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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Angiogenesis and Pancreatic Cancer: Novel Approaches to Overcome Treatment Resistance

Author(s): Craig Grobbelaar, Mpho Kgomo and Peace Mabeta*

Volume 24, Issue 11, 2024

Published on: 31 January, 2024

Page: [1116 - 1127] Pages: 12

DOI: 10.2174/0115680096284588240105051402

Price: $65

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Abstract

Pancreatic cancer (PCa) is acknowledged as a significant contributor to global cancer- related mortality and is widely recognized as one of the most challenging malignant diseases to treat. Pancreatic ductal adenocarcinoma (PDAC), which is the most common type of PCa, is highly aggressive and is mostly incurable. The poor prognosis of this neoplasm is exacerbated by the prevalence of angiogenic molecules, which contribute to stromal stiffness and immune escape. PDAC overexpresses various proangiogenic proteins, including vascular endothelial growth factor (VEGF)-A, and the levels of these molecules correlate with poor prognosis and treatment resistance. Moreover, VEGF-targeting anti-angiogenesis treatments are associated with the onset of resistance due to the development of hypoxia, which in turn induces the production of angiogenic molecules. Furthermore, excessive angiogenesis is one of the hallmarks of the second most common form of PCa, namely, pancreatic neuroendocrine tumor (PNET). In this review, the role of angiogenesis regulators in promoting disease progression in PCa, and the impact of these molecules on resistance to gemcitabine and various therapies against PCa are discussed. Finally, the use of anti-angiogenic agents in combination with chemotherapy and other targeted therapeutic molecules is discussed as a novel solution to overcome current treatment limitations in PCa.

Keywords: Pancreatic ductal adenocarcinoma, angiogenesis modulators, immunotherapy, hypoxia, pancreatic neuroendocrine tumor, immune checkpoint inhibitors.

Graphical Abstract
[1]
Mittal, D.; Gubin, M.M.; Schreiber, R.D.; Smyth, M.J. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr. Opin. Immunol., 2014, 27, 16-25.
[http://dx.doi.org/10.1016/j.coi.2014.01.004] [PMID: 24531241]
[2]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. Cancer J Clin, 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[3]
Mizrahi, J.D.; Surana, R.; Valle, J.W.; Shroff, R.T. Pancreatic cancer. Lancet, 2020, 395(10242), 2008-2020.
[http://dx.doi.org/10.1016/S0140-6736(20)30974-0] [PMID: 32593337]
[4]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin, 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[5]
McGuigan, A.; Kelly, P.; Turkington, R.C.; Jones, C.; Coleman, H.G.; McCain, R.S. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J. Gastroenterol., 2018, 24(43), 4846.
[http://dx.doi.org/10.3748/wjg.v24.i43.4846] [PMID: 30487695]
[6]
Kamisawa, T.; Wood, L.D.; Itoi, T.; Takaori, K. Pancreatic cancer. Lancet, 2016, 388(10039), 73-85.
[http://dx.doi.org/10.1016/S0140-6736(16)00141-0] [PMID: 26830752]
[7]
Annese, T.; Tamma, R.; Ruggieri, S.; Ribatti, D. Angiogenesis in pancreatic cancer: Pre-clinical and clinical studies. Cancers, 2019, 11(3), 381.
[http://dx.doi.org/10.3390/cancers11030381] [PMID: 30889903]
[8]
Tamburrino, A.; Piro, G.; Carbone, C.; Tortora, G.; Melisi, D. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy. Front. Pharmacol., 2013, 4, 56.
[http://dx.doi.org/10.3389/fphar.2013.00056] [PMID: 23641216]
[9]
Mabeta, P.; Pepper, M.S. A comparative study on the anti-angiogenic effects of DNA-damaging and cytoskeletal-disrupting agents. Angiogenesis, 2009, 12, 81-90.
[http://dx.doi.org/10.1007/s10456-009-9134-8] [PMID: 19214765]
[10]
Mabeta, P.; Hull, R.; Dlamini, Z. LncRNAs and the angiogenic switch in cancer: Clinical significance and therapeutic opportunities. Genes, 2022, 13(1), 152.
[http://dx.doi.org/10.3390/genes13010152] [PMID: 35052495]
[11]
Ma, S.; Pradeep, S.; Hu, W.; Zhang, D.; Coleman, R.; Sood, A. The role of tumor microenvironment in resistance to anti-angiogenic therapy. F1000 Res., 2018, 7.
[http://dx.doi.org/10.12688/f1000research.11771.1] [PMID: 29560266]
[12]
Itakura, J.; Ishiwata, T.; Friess, H.; Fujii, H.; Matsumoto, Y.; Büchler, M.; Korc, M. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res: Am J Cancer Res, 1997, 3(8), 1309-1316.
[PMID: 9815813]
[13]
Ikeda, N.; Adachi, M.; Taki, T.; Huang, C.; Hashida, H.; Takabayashi, A.; Sho, M.; Nakajima, Y.; Kanehiro, H.; Hisanaga, M. Prognostic significance of angiogenesis in human pancreatic cancer. Br. J. Cancer, 1999, 79(9), 1553-1563.
[http://dx.doi.org/10.1038/sj.bjc.6690248] [PMID: 10188906]
[14]
Morin, E.; Sjöberg, E.; Tjomsland, V.; Testini, C.; Lindskog, C.; Franklin, O.; Sund, M.; Öhlund, D.; Kiflemariam, S.; Sjöblom, T. VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. J. Pathol., 2018, 246(3), 311-322.
[http://dx.doi.org/10.1002/path.5141] [PMID: 30027561]
[15]
Kuwahara, K.; Sasaki, T.; Kuwada, Y.; Murakami, M.; Yamasaki, S.; Chayama, K. Expressions of angiogenic factors in pancreatic ductal carcinoma: A correlative study with clinicopathologic parameters and patient survival. Pancreas, 2003, 26(4), 344-349.
[http://dx.doi.org/10.1097/00006676-200305000-00006] [PMID: 12717266]
[16]
Hoffmann, A-C.; Mori, R.; Vallbohmer, D.; Brabender, J.; Klein, E.; Drebber, U.; Baldus, S.E.; Cooc, J.; Azuma, M.; Metzger, R. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia, 2008, 10(7), 674-679.
[http://dx.doi.org/10.1593/neo.08292] [PMID: 18592007]
[17]
Lee, J.; Lee, J.; Yun, J.H.; Choi, C.; Cho, S.; Kim, S.J.; Kim, J.H. Autocrine DUSP28 signaling mediates pancreatic cancer malignancy via regulation of PDGF-A. Sci. Rep., 2017, 7(1), 12760.
[http://dx.doi.org/10.1038/s41598-017-13023-w] [PMID: 28986588]
[18]
Zahra, F.T.; Sajib, M.S.; Mikelis, C.M. Role of bFGF in acquired resistance upon anti-VEGF therapy in cancer. Cancers, 2021, 13(6), 1422.
[http://dx.doi.org/10.3390/cancers13061422] [PMID: 33804681]
[19]
Pavel, M.E.; Hassler, G.; Baum, U.; Hahn, E.G.; Lohmann, T.; Schuppan, D. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas. Clin. Endocrinol., 2005, 62(4), 434-443.
[http://dx.doi.org/10.1111/j.1365-2265.2005.02238.x] [PMID: 15807874]
[20]
Inman, K.S.; Francis, A.A.; Murray, N.R. Complex role for the immune system in initiation and progression of pancreatic cancer. World J. Gastroenterol., 2014, 20(32), 11160-11181.
[http://dx.doi.org/10.3748/wjg.v20.i32.11160] [PMID: 25170202]
[21]
Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. Cancer immunoediting: From immunosurveillance to tumor escape. Nat. Immunol., 2002, 3(11), 991-998.
[http://dx.doi.org/10.1038/ni1102-991] [PMID: 12407406]
[22]
Arum, C-J.; Anderssen, E.; Viset, T.; Kodama, Y.; Lundgren, S.; Chen, D.; Zhao, C-M. Cancer immunoediting from immunosurveillance to tumor escape in microvillus-formed niche: A study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer. Neoplasia, 2010, 12(6), 434-442.
[http://dx.doi.org/10.1593/neo.91824] [PMID: 20563246]
[23]
O’Donnell, J.S.; Teng, M.W.; Smyth, M.J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol., 2019, 16(3), 151-167.
[http://dx.doi.org/10.1038/s41571-018-0142-8] [PMID: 30523282]
[24]
Fukumura, D.; Kloepper, J.; Amoozgar, Z.; Duda, D.G.; Jain, R.K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol., 2018, 15(5), 325-340.
[http://dx.doi.org/10.1038/nrclinonc.2018.29] [PMID: 29508855]
[25]
Riboldi, E.; Musso, T.; Moroni, E.; Urbinati, C.; Bernasconi, S.; Rusnati, M.; Adorini, L.; Presta, M.; Sozzani, S. Cutting edge: Proangiogenic properties of alternatively activated dendritic cells. J. Immun., 2005, 175(5), 2788-2792.
[http://dx.doi.org/10.4049/jimmunol.175.5.2788] [PMID: 16116163]
[26]
Li, Y-L.; Zhao, H.; Ren, X-B. Relationship of VEGF/VEGFR with immune and cancer cells: Staggering or forward? Cancer Biol. Med., 2016, 13(2), 206.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2015.0070] [PMID: 27458528]
[27]
Esposito, I.; Menicagli, M.; Funel, N.; Bergmann, F.; Boggi, U.; Mosca, F.; Bevilacqua, G.; Campani, D. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J. Clin. Pathol., 2004, 57(6), 630-636.
[http://dx.doi.org/10.1136/jcp.2003.014498] [PMID: 15166270]
[28]
Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis, 2018, 7(1), 10.
[http://dx.doi.org/10.1038/s41389-017-0011-9] [PMID: 29362402]
[29]
Tao, J.; Yang, G.; Zhou, W.; Qiu, J.; Chen, G.; Luo, W.; Zhao, F.; You, L.; Zheng, L.; Zhang, T. Targeting hypoxic tumor microenvironment in pancreatic cancer. J. Hematol. Oncol., 2021, 14, 1-25.
[http://dx.doi.org/10.1186/s13045-020-01030-w] [PMID: 33436044]
[30]
Muz, B.; de la Puente, P.; Azab, F.; Kareem Azab, A. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia, 2015, 83-92.
[http://dx.doi.org/10.2147/HP.S93413] [PMID: 27774485]
[31]
Hao, J. HIF-1 is a critical target of pancreatic cancer. OncoImmunology, 2015, 4(9), e1026535.
[http://dx.doi.org/10.1080/2162402X.2015.1026535] [PMID: 26405594]
[32]
Fuentes, N.R.; Phan, J.; Huang, Y.; Lin, D.; Taniguchi, C.M. Resolving the HIF paradox in pancreatic cancer. Cancer Lett., 2020, 489, 50-55.
[http://dx.doi.org/10.1016/j.canlet.2020.05.033] [PMID: 32512024]
[33]
Garvalov, B.K.; Acker, T. Implications of oxygen homeostasis for tumor biology and treatment. Hypoxia, 2016, 169-185.
[http://dx.doi.org/10.1007/978-1-4899-7678-9_12] [PMID: 27343096]
[34]
Unger, K.; Mehta, K.Y.; Kaur, P.; Wang, Y.; Menon, S.S.; Jain, S.K.; Moonjelly, R.A.; Suman, S.; Datta, K.; Singh, R. Metabolomics based predictive classifier for early detection of pancreatic ductal adenocarcinoma. Oncotarget, 2018, 9(33), 23078-23090.
[http://dx.doi.org/10.18632/oncotarget.25212] [PMID: 29796173]
[35]
Canto, M.I.; Harinck, F.; Hruban, R.H.; Offerhaus, G.J.; Poley, J-W.; Kamel, I.; Nio, Y.; Schulick, R.S.; Bassi, C.; Kluijt, I. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut, 2013, 62(3), 339-347.
[http://dx.doi.org/10.1136/gutjnl-2012-303108] [PMID: 23135763]
[36]
Henrikson, N.B.; Bowles, E.J.A.; Blasi, P.R.; Morrison, C.C.; Nguyen, M.; Pillarisetty, V.G.; Lin, J.S. Screening for pancreatic cancer: Updated evidence report and systematic review for the us preventive services task force. JAMA, 2019, 322(5), 445-454.
[http://dx.doi.org/10.1001/jama.2019.6190] [PMID: 31386140]
[37]
van Manen, L.; Groen, J.V.; Putter, H.; Vahrmeijer, A.L.; Swijnenburg, R-J.; Bonsing, B.A.; Mieog, J.S.D. Elevated CEA and CA19-9 serum levels independently predict advanced pancreatic cancer at diagnosis. Biomarkers, 2020, 25(2), 186-193.
[http://dx.doi.org/10.1080/1354750X.2020.1725786] [PMID: 32009482]
[38]
Meng, Q.; Shi, S.; Liang, C.; Xiang, J.; Liang, D.; Zhang, B.; Qin, Y.; Ji, S.; Xu, W.; Xu, J. Diagnostic accuracy of a CA125-based biomarker panel in patients with pancreatic cancer: A systematic review and meta-analysis. J. Cancer, 2017, 8(17), 3615-3622.
[http://dx.doi.org/10.7150/jca.18901] [PMID: 29151947]
[39]
Cai, J.; Chen, H.; Lu, M.; Zhang, Y.; Lu, B.; You, L.; Zhang, T.; Dai, M.; Zhao, Y. Advances in the epidemiology of pancreatic cancer: Trends, risk factors, screening, and prognosis. Cancer Lett., 2021, 520, 1-11.
[http://dx.doi.org/10.1016/j.canlet.2021.06.027] [PMID: 34216688]
[40]
Chun, Y.S.; Pawlik, T.M.; Vauthey, J-N. Of the AJCC cancer staging manual: Pancreas and hepatobiliary cancers. Ann. Surg. Oncol., 2018, 25, 845-847.
[http://dx.doi.org/10.1245/s10434-017-6025-x] [PMID: 28752469]
[41]
Board, P.A.T.E. Pancreatic cancer treatment (PDQ®). PDQ cancer information summaries; National Cancer Institute: US, 2023.
[42]
Hidalgo, M. Pancreatic cancer. N. Engl. J. Med., 2010, 362(17), 1605-1617.
[http://dx.doi.org/10.1056/NEJMra0901557] [PMID: 20427809]
[43]
Crane, C.H.; Winter, K.; Regine, W.F.; Safran, H.; Rich, T.A.; Curran, W.; Wolff, R.A.; Willett, C.G. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation therapy oncology group RTOG 0411. J. Clin. Oncol., 2009, 27(25), 4096-4102.
[http://dx.doi.org/10.1200/JCO.2009.21.8529] [PMID: 19636002]
[44]
Koukourakis, M.I.; Giatromanolaki, A., II; Sheldon, H.; Buffa, F.M.; Kouklakis, G.; Ragoussis, I.; Sivridis, E.; Harris, A.L. Tumour; Group, A.R. Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: Vasculature-independent radiosensitizing effect of bevacizumab. Clin. Cancer Res., 2009, 15(22), 7069-7076.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0688] [PMID: 19887481]
[45]
Kindler, H.L.; Friberg, G.; Singh, D.A.; Locker, G.; Nattam, S.; Kozloff, M.; Taber, D.A.; Karrison, T.; Dachman, A.; Stadler, W.M. Phase trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J. Clin. Oncol., 2005, 23(31), 8033-8040.
[http://dx.doi.org/10.1200/JCO.2005.01.9661] [PMID: 16258101]
[46]
Spano, J-P.; Chodkiewicz, C.; Maurel, J.; Wong, R.; Wasan, H.; Barone, C.; Létourneau, R.; Bajetta, E.; Pithavala, Y.; Bycott, P. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: An open-label randomised phase II study. Lancet, 2008, 371(9630), 2101-2108.
[http://dx.doi.org/10.1016/S0140-6736(08)60661-3] [PMID: 18514303]
[47]
Kindler, H.L.; Ioka, T.; Richel, D.J.; Bennouna, J.; Létourneau, R.; Okusaka, T.; Funakoshi, A.; Furuse, J.; Park, Y.S.; Ohkawa, S. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: A double-blind randomised phase 3 study. Lancet Oncol., 2011, 12(3), 256-262.
[http://dx.doi.org/10.1016/S1470-2045(11)70004-3] [PMID: 21306953]
[48]
Awasthi, N.; Schwarz, M.A.; Schwarz, R.E. Antitumour activity of sunitinib in combination with gemcitabine in experimental pancreatic cancer. HPB, 2011, 13(9), 597-604.
[http://dx.doi.org/10.1111/j.1477-2574.2011.00333.x] [PMID: 21843259]
[49]
Bergmann, L.; Maute, L.; Heil, G.; Rüssel, J.; Weidmann, E.; Köberle, D.; Fuxius, S.; Weigang-Köhler, K.; Aulitzky, W.; Wörmann, B. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR central european society for anticancer drug research–EWIV. Eur. J. Cancer, 2015, 51(1), 27-36.
[http://dx.doi.org/10.1016/j.ejca.2014.10.010] [PMID: 25459392]
[50]
Pant, S.; Martin, L.K.; Geyer, S.; Wei, L.; Van Loon, K.; Sommovilla, N.; Zalupski, M.; Iyer, R.; Fogelman, D.; Ko, A.H. Treatment-related hypertension as a pharmacodynamic biomarker for the efficacy of bevacizumab in advanced pancreas cancer: A pooled analysis of 4 prospective trials of gemcitabine-based therapy with bevacizumab. Am. J. Clin. Oncol., 2016, 39(6), 614-618.
[http://dx.doi.org/10.1097/COC.0000000000000108] [PMID: 25068471]
[51]
Awasthi, N.; Hinz, S.; Brekken, R.A.; Schwarz, M.A.; Schwarz, R.E. Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. Cancer Lett., 2015, 358(1), 59-66.
[http://dx.doi.org/10.1016/j.canlet.2014.12.027] [PMID: 25527450]
[52]
Bill, R.; Fagiani, E.; Zumsteg, A.; Antoniadis, H.; Johansson, D.; Haefliger, S.; Albrecht, I.; Hilberg, F.; Christofori, G. Nintedanib is a highly effective therapeutic for neuroendocrine carcinoma of the pancreas (PNET) in the Rip1Tag2 transgenic mouse model. Clin. Cancer Res., 2015, 21(21), 4856-4867.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3036] [PMID: 26206868]
[53]
Faloppi, L.; Bianconi, M.; Giampieri, R.; Sobrero, A.; Labianca, R.; Ferrari, D.; Barni, S.; Aitini, E.; Zaniboni, A.; Boni, C. The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib. Oncotarget, 2015, 6(33), 35087-35094.
[http://dx.doi.org/10.18632/oncotarget.5197] [PMID: 26397228]
[54]
Wegner, C.S.; Hauge, A.; Simonsen, T.G.; Gaustad, J-V.; Andersen, L.M.K.; Rofstad, E.K. DCE-MRI of sunitinib-induced changes in tumor microvasculature and hypoxia: A study of pancreatic ductal adenocarcinoma xenografts. Neoplasia, 2018, 20(7), 734-744.
[http://dx.doi.org/10.1016/j.neo.2018.05.006] [PMID: 29886124]
[55]
O’Reilly, E.M.; Niedzwiecki, D.; Hall, M.; Hollis, D.; Bekaii-Saab, T.; Pluard, T.; Douglas, K.; Abou-Alfa, G.K.; Kindler, H.L.; Schilsky, R.L. A cancer and leukemia group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603). Oncol, 2010, 15(12), 1310-1319.
[http://dx.doi.org/10.1634/theoncologist.2010-0152] [PMID: 21148613]
[56]
Grande, E.; Rodriguez-Antona, C.; López, C.; Alonso-Gordoa, T.; Benavent, M.; Capdevila, J.; Teulé, A.; Custodio, A.; Sevilla, I.; Hernando, J. Sunitinib and evofosfamide (TH-302) in systemic treatment-naive patients with grade 1/2 metastatic pancreatic neuroendocrine tumors: The GETNE-1408 trial. Oncol, 2021, 26(11), 941-949.
[http://dx.doi.org/10.1002/onco.13885] [PMID: 34190375]
[57]
Bendell, J.C.; Zakari, A.; Lang, E.; Waterhouse, D.; Flora, D.; Alguire, K.; McCleod, M.; Peacock, N.; Ruehlman, P.; Lane, C.M. A phase II study of the combination of bevacizumab, pertuzumab, and octreotide LAR for patients with advanced neuroendocrine cancers. Cancer Invest., 2016, 34(5), 213-219.
[http://dx.doi.org/10.3109/07357907.2016.1174257] [PMID: 27127841]
[58]
Reni, M.; Cereda, S.; Milella, M.; Novarino, A.; Passardi, A.; Mambrini, A.; Di Lucca, G.; Aprile, G.; Belli, C.; Danova, M. Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: A phase II randomised trial. Eur. J. Cancer, 2013, 49(17), 3609-3615.
[http://dx.doi.org/10.1016/j.ejca.2013.06.041] [PMID: 23899530]
[59]
Jain, R.K. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell, 2014, 26(5), 605-622.
[http://dx.doi.org/10.1016/j.ccell.2014.10.006] [PMID: 25517747]
[60]
Zhou, P.; Li, B.; Liu, F.; Zhang, M.; Wang, Q.; Liu, Y.; Yao, Y.; Li, D. The epithelial to mesenchymal transition (EMT) and cancer stem cells: Implication for treatment resistance in pancreatic cancer. Mol. Cancer, 2017, 16, 1-52.
[http://dx.doi.org/10.1186/s12943-017-0624-9] [PMID: 28245823]
[61]
Ribatti, D. Tumor refractoriness to anti-VEGF therapy. Oncotarget, 2016, 7(29), 46668-46677.
[http://dx.doi.org/10.18632/oncotarget.8694] [PMID: 27081695]
[62]
Zang, J.; Liang, X.; Huang, Y.; Jia, Y.; Li, X.; Xu, W.; Chou, C.J.; Zhang, Y. Discovery of novel pazopanib-based HDAC and VEGFR dual inhibitors targeting cancer epigenetics and angiogenesis simultaneously. J. Med. Chem., 2018, 61(12), 5304-5322.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00384] [PMID: 29787262]
[63]
Aggarwal, R.; Thomas, S.; Pawlowska, N.; Bartelink, I.; Grabowsky, J.; Jahan, T.; Cripps, A.; Harb, A.; Leng, J.; Reinert, A. Inhibiting histone deacetylase as a means to reverse resistance to angiogenesis inhibitors: Phase I study of abexinostat plus pazopanib in advanced solid tumor malignancies. J. Clin. Oncol., 2017, 35(11), 1231-1239.
[http://dx.doi.org/10.1200/JCO.2016.70.5350] [PMID: 28221861]
[64]
Barnes, J.A.; Redd, R.; Fisher, D.C.; Hochberg, E.P.; Takvorian, T.; Neuberg, D.; Jacobsen, E.; Abramson, J.S. Panobinostat in combination with rituximab in heavily pretreated diffuse large B-cell lymphoma: Results of a phase II study. Hematol. Oncol., 2018, 36(4), 633-637.
[http://dx.doi.org/10.1002/hon.2515] [PMID: 29956350]
[65]
Di Federico, A.; Mosca, M.; Pagani, R.; Carloni, R.; Frega, G.; De Giglio, A.; Rizzo, A.; Ricci, D.; Tavolari, S.; Di Marco, M. Immunotherapy in pancreatic cancer: Why do we keep failing? A focus on tumor immune microenvironment, predictive biomarkers and treatment outcomes. Cancers, 2022, 14(10), 2429.
[http://dx.doi.org/10.3390/cancers14102429] [PMID: 35626033]
[66]
McCormick, K.A.; Coveler, A.L.; Rossi, G.R.; Vahanian, N.N.; Link, C.; Chiorean, E.G. Pancreatic cancer: Update on immunotherapies and algenpantucel-L. Hum. Vaccin. Immunother., 2016, 12(3), 563-575.
[http://dx.doi.org/10.1080/21645515.2015.1093264] [PMID: 26619245]
[67]
Luo, W.; Yang, G.; Luo, W.; Cao, Z.; Liu, Y.; Qiu, J.; Chen, G.; You, L.; Zhao, F.; Zheng, L. Novel therapeutic strategies and perspectives for metastatic pancreatic cancer: Vaccine therapy is more than just a theory. Cancer Cell Int., 2020, 20(1), 66.
[http://dx.doi.org/10.1186/s12935-020-1147-9] [PMID: 32158356]
[68]
Miyazawa, M.; Katsuda, M.; Maguchi, H.; Katanuma, A.; Ishii, H.; Ozaka, M.; Yamao, K.; Imaoka, H.; Kawai, M.; Hirono, S. Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients. Int. J. Cancer, 2017, 140(4), 973-982.
[http://dx.doi.org/10.1002/ijc.30510] [PMID: 27861852]
[69]
Mucileanu, A.; Chira, R.; Mircea, P.A. PD-1/PD-L1 expression in pancreatic cancer and its implication in novel therapies. Med. Pharm. Rep., 2021, 94(4), 402-410.
[http://dx.doi.org/10.15386/mpr-2116] [PMID: 36105495]
[70]
Bengsch, F.; Knoblock, D.M.; Liu, A.; McAllister, F.; Beatty, G.L. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol. Immunother., 2017, 66(12), 1609-1617.
[http://dx.doi.org/10.1007/s00262-017-2053-4] [PMID: 28856392]
[71]
Seifert, L.; Plesca, I.; Müller, L.; Sommer, U.; Heiduk, M.; von Renesse, J.; Digomann, D.; Glück, J.; Klimova, A.; Weitz, J. LAG-3-expressing tumor-infiltrating T cells are associated with reduced disease-free survival in pancreatic cancer. Cancers, 2021, 13(6), 1297.
[http://dx.doi.org/10.3390/cancers13061297] [PMID: 33803936]
[72]
Peng, P-j.; Li, Y.; Sun, S. On the significance of Tim-3 expression in pancreatic cancer. Saudi J. Biol. Sci., 2017, 24(8), 1754-1757.
[http://dx.doi.org/10.1016/j.sjbs.2017.11.006] [PMID: 29551917]
[73]
Noubissi Nzeteu, G.A.; Gibbs, B.F.; Kotnik, N.; Troja, A.; Bockhorn, M.; Meyer, N.H. Nanoparticle-based immunotherapy of pancreatic cancer. Front. Mol. Biosci., 2022, 9, 948898.
[http://dx.doi.org/10.3389/fmolb.2022.948898] [PMID: 36106025]
[74]
Hou, Z.; Pan, Y.; Fei, Q.; Lin, Y.; Zhou, Y.; Liu, Y.; Guan, H.; Yu, X.; Lin, X.; Lu, F. Prognostic significance and therapeutic potential of the immune checkpoint VISTA in pancreatic cancer. J. Cancer Res. Clin. Oncol., 2021, 147, 517-531.
[http://dx.doi.org/10.1007/s00432-020-03463-9] [PMID: 33237432]
[75]
Muth, S.T.; Saung, M.T.; Blair, A.B.; Henderson, M.G.; Thomas, D.L., II; Zheng, L. CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma. Cancer Lett., 2021, 499, 99-108.
[http://dx.doi.org/10.1016/j.canlet.2020.11.041] [PMID: 33271264]
[76]
Starzer, A.M.; Berghoff, A.S. New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO Open, 2019, 4, e000629.
[http://dx.doi.org/10.1136/esmoopen-2019-000629] [PMID: 32152062]
[77]
Yeo, D.; Giardina, C.; Saxena, P.; Rasko, J.E. The next wave of cellular immunotherapies in pancreatic cancer. Mol. Ther. Oncolytics, 2022, 24, 561-576.
[http://dx.doi.org/10.1016/j.omto.2022.01.010] [PMID: 35229033]
[78]
Lim, C.Y.; Chang, J.H.; Lee, W.S.; Kim, J.; Park, I.Y. CD40 agonists alter the pancreatic cancer microenvironment by shifting the macrophage phenotype toward M1 and suppress human pancreatic cancer in organotypic slice cultures. Gut Liver, 2022, 16(4), 645-659.
[http://dx.doi.org/10.5009/gnl210311] [PMID: 34933280]
[79]
Vence, L.; Bucktrout, S.L.; Fernandez Curbelo, I.; Blando, J.; Smith, B.M.; Mahne, A.E.; Lin, J.C.; Park, T.; Pascua, E.; Sai, T. Characterization and comparison of GITR expression in solid tumors. Clin. Cancer Res., 2019, 25(21), 6501-6510.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-0289] [PMID: 31358539]
[80]
Yadav, R.; Redmond, W.L. Current clinical trial landscape of OX40 agonists. Curr. Oncol. Rep., 2022, 24(7), 951-960.
[http://dx.doi.org/10.1007/s11912-022-01265-5] [PMID: 35352295]
[81]
Kadomoto, S.; Izumi, K.; Mizokami, A. Roles of CCL2-CCR2 axis in the tumor microenvironment. Int. J. Mol. Sci., 2021, 22(16), 8530.
[http://dx.doi.org/10.3390/ijms22168530] [PMID: 34445235]
[82]
Xu, M.; Wang, Y.; Xia, R.; Wei, Y.; Wei, X. Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting. Cell Prolif., 2021, 54(10), e13115.
[http://dx.doi.org/10.1111/cpr.13115] [PMID: 34464477]
[83]
Meireson, A.; Devos, M.; Brochez, L. Ido expression in cancer: Different compartment, different functionality? Front. Immunol., 2020, 11, 531491.
[http://dx.doi.org/10.3389/fimmu.2020.531491] [PMID: 33072086]
[84]
Shen, W.; Tao, G-Q.; Zhang, Y.; Cai, B.; Sun, J.; Tian, Z-Q. Tgf-β in pancreatic cancer initiation and progression: Two sides of the same coin. Cell Biosci., 2017, 7, 1-39.
[http://dx.doi.org/10.1186/s13578-017-0168-0] [PMID: 28794854]
[85]
Padoan, A.; Plebani, M.; Basso, D. Inflammation and pancreatic cancer: Focus on metabolism, cytokines, and immunity. Int. J. Mol. Sci., 2019, 20(3), 676.
[http://dx.doi.org/10.3390/ijms20030676] [PMID: 30764482]
[86]
Candido, J.B.; Morton, J.P.; Bailey, P.; Campbell, A.D.; Karim, S.A.; Jamieson, T.; Lapienyte, L.; Gopinathan, A.; Clark, W.; McGhee, E.J. CSF1R+ macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype. Cell Rep., 2018, 23(5), 1448-1460.
[http://dx.doi.org/10.1016/j.celrep.2018.03.131] [PMID: 29719257]
[87]
Xia, C.; Yin, S.; To, K.K.; Fu, L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol. Cancer, 2023, 22(1), 1-17.
[http://dx.doi.org/10.1186/s12943-023-01733-x] [PMID: 36859386]
[88]
Matkar, P.N.; Jong, E.D.; Ariyagunarajah, R.; Prud’homme, G.J.; Singh, K.K.; Leong-Poi, H. Jack of many trades: Multifaceted role of neuropilins in pancreatic cancer. Cancer Med., 2018, 7(10), 5036-5046.
[http://dx.doi.org/10.1002/cam4.1715] [PMID: 30216699]
[89]
Henriksen, A.; Dyhl-Polk, A.; Chen, I.; Nielsen, D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat. Rev., 2019, 78, 17-30.
[http://dx.doi.org/10.1016/j.ctrv.2019.06.005] [PMID: 31325788]
[90]
Li, H-B.; Yang, Z-H.; Guo, Q-Q. Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: Limitations and prospects: A systematic review. Cell Commun. Signal., 2021, 19, 117.
[http://dx.doi.org/10.1186/s12964-021-00789-w] [PMID: 34819086]
[91]
Darvin, P.; Toor, S.M.; Sasidharan Nair, V.; Elkord, E. Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med., 2018, 50(12), 1-11.
[http://dx.doi.org/10.1038/s12276-018-0191-1] [PMID: 30546008]
[92]
Johansson, H.; Andersson, R.; Bauden, M.; Hammes, S.; Holdenrieder, S.; Ansari, D. Immune checkpoint therapy for pancreatic cancer. World J. Gastroenterol., 2016, 22(43), 9457-9476.
[http://dx.doi.org/10.3748/wjg.v22.i43.9457] [PMID: 27920468]
[93]
Macherla, S.; Laks, S.; Naqash, A.R.; Bulumulle, A.; Zervos, E.; Muzaffar, M. Emerging role of immune checkpoint blockade in pancreatic cancer. Int. J. Mol. Sci., 2018, 19(11), 3505.
[http://dx.doi.org/10.3390/ijms19113505] [PMID: 30405053]
[94]
Bian, J.; Almhanna, K. Pancreatic cancer and immune checkpoint inhibitors—still a long way to go. Transl. Gastroenterol. Hepatol., 2021, 6.
[http://dx.doi.org/10.21037/tgh.2020.04.03] [PMID: 33409400]
[95]
Patel, K.; Siraj, S.; Smith, C.; Nair, M.; Vishwanatha, J.K.; Basha, R. Pancreatic cancer: An emphasis on current perspectives in immunotherapy. Crit. Rev. Oncog., 2019, 24(2), 105-118.
[http://dx.doi.org/10.1615/CritRevOncog.2019031417] [PMID: 31679206]
[96]
Hargadon, K.M.; Johnson, C.E.; Williams, C.J. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol., 2018, 62, 29-39.
[http://dx.doi.org/10.1016/j.intimp.2018.06.001] [PMID: 29990692]
[97]
Varghese, A.M. Chimeric antigen receptor (CAR) T and other T cell strategies for pancreas adenocarcinoma. Linchuang Zhongliuxue Zazhi, 2017, 6(6), 66-66.
[http://dx.doi.org/10.21037/cco.2017.09.04] [PMID: 29156888]
[98]
Yoon, J.H.; Jung, Y-J.; Moon, S-H. Immunotherapy for pancreatic cancer. World J. Clin. Cases, 2021, 9(13), 2969-2982.
[http://dx.doi.org/10.12998/wjcc.v9.i13.2969] [PMID: 33969083]
[99]
de Miguel, M.; Calvo, E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell, 2020, 38(3), 326-333.
[http://dx.doi.org/10.1016/j.ccell.2020.07.004] [PMID: 32750319]
[100]
Shi, Y.; Li, Y.; Wu, B.; Zhong, C.; Lang, Q.; Liang, Z.; Zhang, Y.; Lv, C.; Han, S.; Yu, Y. Normalization of tumor vasculature: A potential strategy to increase the efficiency of immune checkpoint blockades in cancers. Int. Immunopharmacol., 2022, 110, 108968.
[http://dx.doi.org/10.1016/j.intimp.2022.108968] [PMID: 35764018]

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