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    1. ФГБНУ «Научно-исследовательский институт терапии и профилактической медицины»
    2. Новосибирский государственный университет

    Ключевые слова:РПЖ,гены,молекулярные пути,молекулярные пути,иммунотерапия

    Резюме:РПЖ (РПЖ) является одним из самых опасных и клинически сложных видов рака. Отсутствие эффективных методов скрининга, поздняя выявляемость являются основными причинами того, что РПЖ остается одним из заболеваний, при котором уровень смертности практически равен уровню заболеваемости. При этом хирургические и терапевтические методы лечения остаются малоэффективными. Использование различных видов химиотерапии увеличивает продолжительность жизни больных с 5-7 месяцев при лечении одним гемцитабином до 8,5-11 месяцев при комбинированной терапии. Поэтому поиск новых мишеней для терапии является ключевой задачей при данной патологии. В обзорной статье представлены результаты последних исследований в области генетики и молекулярной биологии РПЖ. Описаны мутации основных генов: KRAS, TP53, CDKN 2A, SMAD 4, ARID 1A и также часто выявляемые дефекты других генов: TGFBR 2, KDM6A, AXIN 1, ACVR 1B, PIK3CA, RNF43, GNAS, ATM, GLI3, ARID 1A и RBM10. Представлены результаты анализа связи мутаций этих генов с изменениями индуцируемых ими сигнальных путей и освещены возможности использования найденных особенностей в качестве мишеней для таргетной терапии РПЖ. В обзоре отражены проблемы изменения иммунного статуса, механизмы участия клеточного компонента стромы в процессах опухолевой прогрессии и метастазирования, возможности использования специфических антител в комбинированных схемах химиотерапии при РПЖ.

      1. Siegel R. L., Miller K. D., Jemal A. Cancer statistics, 2016. CA Cancer J. Clin. 2016; 66:7-30.
      2. Давыдов М. И., Аксель Е. М. Статистика злокачественных новообразований в России и странах СНГ в 2012 году. М.: Издательская группа РОНЦ, 2014. - 226 с.
      3. Ryan D. P., Hong T. S., Bardeesy N. Pancreatic adenocarcinoma. N. Engl. J. Med. 2014; 371 (11): 1039-1049.
      4. Котельников А. Г., Патютко Ю. И., Трякин А. А. Клинические рекомендации по диагностике и лечению злокачественных опухолей поджелудочной железы. Москва, 2014. - 44 с.
      5. Yadav D., Lowenfels A. B. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013; 144:1252-1261.
      6. Goggins M. Markers of pancreatic cancer: working toward early detection. Clin. Cancer. Res.2011;5:635-637.
      7. Makohon-Moore A., Brosnan J. A., Iacobuzio-Donahue C. A. Pancreatic cancer genomics: insights and opportunities for clinical translation. Genome Med. 2013; 5: 26-37.
      8. Hidalgo M. Pancreatic cancer. N. Engl. J. Med. 2010; 5:1605-1617.
      9. Wong K.K, Qian Z, Le Y. The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations. Cancer Transl. Med. 2016; 2(2):41-47.
      10. Takai E., Yachida Sh. Genomic alterations in pancreatic cancer and their relevance to therapy. World J. Gastrointest. Oncol. 2015; 7(10): 250-258.
      11. Vaccaro V., Sperduti I., Milella M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011; 365:768-779.
      12. Von Hoff D. D., Ervin T., Arena F. P. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New Engl. J. med. 2013; 369:1691-1703.
      13. Heestand G. M., Kurzrock R. Molecular landscape of pancreatic cancer: implications for current clinical trials. Oncotarget. 2015; 6:4553-4561.
      14. Sahin I. H., Iacobuzio-Donahue C.A., O’Reilly E. M. Molecular signature of pancreatic adenocarcinoma: An insight from genotype to phenotype and challenges for targeted therapy. Expert Opin. Ther. Targets. 2016; 20(3):341-359.
      15. Witkiewicz A. K., McMillan E.A., Balaji U. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 2015; 6: 6744-6755.
      16. Forbes S. A., Bindal N., Bamford S. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic acids research. 2011; 39:945-950.
      17. Catalogue of Somatic Mutations in Cancer (COSMIC) Wellcome Trust Sanger Institute; Hinxton, UK: http://www.sanger.ac.uk/cosmic accessed December 1, 2014.
      18. Jamieson N. B., Chang D. K., Grimmond S. M., Biankin A. V. Can we move towards personalised pancreatic cancer therapy? Expert Rev. Gastroenterol. Hepatol. 2014; 8(4): 335-338.
      19. Mohammed S., Van Buren G. 2nd, Fisher W. E. Pancreatic cancer: advances in treatment. World J. Gastroenterol. 2014; 20(28): 9354-9360.
      20. Okano K., Suzuki Y. Strategies for early detection of resectable pancreatic cancer. World J. Gastroenterol. 2014; 20(32): 11230-11240.
      21. Григорьева И. Н., Ефимова О. В., Суворова Т. С., Тов Н. Л. Генетические аспекты РПЖ. Экспериментальная и клиническая гастроэнтерология 2014; 110 (10):70-76.
      22. Григорьева И. Н. Острый и хронический панкреатит. Изд. «Наука», Новосибирск. 2010. 101 с.
      23. Jancík S., Drábek J., Radzioch D., Hajdúch M. Clinical relevance of KRAS in human cancers. Biomed. Biotechnol. 2010; 5:150960.
      24. Heldin C.-H., Moustakas A. Role of Smads in TGFβ signaling. Cell Tissue Res. 2012; 5: 21-36.
      25. Lüttges J., Galehdari H., Bröcker V. et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC 4 genes during pancreatic carcinogenesis. Am. J. Pathol. 2001; 5:1677-1683.
      26. Calhoun E. S., Hucl T., Gallmeier E. et al. Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays. Cancer Res. 2006; 66 (16):7920-7928.
      27. Mermel C. H., Schumacher S. E., Hill B. et al. GISTIC 2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12 (4): R 41.
      28. Biankin A. V., Waddell N., Kassahn K. S. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491(7424): 399-405.
      29. Vakiani E., Solit D. B. KRAS and BRAF: drug targets and predictive biomarkers. J. Pathol. 2011; 223: 219-229.
      30. Malumbres M., Barbacid M. RAS oncogenes: the first 30 years. Nat. Rev. Cancer. 2003; 3:459-465.
      31. Alagesan B., Contino G., Guimaraes A. R. et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin. Cancer Res. 2015; 21(2): 396-404.
      32. Infante J. R., Fecher L. A., Falchook G. S. et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. lancet oncology. 2012; 13:773-781.
      33. Infante J. R., Somer B. G., Park J. O. et al. A randomised, double-blind, placebo-controlled trial of rametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur. J. cancer. 2014; 50:2072-2081.
      34. Schonleben F., Qiu W., Ciau N. T. et al. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin. Cancer. Res. 2006; 12(12): 3851-3855.
      35. Wolpin B. M., Hezel A. F., Abrams T. et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J. Clin. Oncol. 2009; 27 (2): 193-198.
      36. Heldin C-H., Miyazono K., ten Dijke P. TGF-b signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997; 390:465-471.
      37. Massague J. The TGF-beta family of growth and differentiation factors. Cell 1987; 49(4): 437-438.
      38. Ellenrieder V., Hendler S. F., Boeck W. et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001; 61(10): 4222-4228.
      39. Derynck R., Zhang Y., Feng X. H. Smads: transcriptional activators of TGF-beta responses. Cell.1998; 11: 95(6):737-740.
      40. Tascilar M., Skinner H. G., Rosty C. et al. The SMAD 4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 2001; 7(12):4115-4121.
      41. Iacobuzio-Donahue C.A., Fu B., Yachida S. et al. DPC 4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 2009; 27(11):1806-1813.
      42. Winter J. M., Tang L. H., Klimstra D. S. et al. Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD 4 expression. Ann. Surg. 2013; 258(2):331-335.
      43. Crane C. H., Varadhachary G. R., Yordy J. S. et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4 (Dpc4) immunostaining with pattern of disease progression. J. Clin. Oncol. 2011; 29(22):3037-3043.
      44. Blackford A., Serrano O. K., Wolfgang C. L. et al. SMAD 4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin. Cancer Res. 2009; 15(14):4674-4679.
      45. Casey G., Yamanaka Y., Friess H. et al. p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett. 1993; 69(3):151-160.
      46. Polyak K., Xia Y., Zweier J. L. et al. A model for p53-induced apoptosis. Nature. 1997; 389(6648):300-305.
      47. Izetti P., Hautefeuille A., Abujamra A. L. et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest. New Drugs. 2014; 32(5):783-794.
      48. Azmi A. S., Philip P. A., Wang Z. et al. Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. Curr. Cancer Drug Targets. 2010; 10(3):319.
      49. Liggett W., Sidransky D. Role of the p16 tumor suppressor gene in cancer. J. Clin. Oncol.1998; 16(3):1197-1206.
      50. Stott F. J., Bates S., James M. C. et al. The alternative product from the human CDKN 2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998; 17(17):5001-5014.
      51. Caldas C., Hahn S. A., da Costa L. T., et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS 1) gene in pancreatic adenocarcinoma. Nature Genet. 1994; 8(1):27-32.
      52. Schutte M., Hruban R. H., Geradts J. et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126-3130.
      53. Heilmann A. M., Perera R. M., Ecker V. et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 2014; 74(14):3947-3958.
      54. Liu F., Korc M. Cdk4/6 Inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol. Cancer Ther. 2012; 11(10):2138-2148.
      55. Finn R. S., Crown J. P., Lang I. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER 2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
      56. Allenspach E. J., Maillard I., Aster J. C., Pear W. S. Notch signaling in cancer. Cancer Biol. Ther. 2002; 1 (5): 466-476.
      57. Ranganathan P., Weaver K. L., Capobianco A. J. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer. 2011; 11(5):338-351.
      58. Andersson E. R., Lendahl U. Therapeutic modulation of Notch signalling - Are we there yet? Nat. Rev. Drug. Discov. 2014; 13(5): 357-378.
      59. Lee J. Y., Song S. Y., Park J. Y. Notch pathway activation is associated with pancreatic cancer treatment failure. Pancreatology 2014; 14(1):48-53.
      60. Waddell N., Pajic M., Patch A. M. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518(7540): 495-501.
      61. Waddell N., Pajic M., Patch A. M. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518(7540): 495-501.
      62. Ikemoto T., Yamaguchi T., Morine Y. et al. Clinical roles of increased populations of Foxp3+CD 4+T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 2006; 33(4): 386-390.
      63. Yamagiwa S., Gray J. D., Hashimoto S., Horwitz D. A. A role for TGF-beta in the generation and expansion of CD 4+CD 25 + regulatory T cells from human peripheral blood. J. Immunol. 2001; 166(12):7282-7289.
      64. Blauenstein U. W. On the effects of moderate hypothermia on the acid base and electrolyte ratio in cerebrospinal fluid and arterial blood. Anaesthesist 1965; 14(12):361-366.
      65. Clark C. E., Hingorani S. R., Mick R. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007; 67(19):9518-9527.
      66. Davis M., Conlon K., Bohac G. C. et al. Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas. J. Immunother. 2012; 35(8):629-640.
      67. Kurahara H., Shinchi H., Mataki Y. et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J. Surg. Res. 2011; 167(2): e211-219.
      68. Rucki A. A., Zheng L. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J. Gastroenterol. 2014; 20(9):2237-2246.
      69. Farrow B., Albo D., Berger D. H. The role of the tumor microenvironment in the progression of pancreatic cancer. J. Surg. Res. 2008;149:319-328.
      70. Lewin C. S., Allen R. A., Amyes S. G. Mechanisms of zidovudine resistance in bacteria. J. Med. Microbiol.1990; 33:235-238.
      71. Waghray M., Yalamanchili M., di Magliano M. P., Simeone D. M. Deciphering the role of stroma in pancreatic cancer. Curr. Opin. Gastroenterol. 2013; 29:537-543.
      72. Feig C., Gopinathan A., Neesse A. et al. The pancreas cancer microenvironment. Clin. Cancer Res. 2012; 18:4266-4276.
      73. Erkan M., Michalski C. W., Rieder S. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 2008; 6:1155-1161.
      74. Olive K. P., Jacobetz M. A., Davidson C. J. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324:1457-1461.
      75. Beatty G. L., Chiorean E. G., Fishman M. P. et al. CD 40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011; 331:1612-1616.
      76. Heinemann V., Reni M., Ychou M. et al. Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. Cancer Treat. Rev. 2014; 40:118-128.
      77. Burris H. A., Moore M. J., Andersen J. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 1997; 15:2403-2413.
      78. Brahmer J. R., Tykodi S. S., Chow L. Q. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012; 366(26): 2455-2465.
      79. Beatty G. L., Chiorean E. G., Fishman M. P. et al. CD 40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331(6024): 1612-1616.
      80. Vonderheide R. H., Bajor D. L., Winograd R. et al. CD 40 immunotherapy for pancreatic cancer. Cancer Immunol. Immunother. 2013; 62(5):949-954.
     


    Для цитирования :
    Романова Т.И., Григорьева И.Н., Ефимова О.В. РАК ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ. НЕКОТОРЫЕ МОЛЕКУЛЯРНЫЕ И ГЕНЕТИЧЕСКИЕ МЕХАНИЗМЫ ОНКОГЕНЕЗА КАК МИШЕНЬ ДЛЯ ТЕРАПИИ. Экспериментальная и клиническая гастроэнтерология. 2017;138(02):103-109
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