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Pancreatic Cancer: Recent Progress of Drugs in Clinical Trials

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
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Abstract

Pancreatic cancer is a highly malignant tumor and one of the primary causes of cancer-related death. Because pancreatic cancer is difficult to diagnose in the early course of the disease, most patients present with advanced lesions at the time of diagnosis, and only 20% of patients are eligible for surgery. Consequently, drug treatment has become extremely important. At present, the main treatment regimens for pancreatic cancer are gemcitabine and the FORFIRINOX and MPACT regimens. However, none of these regimens substantially improves the prognosis of patients with pancreatic cancer. Extensive efforts have been dedicated to the study of pancreatic cancer in recent years. With the development and clinical application of biological targeted drugs, the biological targeted treatment of tumors has been widely accepted. Therefore, this article used relevant clinical trial data to summarize the research progress of traditional chemotherapy drugs and biological targeted drugs for the treatment of pancreatic cancer.

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References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.

    Article  PubMed  Google Scholar 

  2. Pandol S, Gukovskaya A, Edderkaoui M, Dawson D, Eibl G, Lugea A. Epidemiology, risk factors, and the promotion of pancreatic cancer: role of the stellate cell. J Gastroenterol Hepatol. 2012;27 Suppl 2(02):127–134.

  3. Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. 2018;15(6):333–48.

    Article  PubMed  Google Scholar 

  4. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2014;155(6):977–88.

    Article  PubMed  Google Scholar 

  6. Ellenrieder V, König A, Seufferlein T. Current standard and future perspectives in first- and second-line treatment of metastatic pancreatic adenocarcinoma. Digestion. 2016;94(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  7. Pliarchopoulou K, Pectasides D. Pancreatic cancer: current and future treatment strategies. Cancer Treat Rev. 2009;35(5):431–6.

    Article  CAS  PubMed  Google Scholar 

  8. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    Article  CAS  PubMed  Google Scholar 

  9. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013;31(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  10. Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015;107(2).

  11. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.

    Article  PubMed  Google Scholar 

  12. Müller S, Chaikuad A, Gray NS, Knapp S. The ins and outs of selective kinase inhibitor development. Nat Chem Biol. 2015;11(11):818–21.

    Article  PubMed  Google Scholar 

  13. Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer. 2002;38(Suppl 5):S3–S10.

    Article  PubMed  Google Scholar 

  14. Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17(1):58.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Yamaoka T, Kusumoto S, Ando K, Ohba M, Ohmori T. Receptor tyrosine kinase-targeted cancer therapy. Int J Mol Sci. 2018;19(11):3491.

    Article  PubMed Central  Google Scholar 

  16. Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010;277(2):301–8.

    Article  CAS  PubMed  Google Scholar 

  17. Abdel-Rahman O. Vascular endothelial growth factor (VEGF) pathway and neuroendocrine neoplasms (NENs): prognostic and therapeutic considerations. Tumour Biol. 2014;35(11):10615–25.

    Article  CAS  PubMed  Google Scholar 

  18. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 2006;12(17):5018–22.

    Article  CAS  PubMed  Google Scholar 

  19. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, 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(22):3617–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ko AH, Venook AP, Bergsland EK, Kelley RK, Korn WM, Dito E, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2010;66(6):1051–7.

    Article  CAS  PubMed  Google Scholar 

  21. Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.

    Article  PubMed  Google Scholar 

  22. English DP, Roque DM, Santin AD. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther. 2013;17(2):85–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shibata W, Kinoshita H, Hikiba Y, et al. Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice. Rep. 2018;8(1):6150.

    Google Scholar 

  24. Momeny M, Esmaeili F, Hamzehlou S, et al. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cellular Oncology, 2019.

  25. Kimura K, Sawada T, Komatsu M, Inoue M, Muguruma K, Nishihara T, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res. 2006;12(16):4925–32.

    Article  CAS  PubMed  Google Scholar 

  26. Harder J, Ihorst G, Heinemann V, Hofheinz R, Moehler M, Buechler P, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Walsh N, Kennedy S, Larkin A, Corkery B, O’Driscoll L, Clynes M, et al. EGFR and HER2 inhibition in pancreatic cancer. Investig New Drugs. 2013;31(3):558–66.

    Article  CAS  Google Scholar 

  28. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  29. McCaffery I, Tudor Y, Deng H, Tang R, Suzuki S, Badola S, et al. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res. 2013;19(15):4282–9.

    Article  CAS  PubMed  Google Scholar 

  30. Fuchs CS, Azevedo S, Okusaka T, van Laethem JL, Lipton LR, Riess H, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26(5):921–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gocek E, Moulas AN, Studzinski GP. Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci. 2014;51(3):125–37.

    Article  CAS  PubMed  Google Scholar 

  32. Groner B, von Manstein V. Jak Stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol. 2017;451:1–14.

    Article  CAS  PubMed  Google Scholar 

  33. Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM III, et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol. 2015;33(34):4039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feng Y, Duan W, Cu X, Liang C, Xin M. Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018). Expert Opin Ther Pat. 2019;29(4):217–41.

    Article  CAS  PubMed  Google Scholar 

  35. Overman M, Javle M, Davis RE, Vats P, Kumar-Sinha C, Xiao L, et al. Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. J Immunother Cancer. 2020;8(1):e000587.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Halder SK, Anumanthan G, Maddula R, Mann J, Chytil A, Gonzalez AL, et al. Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. Cancer Res. 2006;66(12):6156–66.

    Article  CAS  PubMed  Google Scholar 

  37. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.

    Article  CAS  PubMed  Google Scholar 

  38. Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50(12):2072–81.

    Article  CAS  PubMed  Google Scholar 

  39. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25(4):620–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol. 2004;16(6):564–75.

    Article  CAS  PubMed  Google Scholar 

  41. Cohen Y, Merhavi-Shoham E, Avraham-Lubin BC, et al. PI3K/Akt pathway mutations in retinoblastoma. Invest Ophthalmol Vis Sci. 2009;50(11):5054–6.

    Article  PubMed  Google Scholar 

  42. Zhong Z, Sepramaniam S, Chew XH, et al. PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers. Oncogene, 2019(12).

  43. Falletta S, Partelli S, Rubini C, Nann D, Doria A, Marinoni I, et al. mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. Endocrine Related Cancer. 2016;23(11):883–91.

    Article  CAS  PubMed  Google Scholar 

  44. Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors [published correction appears in N Engl J Med. 2011 Mar 17;364(11):1082]. N Engl J Med. 2011;364(6):501–13.

    Article  CAS  PubMed  Google Scholar 

  46. Waheed A, Purvey S, Saif MW. Masitinib in treatment of pancreatic cancer. Expert Opin Pharmacother. 2018;19(7):759–64.

    Article  CAS  PubMed  Google Scholar 

  47. Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol. 2015;44–46:94–112.

  48. Casey SC, Amedei A, Aquilano K, et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol. 2015;35 Suppl(Suppl):S199-S223.

  49. Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17(8):487–505.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Eichhorn ME, Ischenko I, Luedemann S, Strieth S, Papyan A, Werner A, et al. Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer. Int J Cancer. 2010;126(5):1235–45.

    Article  CAS  PubMed  Google Scholar 

  51. Löhr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, et al. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol. 2012;23(5):1214–22.

    Article  PubMed  Google Scholar 

  52. Sleightholm RL, Neilsen BK, Li J, Steele MM, Singh RK, Hollingsworth MA, et al. Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacol Ther. 2017;179:158–70.

    Article  CAS  PubMed  Google Scholar 

  53. Righetti A, Giulietti M, Šabanović B, Occhipinti G, Principato G, Piva F. CXCL12 and its isoforms: different roles in pancreatic cancer? J Oncol. 2019;2019:9681698.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26(6):878–85.

    Article  CAS  PubMed  Google Scholar 

  55. Hochster HS, Uboha N, Messersmith W, Gold PJ, ONeil BH, Cohen D, et al. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer [published correction appears in Cancer Chemother Pharmacol. 2015 Jan;75(1):25. Lenz, H-J [added]]. Cancer Chemother Pharmacol. 2015;75(1):17–23.

    Article  CAS  PubMed  Google Scholar 

  56. Anders C, Deal AM, Abramson V, Liu MC, Storniolo AM, Carpenter JT, et al. TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. Breast Cancer Res Treat. 2014;146(3):557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. In brief: liposomal irinotecan (Onivyde) for pancreatic cancer. Med Lett Drugs Ther. 2016;58(1496):e76.

  58. Lamb YN, Scott LJ. Liposomal irinotecan: a review in metastatic pancreatic adenocarcinoma. Drugs. 2017;77(7):785–92.

    Article  CAS  PubMed  Google Scholar 

  59. Passero FC Jr, Grapsa D, Syrigos KN, Saif MW. The safety and efficacy of Onivyde (irinotecan liposome injection) for the treatment of metastatic pancreatic cancer following gemcitabine-based therapy. Expert Rev Anticancer Ther. 2016;16(7):697–703.

    Article  CAS  PubMed  Google Scholar 

  60. Zhu H, Wei M, Xu J, Hua J, Liang C, Meng Q, et al. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications. Mol Cancer. 2020;19(1):49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Golan T, Hammel P, Reni M, van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stathopoulos GP. Liposomal cisplatin: a new cisplatin formulation. Anti-Cancer Drugs. 2010;21(8):732–6.

    Article  CAS  PubMed  Google Scholar 

  63. Stathopoulos GP, Boulikas T, Vougiouka M, Rigatos SK, Stathopoulos JG. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study. Oncol Rep. 2006;15(5):1201–4.

    CAS  PubMed  Google Scholar 

  64. Boulikas T. Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin. Expert Opin Investig Drugs. 2009;18(8):1197–218.

    Article  CAS  PubMed  Google Scholar 

  65. Pourmorteza M, Rahman ZU, Young M. Evofosfamide, a new horizon in the treatment of pancreatic cancer. Anti-Cancer Drugs. 2016;27(8):723–5.

    Article  CAS  PubMed  Google Scholar 

  66. Kishimoto S, Brender JR, Chandramouli GVR, et al. Hypoxia-activated prodrug evofosfamide treatment in pancreatic ductal adenocarcinoma xenografts alters the tumor redox status to potentiate radiotherapy. Antioxid Redox Signal. 2020;10:1089.

    Google Scholar 

  67. Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, et al. Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2015;33(13):1475–81.

    Article  CAS  PubMed  Google Scholar 

  68. Chiorean EG, Dragovich T, Hamm J, et al. A phase 2 trial of glufosfamide in combination with gemcitabine in chemotherapy-naive pancreatic adenocarcinoma. Am J Clin Oncol. 2010;33(2):111–6.

    Article  CAS  PubMed  Google Scholar 

  69. Balboni B, El Hassouni B, Honeywell RJ, et al. RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment. Expert Opin Investig Drugs. 2019;28(4):311–22.

    Article  CAS  PubMed  Google Scholar 

  70. El Hassouni B, Infante J, Mantini G, et al. Uridine cytidine kinase 2 as a potential biomarker for treatment with RX-3117 in pancreatic cancer. Anticancer Res. 2019;39(7):3609–14.

    Article  PubMed  Google Scholar 

  71. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011–24.

    Article  CAS  PubMed  Google Scholar 

  72. Hoang NT, Kadonosono T, Kuchimaru T, Kizaka-Kondoh S. Hypoxia-inducible factor-targeting prodrug TOP3 combined with gemcitabine or TS-1 improves pancreatic cancer survival in an orthotopic model. Cancer Sci. 2016;107(8):1151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol. 2009;39(1):2–15.

    Article  PubMed  Google Scholar 

  74. Hagiwara Y, Ohashi Y, Okusaka T, Ueno H, Ioka T, Boku N, et al. Health-related quality of life in a randomised phase III study of gemcitabine plus S-1, S-1 alone and gemcitabine alone for locally advanced or metastatic pancreatic cancer: GEST study. ESMO Open. 2017;2(1):e000151.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Novel therapy elicits responses in pancreatic cancer. Cancer Discov. 2019;9(9):OF3.

  76. van Vuuren RJ, Visagie MH, Theron AE, Joubert AM. Antimitotic drugs in the treatment of cancer. Cancer Chemother Pharmacol. 2015;76(6):1101–12.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Lopus M. Editorial: Tubulin-targeted cancer chemotherapeutics: advances and challenges. Curr Top Med Chem. 2017;17(22):2522.

    Article  CAS  PubMed  Google Scholar 

  78. Gallery M, Zhang J, Bradley DP, Brauer P, Cvet D, Estevam J, et al. A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo. PLoS One. 2018;13(1):e0191046.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, et al. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. 2014;13(6):1537–48.

    Article  CAS  PubMed  Google Scholar 

  80. Dan, Laheru, Elizabeth M, et al. Immunotherapy for pancreatic cancer - science driving clinical progress. Nature reviews. Cancer, 2005.

  81. Katsuda M, Miyazawa M, Ojima T, et al. A double-blind randomized comparative clinical trial to evaluate the safety and efficacy of dendritic cell vaccine loaded with WT1 peptides (TLP0-001) in combination with S-1 in patients with advanced pancreatic cancer refractory to standard chemotherapy. Trials, 2019, 20(1).

  82. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23:viii6–9.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Novel anti-melanoma immunotherapies: disarming tumor escape mechanisms[J]. Clinical & Developmental Immunology, 2012.

  84. O'Reilly E M, Oh D Y, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncology, 2019, 5(10).

  85. Grant TJ, Hua K, Singh A. Molecular pathogenesis of pancreatic cancer. Prog Mol Biol Transl Sci. 2016;144:241–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gao CC, Gong BG, Wu JB, Cheng PG, Xu HY, Song DK, et al. MMI-166, a selective matrix metalloproteinase inhibitor, promotes apoptosis in human pancreatic cancer. Med Oncol. 2015;32(1):418.

    Article  PubMed  Google Scholar 

  88. Matsushita A, Onda M, Uchida E, Maekawa R, Yoshioka T. Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer. Int J Cancer. 2001;92(3):434–40.

    Article  CAS  PubMed  Google Scholar 

  89. Giri B, Sethi V, Modi S, Garg B, Banerjee S, Saluja A, et al. Heat shock protein 70 in pancreatic diseases: friend or foe. J Surg Oncol. 2017;116(1):114–22.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Noel P, Von Hoff DD, Saluja AK, Velagapudi M, Borazanci E, Han H. Triptolide and its derivatives as cancer therapies. Trends Pharmacol Sci. 2019;40(5):327–41.

    Article  CAS  PubMed  Google Scholar 

  91. Banerjee S, Saluja A. Minnelide, a novel drug for pancreatic and liver cancer. Pancreatology. 2015;15(4 Suppl):S39–43.

    Article  CAS  PubMed  Google Scholar 

  92. Mazar AP, Ahn RW, O'Halloran TV. Development of novel therapeutics targeting the urokinase plasminogen activator receptor (uPAR) and their translation toward the clinic. Curr Pharm Des. 2011;17(19):1970–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bauer TW, Liu W, Fan F, Camp ER, Yang A, Somcio RJ, et al. Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res. 2005;65(17):7775–81.

    Article  CAS  PubMed  Google Scholar 

  94. Froriep D, Clement B, Bittner F, Mendel RR, Reichmann D, Schmalix W, et al. Activation of the anti-cancer agent upamostat by the mARC enzyme system. Xenobiotica. 2013;43(9):780–4.

    Article  CAS  PubMed  Google Scholar 

  95. Heinemann V, Ebert MP, Laubender RP, Bevan P, Mala C, Boeck S. Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. Br J Cancer. 2013;108(4):766–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. MacDonald A, Priess M, Curran J, Guess J, Farutin V, Oosterom I, et al. Necuparanib, a multitargeting heparan sulfate mimetic, targets tumor and stromal compartments in pancreatic cancer. Mol Cancer Ther. 2019;18(2):245–56.

    Article  CAS  PubMed  Google Scholar 

  97. O'Reilly EM, Roach J, Miller P, Yu KH, Tjan C, Rosano M, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: phase I results. Oncologist. 2017;22(12):1429–e139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. O'Reilly EM, Barone D, Mahalingam D, Bekaii-Saab T, Shao SH, Wolf J, et al. Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma. Eur J Cancer. 2020;132:112–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Marie R, Marine L, Fabian G, et al. Gene therapy for pancreatic cancer: specificity, issues and hopes. Int J Mol Sci,2017,18(6).

  100. Buscail L, Bournet B, Vernejoul F, et al. First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings. Molecular therapy, 2015,23(4).

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Funding

This work was supported by the National Science Foundation of China (Grant no. 81973249); the Shanghai Commission of science and technology (Grant no. 20S11905500); the National Science Foundation of China (Grant no. 81690263); the Foundation Program of Key Laboratory of Smart Drug Delivery of the Ministry of Education; the Shanghai Education Commission Major Project (2017-01-07-00-07- E00052).This research is helped by Clarivate Cortellis Drug Discovery Intelligence.

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  1. Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People’s Republic of China

    Zhiyi Zhang, Jie Song, Cao Xie, Jun Pan, Weiyue Lu & Min Liu

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  1. Zhiyi Zhang
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Correspondence to Min Liu.

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Zhang, Z., Song, J., Xie, C. et al. Pancreatic Cancer: Recent Progress of Drugs in Clinical Trials. AAPS J 23, 29 (2021). https://doi.org/10.1208/s12248-021-00556-2

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