, Kuji I. Assessing oxygenation response to eribulin in a patient with recurrent breast cancer after resistance to endocrine therapy. OMICS J Radiol 2017; 6: 250. https://doi.org/ 10.4172/2167-7964.1000250
53. Yardley DA, Chandra P, Hart L et al. A phase II randomized study with eribulin/cyclophosphamide (ErC) or docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer: Final efficacy analysis and results of correlative studies. Presented at: San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX, USA.
54. Goto W, Kashiwagi S, Asano Y et al. Clinical verification of antitumor autoimmune response in eribulin chemotherapy for breast cancer. Presented at: Annual Meeting of the American Association for Cancer Research, April 16–20, 2016, New Orleans, LA, USA.
55. Kashiwagi S, Asano Y, Goto W et al. Mesenchymal-epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. Anticancer Res 2018; 38: 401–10.
56. Chen L, Gibbons DL, Goswami S et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5: 5241.
57. Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol 2017; 11: 805–23.
58. Demetri GD, Schöffski P, Grignani G et al. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol 2017; 35: 3433–9.
59. Yang J, Eddy JA, Pan Y et al. Integrated proteomics and genomics analysis reveals a novel mesenchymal to epithelial reverting transition in leiomyosarcoma through regulation of slug. Mol Cell Proteomics 2010; 9: 2405–13.
60. Cioffi A, Reichert S, Antonescu CR, Maki RG. Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am 2013; 27: 975–88.
61. Prat A, Ortega V, Pare L et al. Efficacy and gene expression results from eribulin SOLTI1007 neoadjuvant study. Presented at: San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX, USA.
62. Parker JS, Mullins M, Cheang MC et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009; 27: 1160–7.
63. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014; 5: 412–24.
64. Kobayashi K, Ito Y, Shibayama T, Fukada I et al. Eribulin mesylate may improve the sensitivity of endocrine therapy in metastatic breast cancer. Presented at: European Society for Medical Oncology, October 7–11, 2016, Copenhagan, Denmark.
65. Jiang WG, Sanders AJ, Katoh M et al. Tissue invasion and metastasis: molecular, biological and clinical perspectives. Semin Cancer Biol 2015; 35 (Suppl.): S244–75.
66. Pernas S, Martin M, Kaufman PA et al. Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. Lancet Oncol 2018; 19: 812–24.
67. U.S. FDA grants Fast Track designation for Polyphor's innovative immuno-oncology candidate balixafortide in combination with eribulin as third line therapy for metastatic breast cancer [press release]. 19 April 2018. https://www.polyphor.com/news/corporate-news-details/?newsid= 1689641
68. ClinicalTrials.gov. https://clinicaltrials.gov/
69. Wiemer EAC, Wozniak A, Burger H et al. Identification of microRNA biomarkers for response of advanced soft tissue sarcomas to eribulin: Translational results of the EORTC 62052 trial. Eur J Cancer 2017; 75: 33–40.
70. Schöffski P, Ray-Coquard IL, Cioffi A et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol 2011; 12: 1045–52.
71. Mao Y, Qu Q, Zhang Y et al. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One 2014; 9: e115103.
72. Kashiwagi S, Asano Y, Goto W et al. Use of tumorinfiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One 2017; 12: e0170634.
________________________________________________
2. Schöffski P, Chawla S, Maki RG et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016; 387: 1629–37.
3. Halaven (eribulin mesylate) injection [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; 2016.
4. Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Hertfordshire, UK: Eisai Europe Limited.
5. Towle MJ, Nomoto K, Asano M et al. Broad spectrum preclinical antitumor activity of eribulin (HalavenR): optimal effectiveness under intermittent dosing conditions. Anticancer Res 2012; 32: 1611–9.
6. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res 2016; 36: 1553–61.
7. Towle MJ, Salvato KA, Budrow J et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001; 61: 1013–21.
8. Kolb EA, Gorlick R, Reynolds CP et al. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 2013; 60: 1325–32.
9. Hirata Y, Uemura D. Halichondrins – antitumor polyether macrolides from a marine sponge. Pure Appl Chem 1986; 58: 701–10.
10. Bai RL, Paull KD, Herald CL et al. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem 1991; 266: 15882–9.
11. Ludueña RF, Roach MC, Prasad V, Pettit GR. Interaction of halichondrin B and homohalichondrin B with bovine brain tubulin. Biochem Pharmacol 1993; 45: 421–7.
12. Jordan MA, Kamath K, Manna T et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005; 4: 1086–95.
13. Doodhi H, Prota AE, Rodríguez-García R et al. Termination of protofilament elongation by eribulin induces lattice defects that promote microtubule catastrophes. Curr Biol 2016; 26: 1713–21.
14. Funahashi Y, Okamoto K, Adachi Y et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 2014; 105: 1334–42.
15. Yoshida T, Ozawa Y, Kimura T et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer 2014; 110: 1497–505.
16. Kuznetsov G, Towle MJ, Cheng H et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 2004; 64: 5760–6.
17. Okouneva T, Azarenko O, Wilson L et al. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008; 7: 2003–11.
18. Smith JA, Wilson L, Azarenko O et al. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 2010; 49: 1331–7.
19. Towle MJ, Salvato KA, Wels BF et al. Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 2011; 71: 496–505.
20. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic effect and complex of nonmitotic effect on tumor biology of eribulin mesilate in soft tissue sarcoma models. Presented at: Japanese Cancer Association, October 6–8, 2016, Yokohama, Japan.
21. Ozawa Y, Okamoto K, Adachi M et al. Supression of metastasis and improvement of drug distribution by eribulin mesylate. Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 18–21, 2014, Spain, Barcelona.
22. Kanthou C, Tozer GM. Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies. Int J Exp Pathol 2009; 90: 284–94.
23. Kruczynski A, Poli M, Dossi R et al. Antiangiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development. Eur J Cancer 2006; 42: 2821–32.
24. Hill SA, Lonergan SJ, Denekamp J, Chaplin DJ. Vinca alkaloids: anti-vascular effects in a murine tumour. Eur J Cancer 1993; 29A: 1320–4.
25. Agoulnik SI, Kawano S, Taylor N et al. Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericytedriven capillary network in vitro. Vasc Cell 2014; 6: 3.
26. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97–110.
27. Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des 2015; 21: 1279–91.
28. Dongre A, Rashidian M, Reinhardt F et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 2017; 77: 3982–9.
29. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res 2015; 21: 962–8.
30. Dezső Z, Oestreicher J, Weaver A et al. Gene expression profiling reveals epithelial mesenchymal transition (EMT) genes can selectively differentiate eribulin sensitive breast cancer cells. PLoS One 2014; 9: e106131.
31. Yang Q, Huang J, Wu Q et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer 2014; 110: 1958–67.
32. Kaul R, Risinger AL, Mooberry S. Eribulin differentially disrupts TGF-b signaling pathway in BT-549 and HCC1937 breast cancer cell lines. Presented at: San Antonio Breast Cancer Symposium, December 5–9, 2017, San Antonio, TX, USA. Poster P5-04-04.
33. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin. Oncotarget 2018; 9: 5545–61.
34. Kitahara H, Hirai M, Kato K et al. Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition. Oncol Rep 2016; 36: 3139–44.
35. Asano M, Matsui J, Towle MJ et al. Broadspectrum preclinical antitumor activity of eribulin (HalavenR): combination with anticancer agents of differing mechanisms. Anticancer Res 2018; 38: 3375–85.
36. Wu Y, Sarkissyan M, Vadgama JV. Epithelial-mesenchymal transition and breast cancer. J Clin Med 2016; 5 (2). https://doi.org/ 10.3390/jcm5020013. pii: E13.
37. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004; 4: 448–56.
38. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73.
39. Suzuki H, Hirata Y, Suzuki N et al. Characterization of a new small bowel adenocarcinoma cell line and screening of anti-cancer drug against small bowel adenocarcinoma. Am J Pathol 2015; 185: 550–62.
40. Jang GB, Kim JY, Cho SD et al. Blockade of Wnt/bcatenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 2015; 5: 12465.
41. Kurebayashi J, Kanomata N, Yamashita T et al. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. Breast Cancer 2016; 23: 425–36.
42. Dong C, Li Z, Alvarez Jr. R, Feng XH, Goldschmidt-Clermont PJ. Microtubule binding to Smads may regulate TGFb activity. Mol Cell 2000; 5: 27–34.
43. Dai P, Nakagami T, Tanaka H et al. Cx43 mediates TGF-b signaling through competitive Smads binding to microtubules. Mol Biol Cell 2007; 18: 2264–73.
44. Sánchez-Tilló E, Liu Y, de Barrios O et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 2012; 69: 3429–56.
45. Kevenaar JT, Hoogenraad CC. The axonal cytoskeleton: from organization to function. Front Mol Neurosci 2015; 8: 44.
46. Wozniak KM, Nomoto K, Lapidus RG et al. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 2011; 71: 3952–62.
47. Wozniak KM, Wu Y, Farah MH et al. Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res 2013; 24: 338–44.
48. LaPointe NE, Morfini G, Brady ST et al. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 2013; 37: 231–9.
49. Vahdat LT, Garcia AA, Vogel C et al. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 2013; 140: 341–51.
50. Vahdat LT, Pruitt B, Fabian CJ et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2009; 27: 2954–61.
51. Ueda S, Saeki T, Takeuchi H et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer 2016; 114: 1212–8.
52. Ueda S, Saeki T, Yamane T, Kuji I. Assessing oxygenation response to eribulin in a patient with recurrent breast cancer after resistance to endocrine therapy. OMICS J Radiol 2017; 6: 250. https://doi.org/ 10.4172/2167-7964.1000250
53. Yardley DA, Chandra P, Hart L et al. A phase II randomized study with eribulin/cyclophosphamide (ErC) or docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer: Final efficacy analysis and results of correlative studies. Presented at: San Antonio Breast Cancer Symposium, December 8–12, 2015, San Antonio, TX, USA.
54. Goto W, Kashiwagi S, Asano Y et al. Clinical verification of antitumor autoimmune response in eribulin chemotherapy for breast cancer. Presented at: Annual Meeting of the American Association for Cancer Research, April 16–20, 2016, New Orleans, LA, USA.
55. Kashiwagi S, Asano Y, Goto W et al. Mesenchymal-epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. Anticancer Res 2018; 38: 401–10.
56. Chen L, Gibbons DL, Goswami S et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5: 5241.
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Авторы
Хавьер Кортес1–3, Патрик Шоффски4, Брюс А.Литтлфилд5
1 Ramon y Cajal University Hospital, Madrid, Spain;
2 Vall d'Hebron Institute of Oncology, Barcelona, Spain;
3 Medica Scientia Innovation Research (MedSIR), Barcelona, Spain;
4 Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium;
5 Global Oncology, Eisai Inc., Andover, MA, USA
*bruce_littlefield@eisai.com
________________________________________________
1 Ramon y Cajal University Hospital, Madrid, Spain;
2 Vall d'Hebron Institute of Oncology, Barcelona, Spain;
3 Medica Scientia Innovation Research (MedSIR), Barcelona, Spain;
4 Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium;
5 Global Oncology, Eisai Inc., Andover, MA, USA
*bruce_littlefield@eisai.com
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