PANCREATIC CANCER, CURRENT THERAPEUTIC APPROACHES AND POSSIBLE PROSPECTS

Cover Page

Cite item

Full Text

Abstract

Prevalence of pancreatic cancer (PC) is not high in the population, but the aggressive nature of the disease leads to the fact that PC is one of the main causes of death in a group of patients with cancer. The prognosis for PC is significantly worse in the case of metastatic spread. It is proved that pancreatic adenocarcinoma from the very beginning is a systemic disease with early micrometastatic spread, so the question of effective drug treatment is extremely relevant. Chemotherapy is the basis for the treatment of patients with metastatic prostate cancer. However, despite numerous clinical studies using known cytostatic and targeted agents, progress in the treatment of this disease remains relatively modest compared to the progress made in the treatment of other types of tumors. The complexities of prostate cancer therapy are explained by the presence of a dense connective tissue tumor stroma, which is not just a barrier to tumor cells. It has a significant impact on various vital cellular processes, including tumor formation, invasion, metastasis, and contributes to the formation of drug resistance. Pancreatic cancer is heterogeneous in terms of molecular and biological characteristics. Many genetic changes, including germ lines and somatic mutations, contribute to the development of this disease. Recent studies have shown that each sample of prostate cancer includes an average of 63 genetic changes and 12 major signalling pathways. Further studies of tumor microenvironment markers and decoding the heterogeneity of the tumor genome in PC should become the basis for a “personalized” approach to treatment. It is likely 19 4'2020 ТОм 19 vol. 19 РОССИЙСКИЙ БИОТЕРАПЕВТИЧЕСКИЙ ЖУРНАЛ Russian journal of biotherapy Обзоры литературы that in the future, the integration of traditional chemotherapeutic treatments and an immunological approach will be the key to effective treatment of this deadly disease.

About the authors

E. A. Bykova

A. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Ministry
of Health of the Russian Federation

Author for correspondence.
Email: bykowayekaterina@yandex.ru
ORCID iD: 0000-0001-8218-6774
4 Korolev street, Obninsk 249036 Russian Federation

N. A. Falaleeva

A. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Ministry
of Health of the Russian Federation

ORCID iD: 0000-0002-0023-4216
4 Korolev street, Obninsk 249036 Russian Federation

L. Yu. Grivtsova

A. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Ministry
of Health of the Russian Federation

ORCID iD: 0000-0001-9103-9688
4 Korolev street, Obninsk 249036 Russian Federation

References

  1. Zhu L., Staley C., Kooby D. et al. Current Status of Biomarker and Targeted Nanoparticle Development: The Precision Oncology Approach for Pancreatic Cancer Therapy. Cancer Lett 2017;388:139–48. doi: 10.1016/j.canlet.2016.11.030.
  2. Ducreux M., Cuhna A., Caramella C. et al. Cancer of the Pancreas: ESMO Clinical Practice Guidelines. Ann Oncol 2015;26(suppl 5):v56–v68.
  3. Chiorean E.G., Coveler A.L. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015;9:3529–45. https://doi.org/10.2147/DDDT.S60328.
  4. Rossi M., Rehman A., Gondi C. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014;20(32):11142–59. doi: 10.3748/wjg.v20.i32.11142.
  5. Bonucci M., Pastore C., Ferrera V. et al. Integrated Cancer Treatment in the Course of Metastatic Pancreatic Cancer: Complete Resolution in 2 Cases. Integr Cancer Ther 2018;17(3):994–9. doi: 10.1177/1534735418755479.
  6. Kaprin A.D., Starinskiy V.V., Petrova G.V. Malignant neoplasms in Russia in 2017 (morbidity and mortality). Moscow: FGBU “MNIOI im. P.A. Gertsena” Ministry of Health of Russia, 2018. Рp. 18–31 (In Russ.).
  7. Davydov M.I., Petrovsky A.B. Oncology. Clinical recommendations, 2018. Рp. 240–59. (In Russ.).
  8. Frank T., Sun X., Zhang Y. et al. Genomic Profiling Guides the Choice of Molecular Targeted Therapy of Pancreatic Cancer. Cancer Lett 2015;363(1):1–6. doi: 10.1016/j.canlet.2015.04.009.
  9. Zhu H., Li T., Du Y. et al. Pancreatic cancer: challenges and opportunities. BMC Med 2018;16:214. doi: 10.1186/s12916-018-1215-3.
  10. Mohammed S., Van Buren G. 2nd, Fisher W.E. et al. Pancreatic cancer: Advances in treatment. World J Gastroenterol 2014;20(28):9354–60. doi: 10.3748/wjg.v20.i28.9354.
  11. Neureiter D., Jäger T., Ocker M., Kiesslich T. Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects. World J Gastroenterol 2014;20(24):7830–48. doi: 10.3748/wjg.v20.i24.7830.
  12. Matsuoka T., Yashiro M. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies. World J Gastroenterol 2016;22(2):776–89. doi: 10.3748/wjg.v22.i2.776.
  13. Müller S., Raulefs S., Bruns P. et al. Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Mol Cancer 2015;14:94. doi: 10.1186/s12943-015-0358-5.
  14. Pancreatic cancer. Clinical recommendations. Ministry of Health of the Russian Federation, 2018. Рp. 14–23. (In Russ.).
  15. Lee H., Park S. Systemic Chemotherapy in Advanced Pancreatic Cancer. Gut Liver 2016;10(3):340–7. doi: 10.5009/gnl15465.
  16. Conroy T., Paillot B., François E. et al. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer – a GroupeTumeurs Digestives of the FédérationNationale des Centres de LutteContre le Cancer study. J Clin Oncol 2005;23:1228–36. doi: 10.1200/JCO.2005.06.050.
  17. Popova A. S., Pokataev I. A., Tyulyandin S. A. Combined chemotherapy regimens for pancreatic cancer. Meditsinskiy sovet = Medical Council 2017;6:62-70. (In Russ.). doi: 10.21518/2079-701X-2017-6-62-70.
  18. Sohal D.P., Mangu P.B., Khorana A.A. et al. Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34(23):2784–96. doi: 10.1200/JCO.2016.67.1412.
  19. Kim S., Signorovitch J., Yang H. et al. Comparative Effectiveness ofnabPaclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Retrospective Nationwide Chart Reviewin the United States. Adv Ther 2018;35:1564–77. doi: 10.1007/s12325-018-0784-z.
  20. Результаты исследования по применению Нимотузумаба у взрослых с раком поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT00561990.
  21. Результаты исследования по применению Селуметиниба и эрлотиниба в лечении пациентов с местнораспространенным или метастатическим раком поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT01222689.
  22. Результаты исследования по применению М402 в комбинации с Набпаклитакселом и гемцитабином при раке поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/ NCT01621243.
  23. Результаты исследования по применению Гемцитабина и Цисплатина с Велипарибом или без него или только Велипариба при лечении пациентов с местнораспространенным или метастатическим раком поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT01585805.
  24. Andrew H.Ko. Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan. Int J Nanomedicine 2016;11:1225–35. doi: 10.2147/IJN.S88084.
  25. Safran H., Iannitti D., Ramanathan R. et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004;22:706–12. doi: 10.1081/cnv-200032974.
  26. Pang H., Starr M. Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). Clin Cancer Res 2013;19(24):6957–66. doi: 10.1158/1078-0432.
  27. Kindler H., Niedzwiecki D., Hollis D. et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B(CALGB 80303). J Clin Oncol 2010;28:3617–22. doi: 10.1200/JCO.2010.28.1386.
  28. Результаты исследования по применению комбинации антиангиогенных препаратов Tl-118 для больных раком поджелудочной железы, которые начинают лечение гемцитабином. Available by: https://clinicaltrials.gov/ct2/show/ NCT01509911.
  29. Chen H., Tsai C., Hung W. Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Oncotarget 2015;6:14940–52. https://doi.org/10.18632/oncotarget.3613.
  30. Philip P., Benedetti J., Corless C. et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010;28:3605–10. doi: 10.1200/JCO.2009.25.7550.
  31. Mendelsohn J. Personalizing oncology: perspectives and prospects. J Clin Oncol 2013;31(15):1904–11. doi: 10.1200/JCO.2012.45.3605.
  32. Результаты исследования по применению Нимотузумаба в сочетании с гемцитабином при местнораспространенном и метастатическом раке поджелудочной железы дикого типа K-RAS. Available by: https://clinicaltrials.gov/ct2/show/NCT02395016.
  33. Pollak M., Schernhammer E., Hankinson S. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004; 4(7):505–18. doi: 10.1038/nrc1387.
  34. Результаты исследования по применению гемцитабина и AMG 479 при метастатической аденокарциноме поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/ NCT01231347.
  35. Urtasun N., Vidal-Pla A., Pérez-Torras S., Mazo A. Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors. BMC Cancer 2015;15:223. doi: 10.1186/s12885-015-1249-2.
  36. Ioannou N., Dalgleish A., Seddon A. et al. Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. Br J Cancer 2011;105(10):1554–62. doi: 10.1038/bjc.2011.396.
  37. Haluska P., Carboni J.M., TenEyck C. et al. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther 2008;7(9):2589–98. doi: 10.1158/1535-7163.MCT-08-0493.
  38. Lu Y., Zi X., Zhao Y., Pollak M. Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun 2004;313(3):709–15. doi: 10.1016/j.bbrc.2003.12.007.
  39. Cox A. D., Fesik S.W., Kimmelman A.C. et al. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 2014;13:828–51. doi: 10.1038/nrd4389.
  40. Dang C.V., Reddy E.P., Shokat K. M., Soucek L. Drugging the “undruggable” cancer targets. Nat Rev Cancer 2017;17:502–8. doi: 10.1038/nrc.2017.36.
  41. McCormick F. c-Raf in KRas mutant cancers: A moving target. Canc Cell 2018;33:158–9. doi: 10.1016/j.ccell.2018.01.017.
  42. Yoshiro Niitsu, Yasushi Sato, Kunihiro Takanashi et al. A CRAF/glutathione-Stransferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations. Proc Natl Acad Sci U S A 2020;117(32):19435–45. doi: 10.1073/pnas.2000361117.
  43. Willems L., Tamburini J., Chapuis N. et al. PI3K and mTOR signaling pathways in cancer: new data on targeted therapies. Curr Oncol Rep 2012;14:129–38. doi: 10.1007/s11912-012-0227-y.
  44. Schlieman M.G., Fahy B.N., Ramsamooj R. et al. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer 2003;89:2110–5. doi: 10.1038/sj.bjc.6601396.
  45. Asano T., Yao Y., Zhu J. et al. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene 2004;23:8571–80. doi: 10.1038/sj.onc.1207902.
  46. Результаты исследования по оценке безопасности и эффективности RX-0201 плюс гемцитабин при метастатическом раке поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT01028495
  47. Результаты исследования по применению BKM120 + mFOLFOX6 при терапии рака поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT01571024
  48. Matsuzaki T., Yashiro M., Kaizaki R. et al. Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer Sci 2009;100:2402–10. doi: 10.1111/j.1349-7006.2009.01315.x.
  49. Kordes S., Klümpen H.J., Weterman M.J. et al. Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 2015;75:1135–41. doi: 10.1007/s00280-015-2730-y
  50. Llovet J.M., Ricci S., Mazzaferro V. et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. doi: 10.1056/NEJMoa0708857.
  51. Результаты исследования по применению Сорафениба и Эверолимуса при лечении пациентов с прогрессирующими солидными опухолями и метастатическим раком поджелудочной железы, которые не реагируют на гемцитабин. Available by: https://clinicaltrials.gov/ct2/show/NCT00981162.
  52. Результаты исследования по применению Метформина в сочетании с химиотерапией рака поджелудочной железы (GEM). Available by: https://clinicaltrials.gov/ct2/show/NCT01210911.
  53. Результаты II фазы исследования 5-ФУ, оксалиплатина плюс дазатиниба при метастатической аденокарциноме поджелудочной железы (ФОЛФОКС-Д). Available by: https://clinicaltrials.gov/ct2/show/NCT01652976.
  54. Thomas S., Brugge J. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 1997;13:513–609. DOI: https://doi.org/10.1146/annurev.cellbio.13.1.513.
  55. Jatiani S.S., Baker S.J., Silverman L.R., Reddy EP. Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer 2010;1:979–93. doi: 10.1177/1947601910397187.
  56. Seidel H.M., Lamb P., Rosen J. Pharmaceutical intervention in the JAK/STAT signaling pathway. Oncogene 2000;19: 2645–56. doi: 10.1038/sj.onc.1203550.
  57. Результаты исследования по применению Руксолитиниба, получаемого с химиотерапией у пациентов с прогрессирующими солидными опухолями. Available by: https://clinicaltrials. gov/ct2/show/NCT01822756.
  58. Результаты исследования по применению Олапариба при мутировавшем раке поджелудочной железы gBRCA, заболевание которого не прогрессировало на первой линии платиновой химиотерапии (POLO). Available by: https://clinicaltrials.gov/ct2/show/NCT02184195.
  59. Pancreatic Adenocarcinoma. NCCN Guidelines Version 1, 2020. Pp. 34–46.
  60. Franck C., Müller C., Rosania R. et al. Advanced Pancreatic Ductal Adenocarcinoma: Moving Forward. Cancers (Basel) 2020;12(7):1955. doi: 10.3390/cancers12071955.
  61. Maloney E., Khokhlova T., Pillarisetty V. et al. Focused ultrasound for immunoadjuvant treatment of pancreatic cancer: an emerging clinical paradigm in the era of personalized oncotherapy. Int Rev Immunol 2017;36(6): 338–51. doi: 10.1080/08830185.2017.1363199.
  62. Lutz E., Yeo C.J., Lillemoe K.D. et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg 2011;253(2):328–35. doi: 10.1097/SLA.0b013e3181fd271c.
  63. Pishvaian M., Blais E., Jonathan R. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. The Lancet Oncology 2020;21(4):508–18. doi: 10.1016/S1470-2045(20)30074-7.
  64. Результаты исследования по оценке безопасности и эффективности комбинированной вакцины против поджелудочной железы Listeria/GVAX при раке поджелудочной железы (ECLIPSE). Available by: https://clinicaltrials.gov/ct2/show/NCT02004262.
  65. Le D., Picozzi V., Ko A. et al. Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). Clin Cancer Res 2019;25(18):5493–502. doi: 10.1158/1078-0432.CCR-18-2992.
  66. Результаты исследования по применению CRS-207, ниволумаба и ипилимумаба с вакциной против рака поджелудочной железы GVAX или без нее(с Cy) у пациентов с раком поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT03190265.
  67. Результаты исследования по применению эпакадостата, пембролизумаба и CRS-207, с или без Cy/GVAX у пациентов с метастатическим раком поджелудочной железы. Available by: https://clinicaltrials.gov/ct2/show/NCT03006302.
  68. Lili L., Matyunina L., Walker L. et al. Evidence for the importance of personalized molecular profiling in pancreatic cancer. Pancreas 2014;43:198–211. doi: 10.1097/MPA.0000000000000020.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c)


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС77-53039 от  04.03.2013.