Emerging agents for metastatic pancreatic cancer: spotlight on early phase clinical trials

References

• Christenson ES, Jaffee E, Azad NS. Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. Lancet Oncol. 2020;21(3):e135–e145.
   PubMed Web of Science ®Google Scholar
• Singh RR, O’Reilly EM. New treatment strategies for metastatic pancreatic ductal adenocarcinoma. Drugs. 2020;80(7):647–669.
   PubMed Web of Science ®Google Scholar
• Gromisch C, Qadan M, Machado MA, et al. Pancreatic adenocarcinoma: unconventional approaches for an unconventional disease. Cancer Res. 2020;80(16):3179.
   PubMed Web of Science ®Google Scholar
• Zeng S, Pöttler M, Lan B, et al. Chemoresistance in Pancreatic Cancer. Int J Mol Sci. 2019;20(18):4504.
   PubMed Web of Science ®Google Scholar
• Elaileh A, Saharia A, Potter L, et al. Promising new treatments for pancreatic cancer in the era of targeted and immune therapies. Am J Cancer Res. 2019;9(9):1871–1888.
   PubMed Web of Science ®Google Scholar
• Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.
   PubMed Web of Science ®Google Scholar
• Abbassi R, Schmid RM. Evolving treatment paradigms for pancreatic cancer. Visc Med. 2019;35(6):362–372.
   PubMed Web of Science ®Google Scholar
• Kane GM, Grünwald BT, Jang G-H, et al. GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. Clin Cancer Res. 2020;26(18):4901.
   PubMed Web of Science ®Google Scholar
• Yao W, Maitra A, Ying H. Recent insights into the biology of pancreatic cancer. EBioMedicine. 2020;53:102655.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg robert A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
   PubMed Web of Science ®Google Scholar
• Mateo J, Lord CJ, Serra V, et al. A decade of clinical development of PARP inhibitors in perspective. Ann Oncol. 2019;30(9):1437–1447.
   PubMed Web of Science ®Google Scholar
• Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol. 2020;17(2):108–123.
   PubMed Web of Science ®Google Scholar
• Golan T, Hammel P, Reni M, et al. Maintenance OLAPARIB FOR GErmline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327.
   PubMed Web of Science ®Google Scholar
• Golan T, Hammel P, Reni M, et al. Overall survival from the phase 3 POLO trial: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol. 2021;39(3_suppl):378.
   Web of Science ®Google Scholar
• Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271–282.
   PubMed Web of Science ®Google Scholar
• Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in trk fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–739.
   PubMed Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.
   PubMed Web of Science ®Google Scholar
• Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.
   PubMed Web of Science ®Google Scholar
• Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of canada clinical trials group. J Clin Oncol. 2007;25(15):1960–1966.
   PubMed Web of Science ®Google Scholar
• Aranda E, Manzano JL, Rivera F, et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol. 2012;23(7):1919–1925.
   PubMed Web of Science ®Google Scholar
• Burris HA, Moore MJ, 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(6):2403–2413.
   PubMed Web of Science ®Google Scholar
• Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in japan and taiwan: GEST study. J Clin Oncol. 2013;31(13):1640–1648.
   PubMed Web of Science ®Google Scholar
• Kwakman JJM, Punt CJA. Oral drugs in the treatment of metastatic colorectal cancer. Expert Opin Pharmacother. 2016;17(10):1351–1361.
   PubMed Web of Science ®Google Scholar
• Aroldi F, Bertocchi P, Savelli G, et al. Pancreatic cancer: new hopes after first line treatment. World J Gastrointest Oncol. 2016;8(9):682–687.
   PubMed Web of Science ®Google Scholar
• Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–557.
   PubMed Web of Science ®Google Scholar
• Abbassi R, Algül H. Palliative chemotherapy in pancreatic cancer-treatment sequences. Transl Gastroenterol Hepatol. 2019;4:56.
   PubMed Web of Science ®Google Scholar
• Portal A, Pernot S, Tougeron D, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after folfirinox failure: an AGEO prospective multicentre cohort. Br J Cancer. 2015;113(7):989–995.
   PubMed Web of Science ®Google Scholar
• Kasi A, Al-Jumayli M, Park R, et al. Update on the role of poly (ADP-ribose) polymerase inhibitors in the DNA repair-deficient pancreatic cancers: a narrative review. J Pancreat Cancer. 2020;6(1):107–115.
   PubMed Web of Science ®Google Scholar
• Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2014;33(3):244–250.
   PubMedGoogle Scholar
• Nishikawa G, Booth C, Prasad V. Olaparib for BRCA mutant pancreas cancer: should the POLO trial change clinical practice? Cancer. 2020;126(18):4087–4088.
   PubMed Web of Science ®Google Scholar
• Golan T, Varadhachary GR, Sela T, et al. Phase II study of olaparib for BRCAness phenotype in pancreatic cancer. J Clin Oncol. 2018;36(4_suppl):297.
   Web of Science ®Google Scholar
• Perkhofer L, Gout J, and Roger E, et al. DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives. Gut. 2021;70(3): 606–617 .
   Web of Science ®Google Scholar
• Yarchoan M, Myzak MC, Johnson BA 3rd, et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget. 2017;8(27):44073–44081.
   PubMedGoogle Scholar
• Bendell J, O’Reilly EM, Middleton MR, et al. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann Oncol. 2015;26(4):804–811.
   PubMed Web of Science ®Google Scholar
• Gupta M, Iyer R, Fountzilas C. Poly(ADP-ribose) polymerase inhibitors in pancreatic cancer: a new treatment paradigms and future implications. Cancers (Basel). 2019;11(12):1980.
   Web of Science ®Google Scholar
• Domchek SM, Hendifar AE, McWilliams RR, et al. RUCAPANC: an open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation. J Clin Oncol. 2016;34(15_suppl):4110.
   PubMed Web of Science ®Google Scholar
• Halder R, Shroff RT. What is the role of PARP inhibitors in pancreatic cancer? Expert Rev Anticancer Ther. 2020;20(11):913–918.
   PubMed Web of Science ®Google Scholar
• Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19–26.
   PubMed Web of Science ®Google Scholar
• O’Reilly EM, Lee JW, Zalupski M, et al. Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation. J Clin Oncol. 2020;38(13):1378–1388.
   PubMed Web of Science ®Google Scholar
• Chiorean EG, Guthrie KA, Philip PA, et al. Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOG S1513. J Clin Oncol. 2019;37(15_suppl):4014.
   Google Scholar
• Pishvaian MJ, Wang H, He AR, et al. A phase I/II study of veliparib (ABT-888) in combination with 5-Fluorouracil and oxaliplatin in patients with metastatic pancreatic cancer. Clin Cancer Res. 2020;26(19):5092.
   PubMed Web of Science ®Google Scholar
• Armstrong SA, Schultz CW, Azimi-Sadjadi A, et al. ATM dysfunction in pancreatic adenocarcinoma and associated therapeutic implications. Mol Cancer Ther. 2019;18(11):1899–1908.
   PubMed Web of Science ®Google Scholar
• Jette NR, Kumar M, Radhamani S, et al. ATM-deficient cancers provide new opportunities for precision oncology. Cancers (Basel). 2020;12(3):687.
   Web of Science ®Google Scholar
• Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399–405.
   PubMed Web of Science ®Google Scholar
• Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.
   PubMed Web of Science ®Google Scholar
• Mann KM, Ying H, Juan J, et al. KRAS-related proteins in pancreatic cancer. Pharmacol Ther. 2016;168:29–42.
   PubMed Web of Science ®Google Scholar
• Pant S, Hubbard J, Martinelli E, et al. Clinical update on K-Ras targeted therapy in gastrointestinal cancers. Crit Rev Oncol Hematol. 2018;130:78–91.
   PubMed Web of Science ®Google Scholar
• McCormick F. K-Ras protein as a drug target. J Mol Med. 2016;94(3):253–258.
   PubMed Web of Science ®Google Scholar
• Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17(3):153–168.
   PubMed Web of Science ®Google Scholar
• Golan T, Khvalevsky EZ, Hubert A, et al. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget. 2015;6(27):24560–24570.
   PubMedGoogle Scholar
• Varghese AM, Ang C, Dimaio CJ, et al. A phase II study of siG12D-LODER in combination with chemotherapy in patients with locally advanced pancreatic cancer (PROTACT). J Clin Oncol. 2020;38(15_suppl): TPS4672.
   Google Scholar
• Infante JR, Somer BG, Park JO, 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):2072–2081.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Hidalgo M, Canon J-L, et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018;143(8):2053–2064.
   PubMed Web of Science ®Google Scholar
• Kenney C, Kunst T, Webb S, et al. Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma. Invest New Drugs. 2021;39:821–828.
   PubMed Web of Science ®Google Scholar
• Ko AH, Bekaii-Saab T, Van Ziffle J, et al. A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res. 2016;22(1):61–68.
   PubMed Web of Science ®Google Scholar
• Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3(4):516–522.
   PubMed Web of Science ®Google Scholar
• Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533–552.
   PubMed Web of Science ®Google Scholar
• Amatu A, Sartore-Bianchi A, Bencardino K, et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019;30(Suppl_8):viii5–viii15.
   PubMedGoogle Scholar
• Lange AM, Lo H-W. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105.
   PubMed Web of Science ®Google Scholar
• Drilon A, Siena S, Ou S-HI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400–409.
   PubMed Web of Science ®Google Scholar
• Singhi AD, Ali SM, Lacy J, et al. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J Natl Compr Canc Netw. 2017;15(5):555–562.
   PubMed Web of Science ®Google Scholar
• Aguirre AJ. Oncogenic NRG1 fusions: a new hope for targeted therapy in pancreatic cancer. Clin Cancer Res. 2019;25(15):4589–4591.
   PubMed Web of Science ®Google Scholar
• Jones MR, Williamson LM, Topham JT, et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin Cancer Res. 2019;25(15):4674.
   PubMed Web of Science ®Google Scholar
• Gligorov J, Richard S, Todorovic V. New anti-HER2 agents: from second-generation tyrosine kinases inhibitors to bifunctional antibodies. Curr Opin Oncol. 2017;29(6):405–410.
   PubMed Web of Science ®Google Scholar
• Kang X, Lin Z, Xu M, et al. Deciphering role of FGFR signalling pathway in pancreatic cancer. Cell Prolif. 2019;52(3):e12605–e12605.
   PubMed Web of Science ®Google Scholar
• Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22(1):259.
   PubMed Web of Science ®Google Scholar
• Haq F, Sung Y-N, Park I, et al. FGFR1 expression defines clinically distinct subtypes in pancreatic cancer. J Transl Med. 2018;16(1):374.
   PubMedGoogle Scholar
• Lai E, Puzzoni M, Ziranu P, et al. New therapeutic targets in pancreatic cancer. Cancer Treat Rev. 2019;81.
   PubMed Web of Science ®Google Scholar
• De Luca A, Esposito Abate R, Rachiglio AM, et al. FGFR fusions in cancer: from diagnostic approaches to therapeutic intervention. Int J Mol Sci. 2020;21(18):6856.
   PubMed Web of Science ®Google Scholar
• Ma WW, Xie H, Fetterly G, et al. A phase ib study of the FGFR/VEGFR inhibitor dovitinib with gemcitabine and capecitabine in advanced solid tumor and pancreatic cancer patients. Am J Clin Oncol. 2019;42(2):184–189.
   PubMed Web of Science ®Google Scholar
• Mitry E, Hammel P, Deplanque G, et al. Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2010;66(2):395–403.
   PubMed Web of Science ®Google Scholar
• Deplanque G, Demarchi M, Hebbar M, et al. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann Oncol. 2015;26(6):1194–1200.
   PubMed Web of Science ®Google Scholar
• Bahleda R, Hollebecque A, Varga A, et al. Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours. Br J Cancer. 2015;113(10):1413–1420.
   PubMed Web of Science ®Google Scholar
• Taylor MH, Lee C-H, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38(11):1154–1163.
   PubMed Web of Science ®Google Scholar
• Khan AA, Liu X, Yan X, et al. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev. 2021;40:245–272.
   PubMed Web of Science ®Google Scholar
• Qian Y, Gong Y, Fan Z, et al. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. J Hematol Oncol. 2020;13(1):130.
   PubMed Web of Science ®Google Scholar
• Al Baghdadi T, Halabi S, Garrett-Mayer E, et al. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: results from the targeted agent and profiling utilization registry study. JCO Precis Oncol. 2019;3:1–8.
   PubMedGoogle Scholar
• Li Z, Zou W, Zhang J, et al. Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer. Front Pharmacol. 2020;11:1723.
   Web of Science ®Google Scholar
• Weinberg BA, Wang H, Witkiewicz AK, et al. A phase I study of ribociclib plus everolimus in patients with metastatic pancreatic adenocarcinoma refractory to chemotherapy. J Pancreat Cancer. 2020;6(1):45–54.
   PubMed Web of Science ®Google Scholar
• Basu A. The interplay between apoptosis and cellular senescence: bcl-2 family proteins as targets for cancer therapy. Pharmacol Ther. 2021;107943. DOI:https://doi.org/10.1016/j.pharmthera.2021.107943
   Google Scholar
• Zhang L, Lu Z, Zhao X. Targeting bcl-2 for cancer therapy. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188569.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Liu H, Xue R, et al. BH3 mimetic abt-199 enhances the sensitivity of gemcitabine in pancreatic cancer in vitro and in vivo. Dig Dis Sci. 2018;63(12):3367–3375.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–322.
   PubMed Web of Science ®Google Scholar
• Balsano R, Tommasi C, Garajova I. State of the art for metastatic pancreatic cancer treatment: where are we now? Anticancer Res. 2019;39(7):3405.
   PubMed Web of Science ®Google Scholar
• Henu KV, Praveen KK, Saikrishna L, et al. A retrospective look at anti-EGFR agents in pancreatic cancer therapy. Curr Drug Metab. 2019;20(12):958–966.
   PubMed Web of Science ®Google Scholar
• Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033–1038.
   PubMed Web of Science ®Google Scholar
• Wu Z, Gabrielson A, Hwang JJ, et al. Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2015;76(6):1309–1314.
   PubMed Web of Science ®Google Scholar
• Schultheis B, Reuter D, Ebert MP, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen inKRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol. 2017;28(10):2429–2435.
   PubMed Web of Science ®Google Scholar
• Assenat E, Mineur L, Mollevi C, et al. Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1). Int J Cancer. 2021;148(3):682–691.
   PubMed Web of Science ®Google Scholar
• Wu X, Kilpatrick T, Chau I. Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials. Cancer Drug Resist. 2018;1(4):204–218.
   Google Scholar
• Criscitiello C, Morganti S, Curigliano G. Antibody-drug conjugates in solid tumors: a look into novel targets. J Hematol Oncol. 2021;14(1):20.
   PubMed Web of Science ®Google Scholar
• Wermke M, Alt J, Kauh J, et al. Preliminary results from a phase I study of GBR 1302, a bispecific antibody T-cell engager, in HER2 positive cancers. Ann Oncol. 2018;29:viii408–viii409.
   Web of Science ®Google Scholar
• Sharma M, Wnt Pathway: PK. An integral hub for developmental and oncogenic signaling networks. Int J Mol Sci. 2020;21(21):8018.
   Web of Science ®Google Scholar
• Ram Makena M, Gatla H, Verlekar D, et al. Wnt/β-Catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance. Int J Mol Sci. 2019;20(17):4242.
   PubMed Web of Science ®Google Scholar
• Davis SL, Cardin DB, Shahda S, et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest New Drugs. 2020;38(3):821–830.
   PubMed Web of Science ®Google Scholar
• Dotan E, Cardin DB, Lenz H-J, et al. Phase Ib study of wnt inhibitor ipafricept with gemcitabine and nab-paclitaxel in patients with previously untreated stage iv pancreatic cancer. Clin Cancer Res. 2020;26(20):5348.
   PubMed Web of Science ®Google Scholar
• Ko AH, Chiorean EG, Kwak EL, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol. 2016;34(15_suppl):e15721–e15721.
   Web of Science ®Google Scholar
• Neesse A, Griesmann H, Gress TM, et al. Claudin-4 as therapeutic target in cancer. Arch Biochem Biophys. 2012;524(1):64–70.
   PubMed Web of Science ®Google Scholar
• Gowrikumar S, Singh AB, Dhawan P. Role of claudin proteins in regulating cancer stem cells and chemoresistance-potential implication in disease prognosis and therapy. Int J Mol Sci. 2019;21(1):53.
   Web of Science ®Google Scholar
• Kyuno D, Yamaguchi H, and Ito, T, et al. Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol. 2014;20(31):10813–10824.
   PubMed Web of Science ®Google Scholar
• Suzuki M, Kato-Nakano M, Kawamoto S, et al. Therapeutic antitumor efficacy of monoclonal antibody against claudin-4 for pancreatic and ovarian cancers. Cancer Sci. 2009;100(9):1623–1630.
   PubMed Web of Science ®Google Scholar
• Sahin U, Ö T, Manikhas GM, et al. Zolbetuximab combined with EOX as first-line therapy in advanced CLDN18.2+ gastric (G) and gastroesophageal junction (GEJ) adenocarcinoma: updated results from the FAST trial. J Clin Oncol. 2019;37(4_suppl):16.
   Web of Science ®Google Scholar
• Lv J, Li P. Mesothelin as a biomarker for targeted therapy. Biomark Res. 2019;7(1):18.
   PubMed Web of Science ®Google Scholar
• Montemagno C, Cassim S, Pouyssegur J, et al. From malignant progression to therapeutic targeting: current insights of mesothelin in pancreatic ductal adenocarcinoma. Int J Mol Sci. 2020;21(11):4067.
   Web of Science ®Google Scholar
• Hassan R, Blumenschein GR, Moore KN, et al. First-in-human, multicenter, phase i dose-escalation and expansion study of anti-mesothelin antibody–drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J Clin Oncol. 2020;38(16):1824–1835.
   PubMed Web of Science ®Google Scholar
• Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–1333.
   PubMed Web of Science ®Google Scholar
• Le DT, Picozzi VJ, Ko AH, 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):5493–5502.
   PubMed Web of Science ®Google Scholar
• Tsujikawa T, Crocenzi T, Durham JN, et al. Evaluation of cyclophosphamide/GVAX pancreas followed by listeria-mesothelin (CRS-207) with or without nivolumab in patients with pancreatic cancer. Clin Cancer Res. 2020;26(14):3578–3588.
   PubMed Web of Science ®Google Scholar
• Li T, Li H, Li S, et al. Research progress and design optimization of CAR-T therapy for pancreatic ductal adenocarcinoma. Cancer Med. 2019;8(11):5223–5231.
   PubMed Web of Science ®Google Scholar
• Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155(1):29–32.
   PubMed Web of Science ®Google Scholar
• Gravina GL, Senapedis W, McCauley D, et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7:85.
   PubMed Web of Science ®Google Scholar
• Huang WY, Yue L, Qiu WS, et al. Prognostic value of CRM1 in pancreas cancer. Clin Invest Med. 2009;32(6):E315.
   PubMed Web of Science ®Google Scholar
• Bader JC, Abdul Razak AR, Shacham S, et al. Pharmacokinetics of selinexor: the First-In-Class Selective Inhibitor Of Nuclear Export. Clin Pharmacokinet. 2021;60(8):957–969.
   PubMed Web of Science ®Google Scholar
• Kazim S, Malafa MP, Coppola D, et al. Selective nuclear export inhibitor KPT-330 enhances the antitumor activity of gemcitabine in human pancreatic cancer. Mol Cancer Ther. 2015;14(7):1570–1581.
   PubMed Web of Science ®Google Scholar
• Azmi AS, Li Y, Muqbil I, et al. Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration. Oncotarget. 2017;8(47):82144–82155.
   PubMedGoogle Scholar
• Azmi AS, Khan HY, Muqbil I, et al. Preclinical assessment with clinical validation of selinexor with gemcitabine and nab-paclitaxel for the treatment of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2020;26(6):1338–1348.
   PubMed Web of Science ®Google Scholar
• Rai V, Targets AS. (metabolic mediators) of therapeutic importance in pancreatic ductal adenocarcinoma. Int J Mol Sci. 2020;21(22):8502.
   Web of Science ®Google Scholar
• Xu R, Yang J, Ren B, et al. Reprogramming of amino acid metabolism in pancreatic cancer: recent advances and therapeutic strategies. Front Oncol. 2020;10:572722.
   PubMed Web of Science ®Google Scholar
• Daemen A, Peterson D, Sahu N, et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A. 2015;112(32):E4410–E4417.
   PubMed Web of Science ®Google Scholar
• Alistar A, Morris BB, Desnoyer R, et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017;18(6):770–778.
   PubMed Web of Science ®Google Scholar
• Lee J-S, Jang E-H, Woo HA, et al. Regulation of autophagy is a novel tumorigenesis-related activity of multifunctional translationally controlled tumor protein. Cells. 2020;9(1):257.
   Web of Science ®Google Scholar
• Zeh HJ, Bahary N, Boone BA, et al. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients. Clin Cancer Res. 2020;26(13):3126.
   PubMed Web of Science ®Google Scholar
• Boone BA, Bahary N, Zureikat AH, et al. Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann Surg Oncol. 2015;22(13):4402–4410.
   PubMed Web of Science ®Google Scholar
• Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al. Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a Phase 2 randomized clinical trial. JAMA Oncol. 2019;5(7):993–998.
   PubMed Web of Science ®Google Scholar
• Bryant KL, Stalnecker CA, Zeitouni D, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25(4):628–640.
   PubMed Web of Science ®Google Scholar
• Kumari N, Bansal S. Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment. Cancer Chemother Pharmacol. 2021;88(4):565–594.
   PubMed Web of Science ®Google Scholar
• Endicott M, Jones M, Hull J. Amino acid metabolism as a therapeutic target in cancer: a review. Amino Acids. 2021;53(8):1169–1179.
   PubMed Web of Science ®Google Scholar
• Singh PK, Deorukhkar AA, Venkatesulu BP, et al. Exploiting arginine auxotrophy with pegylated arginine deiminase (ADI-PEG20) to sensitize pancreatic cancer to radiotherapy via metabolic dysregulation. Mol Cancer Ther. 2019;18(12):2381–2393.
   PubMed Web of Science ®Google Scholar
• Daylami R, Muilenburg DJ, Virudachalam S, et al. Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer. J Exp Clin Cancer Res. 2014;33(1):102.
   PubMedGoogle Scholar
• Lowery MA, Yu KH, Kelsen DP, et al. A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. Cancer. 2017;123(23):4556–4565.
   PubMed Web of Science ®Google Scholar
• Kim S-H, Roszik J, Grimm EA, et al. Impact of l-arginine metabolism on immune response and anticancer immunotherapy. Front Oncol. 2018;8:67.
   PubMed Web of Science ®Google Scholar
• Chang K-Y, Chiang N-J, Wu S-Y, et al. Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus pembrolizumab in advanced solid cancers. Oncoimmunology. 2021;10(1):1943253.
   PubMed Web of Science ®Google Scholar
• Vennin C, Murphy KJ, Morton JP, et al. Reshaping the tumor stroma for treatment of pancreatic cancer. Gastroenterology. 2018;154(4):820–838.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Tempero MA, Sigal D, et al. Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J Clin Oncol. 2020;38(27):3185–3194.
   PubMed Web of Science ®Google Scholar
• Li S, Xu H-X, Wu C-T, et al. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis. 2019;22(1):15–36.
   PubMed Web of Science ®Google Scholar
• Tempero M, Oh DY, Tabernero J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase 3 RESOLVE study. Ann Oncol. 2021;32:600–608.
   PubMed Web of Science ®Google Scholar
• Neesse A, Frese KK, Bapiro TE, et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci U S A. 2013;110(30):12325–12330.
   PubMed Web of Science ®Google Scholar
• Picozzi VJ, Pipas JM, Koong A, et al. FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2013;31(4_suppl):213.
   Web of Science ®Google Scholar
• Picozzi VJ, Pishvaian MJ, Mody K, et al. Effect of anti-CTGF human recombinant monoclonal antibody pamrevlumab on resectability and resection rate when combined with gemcitabine/nab-paclitaxel in phase 1/2 clinical study for the treatment of locally advanced pancreatic cancer patients. J Clin Oncol. 2018;36(15_suppl):4016.
   Web of Science ®Google Scholar
• Picozzi V, Alseidi A, Winter J, et al. Gemcitabine/nab-paclitaxel with pamrevlumab: a novel drug combination and trial design for the treatment of locally advanced pancreatic cancer. ESMO Open. 2020;5(4):e000668.
   PubMed Web of Science ®Google Scholar
• Kanteti R, Mirzapoiazova T, Riehm JJ, et al. Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biol Ther. 2018;19(4):316–327.
   PubMed Web of Science ®Google Scholar
• Weniger M, Honselmann KC, Liss AS. The extracellular matrix and pancreatic cancer: a complex relationship. Cancers (Basel). 2018;10(9):316.
   Web of Science ®Google Scholar
• Jiang H, Liu X, Knolhoff BL, et al. Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut. 2020;69(1):122–132.
   PubMed Web of Science ®Google Scholar
• Wang-Gillam A, McWilliams R, Lockhart AC, et al. Abstract CT118: phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: experiences of pancreatic ductal adenocarcinoma (PDAC) patients. Cancer Res. 2020;80(16 Supplement):CT118.
   Google Scholar
• Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res. 2018;24(6):1326–1336.
   PubMed Web of Science ®Google Scholar
• Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.
   PubMed Web of Science ®Google Scholar
• Leinwand J, Miller G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat Immunol. 2020;21(10):1152–1159.
   PubMed Web of Science ®Google Scholar
• Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunol. 2010;33(8):828–833.
   Google Scholar
• Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465.
   PubMed Web of Science ®Google Scholar
• Patnaik A, Kang SP, Rasco D, et al. Phase I study of pembrolizumab (MK-3475; anti–PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286–4293.
   PubMed Web of Science ®Google Scholar
• O’Reilly EM, 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 Oncol. 2019;5(10):1431–1438.
   PubMed Web of Science ®Google Scholar
• Kamath SD, Kalyan A, Kircher S, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study. Oncologist. 2020;25(5):e808–e815.
   PubMed Web of Science ®Google Scholar
• Aglietta M, Barone C, Sawyer MB, et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol. 2014;25(9):1750–1755.
   PubMed Web of Science ®Google Scholar
• Weiss GJ, Blaydorn L, Beck J, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs. 2018;36(1):96–102.
   PubMed Web of Science ®Google Scholar
• Wainberg ZA, Hochster HS, Kim EJ, et al. Open-label, phase I study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin Cancer Res. 2020;26(18):4814.
   PubMed Web of Science ®Google Scholar
• Renouf DJ, Knox JJ, Kavan P, et al. LBA65 the canadian cancer trials group PA.7 trial: results of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) vs GEM, nab-P, durvalumab (D) and tremelimumab (T) as first line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC). Ann Oncol. 2020;31:S1195.
   Web of Science ®Google Scholar
• Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunol. 2013;36(7):382–389.
   Google Scholar
• Wu AA, Bever KM, Ho WJ, et al. A phase II study of allogeneic GM-CSF–Transfected pancreatic tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer. Clin Cancer Res. 2020;26(19):5129–5139.
   PubMed Web of Science ®Google Scholar
• Hong D, Rasco D, Veeder M, et al. A phase 1b/2 study of the bruton tyrosine kinase inhibitor ibrutinib and the PD-L1 inhibitor durvalumab in patients with pretreated solid tumors. Oncology. 2019;97(2):102–111.
   PubMed Web of Science ®Google Scholar
• Overman M, Javle M, Davis RE, 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.
   PubMed Web of Science ®Google Scholar
• Vonderheide RH. CD40 agonist antibodies in cancer immunotherapy. Annu Rev Med. 2020;71(1):47–58.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Winograd R, Evans RA, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology. 2015;149(1):201–210.
   PubMed Web of Science ®Google Scholar
• Winograd R, Byrne KT, Evans RA, et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res. 2015;3(4):399–411.
   PubMed Web of Science ®Google Scholar
• O’Hara MH, O’Reilly EM, Varadhachary G, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 2021;22(1):118–131.
   PubMed Web of Science ®Google Scholar
• Baghbani E, Noorolyai S, Shanehbandi D, et al. Regulation of immune responses through CD39 and CD73 in cancer: novel checkpoints. Life Sci. 2021;282:119826.
   PubMed Web of Science ®Google Scholar
• Zhao J, Soto LMS, Wang H, et al. Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival. Pancreatology. 2021;21(5):942–949.
   PubMed Web of Science ®Google Scholar
• Zhou L, Jia S, Chen Y, et al. The distinct role of CD73 in the progression of pancreatic cancer. J Mol Med. 2019;97(6):803–815.
   PubMed Web of Science ®Google Scholar
• Harvey JB, Phan LH, Villarreal OE, et al. CD73’s potential as an immunotherapy target in gastrointestinal cancers. Front Immunol. 2020;11:508.
   PubMed Web of Science ®Google Scholar
• Manji GA, Wainberg ZA, Krishnan K, et al. ARC-8: phase I/Ib study to evaluate safety and tolerability of AB680 + chemotherapy + zimberelimab (AB122) in patients with treatment-naive metastatic pancreatic adenocarcinoma (mPDAC). J Clin Oncol. 2021;39(3_suppl):404.
   Web of Science ®Google Scholar
• Blocking. CD73 can shrink pancreatic tumors. Cancer Discov. 2021;11(5):OF4.
   Google Scholar
• Łukaszewicz-Zając M, Gryko M, Mroczko B. The role of selected chemokines and their specific receptors in pancreatic cancer. Int J Biol Markers. 2018;33(2):141–147.
   PubMed Web of Science ®Google Scholar
• Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–662.
   PubMed Web of Science ®Google Scholar
• Noel M, O’Reilly EM, Wolpin BM, et al. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. Invest New Drugs. 2020;38(3):800–811.
   PubMed Web of Science ®Google Scholar
• Bockorny B, Semenisty V, Macarulla T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26(6):878–885.
   PubMed Web of Science ®Google Scholar
• Harrington J, Carter L, Basu B, et al. Drug development and clinical trial design in pancreatico-biliary malignancies. Curr Probl Cancer. 2018;42(1):73–94.
   PubMed Web of Science ®Google Scholar
• Regel I, Mayerle J, Mahajan UM. Current strategies and future perspectives for precision medicine in pancreatic cancer. Cancers (Basel). 2020;12(4):1024.
   Web of Science ®Google Scholar
• Wang Y, Lakoma A, Zogopoulos G. Building towards precision oncology for pancreatic cancer: real-world challenges and opportunities. Genes (Basel). 2020;11(9):1098.
   Web of Science ®Google Scholar
• Pishvaian MJ, Bender RJ, Halverson D, et al. Molecular profiling of patients with pancreatic cancer: initial results from the know your tumor initiative. Clin Cancer Res. 2018;24(20):5018–5027.
   PubMed Web of Science ®Google Scholar
• Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the know your tumor registry trial. Lancet Oncol. 2020;21(4):508–518.
   PubMed Web of Science ®Google Scholar
• Dreyer SB, Jamieson NB, Morton JP, et al. Pancreatic cancer: from genome discovery to PRECISION-Panc. Clin Oncol. 2020;32(1):5–8.
   Web of Science ®Google Scholar
• Martinelli P, Carrillo-de Santa Pau E, Cox T. Carrillo-de Santa Pau E, Cox T, et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017;66(9):1665.
   PubMed Web of Science ®Google Scholar
• Froeling FEM, Casolino R, Pea A, et al. Molecular subtyping and precision medicine for pancreatic cancer. J Clin Med. 2021;10(1):149.
   Web of Science ®Google Scholar
• Dreyer SB, Upstill-Goddard R, Paulus-Hock V, et al. Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology. 2021;160(1):362–377.e313.
   PubMed Web of Science ®Google Scholar
• Martinez-Useros J, Martin-Galan M, Garcia-Foncillas J. The match between molecular subtypes, histology and microenvironment of pancreatic cancer and its relevance for chemoresistance. Cancers (Basel). 2021;13(2):322.
   PubMed Web of Science ®Google Scholar
• Al-Assar O, Demiciorglu F, Lunardi S, et al. Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells. Radiother Oncol. 2014;111(2):243–251.
   PubMed Web of Science ®Google Scholar
• Dalin S, Sullivan MR, Lau AN, et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res. 2019;79(22):5723–5733.
   PubMed Web of Science ®Google Scholar