Pancreatic Cancer: Pathogenesis and Clinical Studies

Abstract

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS–MAPK, PI3K–AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

Keywords

pancreatic ductal adenocarcinoma / gene alteration / signaling pathways / treatment development / personalized management

References

[1] J. D. Mizrahi, R. Surana, J. W. Valle, et al., “Pancreatic Cancer,” Lancet 395, no. 10242 (2020): 2008-2020.

[2] J. X. Hu, C. F. Zhao, W. B. Chen, et al., “Pancreatic Cancer: A Review of Epidemiology, Trend, and Risk Factors,” World Journal of Gastroenterology 27, no. 27 (2021): 4298-4321.

[3] Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017; 32(2): 185-203. e13.

[4] M. H. Sherman and G. L. Beatty, “Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance,” Annual Review of Pathology 18 (2023): 123-148.

[5] N. Martinez-Bosch, J. Vinaixa, and P. Navarro, “Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy,” Cancers (Basel) 10, no. 1 (2018): 6.

[6] S. Li, A. Balmain, and C. M. Counter, “A Model for RAS Mutation Patterns in Cancers: Finding the Sweet Spot,” Nature Reviews Cancer 18, no. 12 (2018): 767-777.

[7] L. Buscail, B. Bournet, and P. Cordelier, “Role of Oncogenic KRAS in the Diagnosis, Prognosis and Treatment of Pancreatic Cancer,” Nature Reviews Gastroenterology & Hepatology 17, no. 3 (2020): 153-168.

[8] Y. Qian, Y. Gong, Z. Fan, et al., “Molecular Alterations and Targeted Therapy in Pancreatic Ductal Adenocarcinoma,” Journal of Hematology & Oncology 13, no. 1 (2020): 130.

[9] B. Song, P. Yang, and S. Zhang, “Cell Fate Regulation Governed by p53: Friends or Reversible Foes in Cancer Therapy,” Cancer Communications 44, no. 3 (2024): 297-360.

[10] D. Y. Shin, “TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited,” Cancers (Basel) 15, no. 19 (2023): 4816.

[11] J. Hu, J. Cao, W. Topatana, et al., “Targeting Mutant p53 for Cancer Therapy: Direct and Indirect Strategies,” Journal of hematology & oncology 14, no. 1 (2021): 157.

[12] C. Wu, P. Yang, B. Liu, and Y. Tang, “Is There a CDKN2A-centric Network in Pancreatic Ductal Adenocarcinoma?,” OncoTargets and Therapy 13 (2020): 2551-2562.

[13] I. Z. M. Kreuger, R. C. Slieker, T. van Groningen, and R. van Doorn, “Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma,” Journal of Investigative Dermatology 143, no. 1 (2023): 18-25. e1.

[14] X. Chen, M. A. Meyer, J. L. Kemppainen, et al., “Risk of Syndrome-Associated Cancers among First-Degree Relatives of Patients with Pancreatic Ductal Adenocarcinoma with Pathogenic or Likely Pathogenic Germline Variants,” JAMA oncology 9, no. 7 (2023): 955-961.

[15] G. Bagias, P. Kanavidis, M. Vailas, et al., “Surgical Management of Familial Pancreatic Cancer: A Systematic Review of the Literature,” Anz Journal of Surgery 92, no. 11 (2022): 2816-2821.

[16] O. Li, L. Li, Y. Sheng, et al., “Biological Characteristics of Pancreatic Ductal Adenocarcinoma: Initiation to Malignancy, Intracellular to Extracellular,” Cancer Letters 574 (2023): 216391.

[17] T. K. Hayes, E. Aquilanti, N. S. Persky, et al., “Comprehensive Mutational Scanning of EGFR Reveals TKI Sensitivities of Extracellular Domain Mutants,” Nature Communications 15, no. 1 (2024): 2742.

[18] S. S. Hassanein, A. L. Abdel-Mawgood, and S. A. Ibrahim, “EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer,” Frontiers in Oncology 11 (2021): 766659.

[19] G. C. Russo, A. J. Crawford, D. Clark, et al., “E-cadherin Interacts With EGFR Resulting in Hyper-activation of ERK in Multiple Models of Breast Cancer,” Oncogene 43, no. 19 (2024): 1445-1462.

[20] R. B. Corcoran, H. Ebi, A. B. Turke, et al., “EGFR-mediated Re-activation of MAPK Signaling Contributes to Insensitivity of BRAF Mutant Colorectal Cancers to RAF Inhibition With Vemurafenib,” Cancer discovery 2, no. 3 (2012): 227-235.

[21] L. Su, S. Wu, C. Huang, et al., “Chemoresistant Fibroblasts Dictate Neoadjuvant Chemotherapeutic Response of Head and Neck Cancer via TGFα-EGFR Paracrine Signaling,” NPJ Precision Oncology 7, no. 1 (2023): 102.

[22] A. Misra, C. Pandey, S. K. Sze, and T. Thanabalu, “Hypoxia Activated EGFR Signaling Induces Epithelial to Mesenchymal Transition (EMT),” PLoS ONE 7, no. 11 (2012): e49766.

[23] Q. Wang, A. Zeng, M. Zhu, and L. Song, “Dual Inhibition of EGFR‑VEGF: An Effective Approach to the Treatment of Advanced Non‑Small Cell Lung Cancer With EGFR Mutation (Review),” International Journal of Oncology 62, no. 2 (2023): 26.

[24] G. J. Yoshida, “Regulation of Heterogeneous Cancer-associated Fibroblasts: The Molecular Pathology of Activated Signaling Pathways,” Journal of Experimental & Clinical Cancer Research 39, no. 1 (2020): 112.

[25] A. K. Murugan, M. Grieco, and N. Tsuchida, “RAS Mutations in human Cancers: Roles in Precision Medicine,” Seminars in Cancer Biology 59 (2019): 23-35.

[26] I. Ozkan-Dagliyan, J. N. Diehl, S. D. George, et al., “Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers,” Cell Reports 31, no. 11 (2020): 107764.

[27] R. Ullah, Q. Yin, A. H. Snell, and L. Wan, “RAF-MEK-ERK Pathway in Cancer Evolution and Treatment,” Seminars in Cancer Biology 85 (2022): 123-154.

[28] Y. Qi, T. Zhao, R. Li, and M. Han, “Macrophage-Secreted S100A4 Supports Breast Cancer Metastasis by Remodeling the Extracellular Matrix in the Premetastatic Niche,” BioMed Research International 2022 (2022): 9895504.

[29] F. Zhao, C. Falk, W. Osen, M. Kato, D. Schadendorf, and V. Umansky, “Activation of p38 Mitogen-activated Protein Kinase Drives Dendritic Cells to Become Tolerogenic in Ret Transgenic Mice Spontaneously Developing Melanoma,” Clinical Cancer Research 15, no. 13 (2009): 4382-4390.

[30] Y. Hu, Y. Lu, F. Xing, and W. Hsu, “FGFR1/MAPK-directed Brachyury Activation Drives PD-L1-mediated Immune Evasion to Promote Lung Cancer Progression,” Cancer Letters 547 (2022): 215867.

[31] M. Hu, J. Xu, L. Shi, L. Shi, H. Yang, and Y. Wang, “The p38 MAPK/Snail Signaling Axis Participates in Cadmium-induced Lung Cancer Cell Migration and Invasiveness,” Environmental Science and Pollution Research International 31, no. 16 (2024): 24042-24050.

[32] N. Y. Li, C. E. Weber, P. Y. Wai, et al., “An MAPK-dependent Pathway Induces Epithelial-mesenchymal Transition via Twist Activation in human Breast Cancer Cell Lines,” Surgery 154, no. 2 (2013): 404-410.

[33] A. Glaviano, A. S. C. Foo, H. Y. Lam, et al., “PI3K/AKT/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer,” Molecular cancer 22, no. 1 (2023): 138.

[34] M. Yang, Y. Lu, W. Piao, and H. Jin, “The Translational Regulation in mTOR Pathway,” Biomolecules 12, no. 6 (2022): 802.

[35] H. C. Zheng, “The Molecular Mechanisms of Chemoresistance in Cancers,” Oncotarget 8, no. 35 (2017): 59950-59964.

[36] M. Li, F. Liu, F. Zhang, et al., “Genomic ERBB2/ERBB3 Mutations Promote PD-L1-mediated Immune Escape in Gallbladder Cancer: A Whole-exome Sequencing Analysis,” Gut 68, no. 6 (2019): 1024-1033.

[37] G. Zhang, G. Zheng, H. Zhang, and L. Qiu, “MUC1 induces the Accumulation of Foxp3+ Treg Cells in the Tumor Microenvironment to Promote the Growth and Metastasis of Cholangiocarcinoma Through the EGFR/PI3K/Akt Signaling Pathway,” International Immunopharmacology 118 (2023): 110091.

[38] W. Shen, G. Q. Tao, Y. Zhang, B. Cai, J. Sun, and Z. Q. Tian, “TGF-β in Pancreatic Cancer Initiation and Progression: Two Sides of the Same Coin,” Cell & Bioscience 7 (2017): 39.

[39] D. L. Marvin, J. Dijkstra, R. M. Zulfiqar, M. Vermeulen, P. Ten Dijke, and L. Ritsma, “TGF-β Type I Receptor Signaling in Melanoma Liver Metastases Increases Metastatic Outgrowth,” International Journal of Molecular Sciences 24, no. 10 (2023): 8676.

[40] H. H. Yang, J. W. Liu, J. H. Lee, H. J. Harn, and T. W. Chiou, “Pancreatic Adenocarcinoma Therapeutics Targetinag RTK and TGF Beta Receptor,” International Journal of Molecular Sciences 22, no. 15 (2021): 8125.

[41] S. H. Wrzesinski, Y. Y. Wan, and R. A. Flavell, “Transforming Growth Factor-beta and the Immune Response: Implications for Anticancer Therapy,” Clinical Cancer Research 13, no. 18 Pt 1 (2007): 5262-5270.

[42] J. Liu, Q. Xiao, J. Xiao, et al., “Wnt/β-catenin Signalling: Function, Biological Mechanisms, and Therapeutic Opportunities,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 3.

[43] J. Bian, M. Dannappel, C. Wan, and R. Firestein, “Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer,” Cells 9, no. 9 (2020): 2125.

[44] C. Disoma, Y. Zhou, S. Li, J. Peng, and Z. Xia, “Wnt/β-catenin Signaling in Colorectal Cancer: Is Therapeutic Targeting Even Possible?,” Biochimie 195 (2022): 39-53.

[45] Ram Makena M, H. Gatla, D. Verlekar, S. Sukhavasi, M. K Pandey, and K. C Pramanik, “Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance,” International Journal of Molecular Sciences 20, no. 17 (2019): 4242.

[46] H. Z. Cao, X. F. Liu, W. T. Yang, Q. Chen, and P. S. Zheng, “LGR5 promotes Cancer Stem Cell Traits and Chemoresistance in Cervical Cancer,” Cell Death & Disease 8, no. 9 (2017): e3039.

[47] B. T. MacDonald, K. Tamai, and X. He, “Wnt/Beta-catenin Signaling: Components, Mechanisms, and Diseases,” Developmental Cell 17, no. 1 (2009): 9-26.

[48] Y. Zhang and X. Wang, “Targeting the Wnt/β-catenin Signaling Pathway in Cancer,” Journal of Hematology & Oncology 13, no. 1 (2020): 165.

[49] M. Kanda, Y. Kasahara, D. Shimizu, et al., “Dual-modified Antisense Oligonucleotides Targeting Oncogenic Protocadherin to Treat Gastric Cancer,” British Journal of Cancer 131, no. 9 (2024): 1555-1566.

[50] G. Q. Zhu, Y. Wang, B. Wang, et al., “Targeting HNRNPM Inhibits Cancer Stemness and Enhances Antitumor Immunity in Wnt-activated Hepatocellular Carcinoma,” Cellular and Molecular Gastroenterology and Hepatology 13, no. 5 (2022): 1413-1447.

[51] I. Espinoza and L. Miele, “Deadly Crosstalk: Notch Signaling at the Intersection of EMT and Cancer Stem Cells,” Cancer Letters 341, no. 1 (2013): 41-45.

[52] J. Ma, J. Xia, L. Miele, F. H. Sarkar, and Z. Wang, “Notch Signaling Pathway in Pancreatic Cancer Progression,” Pancreatic Disorders & Therapy 3, no. 114 (2013): 1000114.

[53] L. Yang, P. Shi, G. Zhao, et al., “Targeting Cancer Stem Cell Pathways for Cancer Therapy,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 8.

[54] X. Du, Y. P. Zhao, T. P. Zhang, et al., “Alteration of the Intrinsic Apoptosis Pathway Is Involved in Notch-induced Chemoresistance to Gemcitabine in Pancreatic Cancer,” Archives of Medical Research 45, no. 1 (2014): 15-20.

[55] L. Yu and W. Li, “Abnormal Activation of Notch 1 Signaling Causes Apoptosis Resistance in Cervical Cancer,” International Journal of Clinical and Experimental Pathology 15, no. 1 (2022): 11-19.

[56] B. D. Giaimo, F. Ferrante, D. M. Vallejo, et al., “Histone Variant H2A.Z Deposition and Acetylation Directs the Canonical Notch Signaling Response,” Nucleic Acids Res. 46, no. 16 (2018): 8197-8215.

[57] S. Han, C. Cao, R. Liu, et al., “GAS41 mediates Proliferation and GEM Chemoresistance via H2A.Z.2 and Notch1 in Pancreatic Cancer,” Cellular Oncology 45, no. 3 (2022): 429-446.

[58] M. Unno, F. Motoi, and Y. Matsuyama, “Randomized Phase II/III Trial of Neoadjuvant Chemotherapy With Gemcitabine and S-1 versus Upfront Surgery for Resectable Pancreatic Cancer (Prep-02/JSAP-05),” Journal of Clinical Oncology 37, no. 4_suppl (2019): 189-189.

[59] D. P. S. Sohal, M. Duong, S. A. Ahmad, et al., “Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial,” JAMA oncology 7, no. 3 (2021): 421-427.

[60] P. Ghaneh, D. Palmer, S. Cicconi, et al., “Immediate Surgery Compared With Short-course Neoadjuvant Gemcitabine plus Capecitabine, FOLFIRINOX, or Chemoradiotherapy in Patients With Borderline Resectable Pancreatic Cancer (ESPAC5): A Four-arm, Multicentre, Randomised, Phase 2 Trial,” Lancet Gastroenterol Hepatol 8, no. 2 (2023): 157-168.

[61] D. Yamada, S. Kobayashi, H. Takahashi, et al., “Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015),” Annals of Surgical Oncology 31, no. 7 (2024): 4621-4633.

[62] E. Versteijne, J. L. van Dam, M. Suker, et al., “Neoadjuvant Chemoradiotherapy versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial,” Journal of Clinical Oncology 40, no. 11 (2022): 1220-1230.

[63] C. Bascoul-Mollevi, S. Gourgou, C. Borg, et al. Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2): A multicenter randomized controlled trial. 2023 ESMO LBA83.

[64] M. H. G. Katz, Q. Shi, J. Meyers, et al., “Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial,” JAMA oncology 8, no. 9 (2022): 1263-1270.

[65] J. P. Neoptolemos, D. D. Stocken, H. Friess, et al., “A Randomized Trial of Chemoradiotherapy and Chemotherapy After Resection of Pancreatic Cancer,” New England Journal of Medicine 350, no. 12 (2004): 1200-1210.

[66] H. Oettle, P. Neuhaus, A. Hochhaus, et al., “Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer: The CONKO-001 Randomized Trial,” Jama 310, no. 14 (2013): 1473-1481.

[67] M. Sinn, M. Bahra, T. Liersch, et al., “CONKO-005: Adjuvant Chemotherapy with Gemcitabine plus Erlotinib versus Gemcitabine Alone in Patients after R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial,” Journal of Clinical Oncology 35, no. 29 (2017): 3330-3337.

[68] J. P. Neoptolemos, D. D. Stocken, C. Bassi, et al., “Adjuvant Chemotherapy With Fluorouracil plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial,” Jama 304, no. 10 (2010): 1073-1081.

[69] J. P. Neoptolemos, D. H. Palmer, P. Ghaneh, 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 389, no. 10073 (2017): 1011-1024.

[70] K. Uesaka, N. Boku, A. Fukutomi, et al., “Adjuvant Chemotherapy of S-1 versus Gemcitabine for Resected Pancreatic Cancer: A Phase 3, Open-label, Randomised, Non-inferiority Trial (JASPAC 01),” Lancet 388, no. 10041 (2016): 248-257.

[71] T. Conroy, P. Hammel, M. Hebbar, et al., “FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer,” New England Journal of Medicine 379, no. 25 (2018): 2395-2406.

[72] M. A. Tempero, U. Pelzer, E. M. O'Reilly, et al., “Adjuvant Nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized, Open-Label, Phase III Trial,” Journal of Clinical Oncology 41, no. 11 (2023): 2007-2019.

[73] D. Cunningham, I. Chau, D. D. Stocken, et al., “Phase III Randomized Comparison of Gemcitabine versus Gemcitabine plus Capecitabine in Patients With Advanced Pancreatic Cancer,” Journal of Clinical Oncology 27, no. 33 (2009): 5513-5518.

[74] T. Conroy, F. Desseigne, M. Ychou, et al., “FOLFIRINOX versus gemcitabine for Metastatic Pancreatic Cancer,” New England Journal of Medicine 364, no. 19 (2011): 1817-1825.

[75] D. D. Von Hoff, T. Ervin, F. P. Arena, et al., “Increased Survival in Pancreatic Cancer With Nab-paclitaxel plus Gemcitabine,” New England Journal of Medicine 369, no. 18 (2013): 1691-1703.

[76] A. Wang-Gillam, C. P. Li, G. Bodoky, 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 387, no. 10018 (2016): 545-557.

[77] Z. A. Wainberg, D. Melisi, T. Macarulla, et al., “NALIRIFOX versus nab-paclitaxel and gemcitabine in Treatment-naive Patients With Metastatic Pancreatic Ductal Adenocarcinoma (NAPOLI 3): A Randomised, Open-label, Phase 3 Trial,” Lancet 402, no. 10409 (2023): 1272-1281.

[78] T. Seufferlein, W. Uhl, M. Kornmann, et al., “Perioperative or Only Adjuvant Gemcitabine plus Nab-paclitaxel for Resectable Pancreatic Cancer (NEONAX)-a Randomized Phase II Trial of the AIO Pancreatic Cancer Group,” Annals of Oncology 34, no. 1 (2023): 91-100.

[79] P. L. S. Uson Junior, D. Dias E Silva, N. M. de Castro, et al., “Does Neoadjuvant Treatment in Resectable Pancreatic Cancer Improve Overall Survival? A Systematic Review and Meta-analysis of Randomized Controlled Trials,” ESMO Open 8, no. 1 (2023): 100771.

[80] H. Ueno, T. Ioka, M. Ikeda, 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,” Journal of Clinical Oncology 31, no. 13 (2013): 1640-1648.

[81] H. A. Burris, M. J. Moore, J. Andersen, et al., “Improvements in Survival and Clinical Benefit with Gemcitabine as First-Line Therapy for Patients with Advanced Pancreas Cancer: A Randomized Trial,” Journal of Clinical Oncology 41, no. 36 (2023): 5482-5492.

[82] F. Moradi Kashkooli, M. Soltani, and M. Souri, “Controlled Anti-cancer Drug Release Through Advanced Nano-drug Delivery Systems: Static and Dynamic Targeting Strategies,” Journal of Controlled Release 327 (2020): 316-349.

[83] G. S. Jameson, E. Borazanci, H. M. Babiker, et al., “Response Rate Following Albumin-Bound Paclitaxel plus Gemcitabine plus Cisplatin Treatment among Patients with Advanced Pancreatic Cancer: A Phase 1b/2 Pilot Clinical Trial,” JAMA oncology 6, no. 1 (2020): 125-132.

[84] K. L. Aung, S. E. Fischer, R. E. Denroche, et al., “Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results From the COMPASS Trial,” Clinical Cancer Research 24, no. 6 (2018): 1344-1354.

[85] G. M. O'Kane, B. T. Grünwald, G. H. Jang, et al., “GATA6 Expression Distinguishes Classical and Basal-Like Subtypes in Advanced Pancreatic Cancer,” Clinical Cancer Research 26, no. 18 (2020): 4901-4910.

[86] J. Fuentes Antrás, G. H. Jang, J. T. Topham, et al., “Molecular Characterization of Long-term and Short-term Survivors of Advanced Pancreatic Ductal Adenocarcinoma,” Journal of Clinical Oncology 40, no. 16_suppl (2022): 4024.

[87] J. H. Park, J. H. Jo, S. I. Jang, et al., “BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX With Pancreatic Ductal Adenocarcinoma in Korean Patients,” Cancers (Basel) 14, no. 1 (2022): 236.

[88] K. A. Reiss, S. Yu, R. Judy, H. Symecko, K. L. Nathanson, and S. M. Domchek, “Retrospective Survival Analysis of Patients with Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations,” JCO Precision Oncology 2 (2018): 1-9.

[89] J. König, M. Hartel, A. T. Nies, et al., “Expression and Localization of human Multidrug Resistance Protein (ABCC) family Members in Pancreatic Carcinoma,” International Journal of Cancer 115, no. 3 (2005): 359-367.

[90] W. Zhang, H. Chen, D. L. Liu, et al., “Emodin Sensitizes the Gemcitabine-resistant Cell Line Bxpc-3/Gem to Gemcitabine via Downregulation of NF-κB and Its Regulated Targets,” International Journal of Oncology 42, no. 4 (2013): 1189-1196.

[91] S. Nath, K. Daneshvar, L. D. Roy, et al., “MUC1 induces Drug Resistance in Pancreatic Cancer Cells via Upregulation of Multidrug Resistance Genes,” Oncogenesis 2, no. 6 (2013): e51.

[92] H. ang, R. Ren, Z. Yang, J. Cai, S. Du, and X. Shen, “The COL11A1/Akt/CREB Signaling Axis Enables Mitochondrial-mediated Apoptotic Evasion to Promote Chemoresistance in Pancreatic Cancer Cells Through Modulating BAX/BCL-2 Function,” Journal of Cancer 12, no. 5 (2021): 1406-1420.

[93] J. Dong, Y. P. Zhao, L. Zhou, T. P. Zhang, and G. Chen, “Bcl-2 Upregulation Induced by miR-21 via a Direct Interaction Is Associated With Apoptosis and Chemoresistance in MIA PaCa-2 Pancreatic Cancer Cells,” Archives of Medical Research 42, no. 1 (2011): 8-14.

[94] Y. Fu, F. Ricciardiello, G. Yang, et al., “The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells,” Cells 10, no. 3 (2021): 497.

[95] H. Masuo, K. Kubota, A. Shimizu, et al., “Increased Mitochondria Are Responsible for the Acquisition of Gemcitabine Resistance in Pancreatic Cancer Cell Lines,” Cancer Science 114, no. 11 (2023): 4388-4400.

[96] H. Sato, T. Hara, S. Meng, et al., “Multifaced Roles of Desmoplastic Reaction and Fibrosis in Pancreatic Cancer Progression: Current Understanding and Future Directions,” Cancer Science 114, no. 9 (2023): 3487-3495.

[97] B. Erdogan and D. J. Webb, “Cancer-associated Fibroblasts Modulate Growth Factor Signaling and Extracellular Matrix Remodeling to Regulate Tumor Metastasis,” Biochemical Society Transactions 45, no. 1 (2017): 229-236.

[98] P. P. Provenzano, C. Cuevas, A. E. Chang, V. K. Goel, D. D. Von Hoff, and S. R. Hingorani, “Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma,” Cancer Cell 21, no. 3 (2012): 418-429.

[99] C. J. Whatcott, C. H. Diep, P. Jiang, et al., “Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer,” Clinical Cancer Research 21, no. 15 (2015): 3561-3568.

[100] NCCN® Clinical Practice Guidelines in Oncology. Hematopoietic growth factors. V3.2024. National Comprehensive Cancer Network website. Accessed on 1 October 2024, https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf.

[101] S. A. Wondm, F. B. Tamene, K. Gubae, S. B. Dagnew, A. A. Worku, and E. A. Belachew, “Potential Drug-drug Interaction and Its Determinants Among Patients With Cancer Receiving Chemotherapy in Oncology Centres of Northwest Ethiopia: An Institutional-based Cross-sectional Study,” BMJ Open 13, no. 12 (2023): e077863.

[102] Y. Y. Lu, D. D. Jing, M. Xu, K. Wu, and X. P. Wang, “Anti-tumor Activity of erlotinib in the BxPC-3 Pancreatic Cancer Cell Line,” World Journal of Gastroenterology 14, no. 35 (2008): 5403-5411.

[103] X. Zhou, M. Zheng, F. Chen, et al., “Gefitinib Inhibits the Proliferation of Pancreatic Cancer Cells via Cell Cycle Arrest,” Anat Rec (Hoboken) 292, no. 8 (2009): 1122-1127.

[104] N. Ioannou, A. G. Dalgleish, A. M. Seddon, et al., “Anti-tumour Activity of afatinib, an Irreversible ErbB family Blocker, in human Pancreatic Tumour Cells,” British Journal of Cancer 105, no. 10 (2011): 1554-1562.

[105] J. P. Overholser, M. C. Prewett, A. T. Hooper, et al., “Epidermal Growth Factor Receptor Blockade by Antibody IMC-C225 Inhibits Growth of a human Pancreatic Carcinoma Xenograft in Nude Mice,” Cancer 89, no. 1 (2000): 74-82.

[106] C. Zhou, L. Zhu, J. Ji, et al., “EGFR High Expression, but Not KRAS Status, Predicts Sensitivity of Pancreatic Cancer Cells to Nimotuzumab Treatment in Vivo,” Current Cancer Drug Targets 17, no. 1 (2017): 89-97.

[107] D. K. Menyhárd, G. Pálfy, Z. Orgován, I. Vida, G. M. Keserű, and A. Perczel, “Structural Impact of GTP Binding on Downstream KRAS Signaling,” Chemical Science 11, no. 34 (2020): 9272-9289.

[108] J. C. Tran, T. Hunsaker, C. Bell, et al., “Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry,” Analytical Chemistry 95, no. 11 (2023): 4834-4839.

[109] J. Hallin, V. Bowcut, A. Calinisan, et al., “Anti-tumor Efficacy of a Potent and Selective Non-covalent KRASG12D Inhibitor,” Nature Medicine 28, no. 10 (2022): 2171-2182.

[110] Y. W. Kang, J. E. Lee, K. H. Jung, et al., “KRAS Targeting Antibody Synergizes Anti-cancer Activity of Gemcitabine Against Pancreatic Cancer,” Cancer Letters 438 (2018): 174-186.

[111] J. E. Lee, Y. W. Kang, K. H. Jung, et al., “Intracellular KRAS-specific Antibody Enhances the Anti-tumor Efficacy of Gemcitabine in Pancreatic Cancer by Inducing Endosomal Escape,” Cancer Letters 507 (2021): 97-111.

[112] D. Kim, L. Herdeis, D. Rudolph, et al., “Pan-KRAS Inhibitor Disables Oncogenic Signalling and Tumour Growth,” Nature 619, no. 7968 (2023): 160-166.

[113] U. N. Wasko, J. Jiang, T. C. Dalton, et al., “Tumour-selective Activity of RAS-GTP Inhibition in Pancreatic Cancer,” Nature 629, no. 8013 (2024): 927-936.

[114] J. Jiang, L. Jiang, B. J. Maldonato, et al., “Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers,” Cancer discovery 14, no. 6 (2024): 994-1017.

[115] M. Lee, I. G. Je, J. E. Kim, et al., “Venadaparib Is a Novel and Selective PARP Inhibitor With Improved Physicochemical Properties, Efficacy, and Safety,” Molecular Cancer Therapeutics 22, no. 3 (2023): 333-342.

[116] A. Herencia-Ropero, A. Llop-Guevara, A. D. Staniszewska, et al., “The PARP1 Selective Inhibitor saruparib (AZD5305) Elicits Potent and Durable Antitumor Activity in Patient-derived BRCA1/2-associated Cancer Models,” Genome Medicine 16, no. 1 (2024): 107.

[117] P. Ulivi, C. Arienti, W. Zoli, et al., “In Vitro and in Vivo Antitumor Efficacy of docetaxel and sorafenib Combination in human Pancreatic Cancer Cells,” Current Cancer Drug Targets 10, no. 6 (2010): 600-610.

[118] K. C. Cuneo, L. Geng, A. Fu, D. Orton, D. E. Hallahan, and A. B. Chakravarthy, “SU11248 (sunitinib) sensitizes Pancreatic Cancer to the Cytotoxic Effects of Ionizing Radiation,” International Journal of Radiation and Oncology in Biology and Physics 71, no. 3 (2008): 873-879.

[119] D. Brauswetter, B. Gurbi, A. Varga, et al., “Molecular Subtype Specific Efficacy of MeK Inhibitors in Pancreatic Cancers,” PLoS ONE 12, no. 9 (2017): e0185687.

[120] C. Moser, P. Schachtschneider, S. A. Lang, et al., “Inhibition of Insulin-Like Growth Factor-I Receptor (IGF-IR) Using NVP-AEW541, a Small Molecule Kinase Inhibitor, Reduces Orthotopic Pancreatic Cancer Growth and Angiogenesis,” European Journal of Cancer 44, no. 11 (2008): 1577-1586.

[121] P. J. Beltran, P. Mitchell, Y. A. Chung, et al., “AMG 479, a Fully human Anti-insulin-Like Growth Factor Receptor Type I Monoclonal Antibody, Inhibits the Growth and Survival of Pancreatic Carcinoma Cells,” Molecular Cancer Therapeutics 8, no. 5 (2009): 1095-1105.

[122] W. C. Yen, M. M. Fischer, F. Axelrod, et al., “Targeting Notch Signaling With a Notch2/Notch3 Antagonist (tarextumab) Inhibits Tumor Growth and Decreases Tumor-initiating Cell Frequency,” Clinical Cancer Research 21, no. 9 (2015): 2084-2095.

[123] R. Plentz, J. S. Park, A. D. Rhim, et al., “Inhibition of Gamma-secretase Activity Inhibits Tumor Progression in a Mouse Model of Pancreatic Ductal Adenocarcinoma,” Gastroenterology 136, no. 5 (2009): 1741-1749. e6.

[124] J. E. Lee, P. Lee, Y. C. Yoon, et al., “Vactosertib, TGF-β Receptor I Inhibitor, Augments the Sensitization of the Anti-cancer Activity of Gemcitabine in Pancreatic Cancer,” Biomedicine & Pharmacotherapy 162 (2023): 114716.

[125] O. Rencuzogulları, P. O. Yerlikaya, A. Ç. Gürkan, E. D. Arısan, and D. Telci, “Palbociclib, a Selective CDK4/6 Inhibitor, Restricts Cell Survival and Epithelial-mesenchymal Transition in Panc-1 and MiaPaCa-2 Pancreatic Cancer Cells,” Journal of Cellular Biochemistry 121, no. 1 (2020): 508-523.

[126] M. Hidalgo, R. Garcia-Carbonero, K. H. Lim, et al., “A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients With Metastatic Adenocarcinoma of the Pancreas,” Cancer Research Communications 2, no. 11 (2022): 1326-1333.

[127] C. M. Goodwin, A. M. Waters, J. E. Klomp, et al., “Combination Therapies With CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer,” Cancer Research 83, no. 1 (2023): 141-157.

[128] S. Bhutkar, A. Yadav, H. Patel, S. Barot, K. Patel, and V. V. Dukhande, “Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells,” Cancers (Basel) 16, no. 15 (2024): 2713.

[129] L. Huang and L. Fu, “Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors,” Acta Pharmaceutica Sinica B 5, no. 5 (2015): 390-401.

[130] M. J. Moore, D. Goldstein, J. Hamm, 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,” Journal of Clinical Oncology 25, no. 15 (2007): 1960-1966.

[131] H. Tang, Y. Xue, B. Li, et al., “Membrane-camouflaged Supramolecular Nanoparticles for co-delivery of Chemotherapeutic and Molecular-targeted Drugs With siRNA Against Patient-derived Pancreatic Carcinoma,” Acta Pharmaceutica Sinica B 12, no. 8 (2022): 3410-3426.

[132] J. Maurel, M. Martin-Richard, C. Conill, et al., “Phase I Trial of gefitinib With Concurrent Radiotherapy and Fixed 2-h Gemcitabine Infusion, in Locally Advanced Pancreatic Cancer,” International Journal of Radiation and Oncology in Biology and Physics 66, no. 5 (2006): 1391-1398.

[133] J. M. Brell, K. Matin, T. Evans, et al., “Phase II Study of docetaxel and gefitinib as Second-line Therapy in Gemcitabine Pretreated Patients With Advanced Pancreatic Cancer,” Oncology 76, no. 4 (2009): 270-274.

[134] M. Ignatiadis, A. Polyzos, G. P. Stathopoulos, et al., “A Multicenter Phase II Study of docetaxel in Combination With gefitinib in Gemcitabine-pretreated Patients With Advanced/Metastatic Pancreatic Cancer,” Oncology 71, no. 3-4 (2006): 159-163.

[135] H. Wecker and C. F. Waller, “Afatinib,” Recent Results in Cancer Research 211 (2018): 199-215.

[136] M. Haas, D. T. Waldschmidt, M. Stahl, et al., “Afatinib plus Gemcitabine versus Gemcitabine Alone as firs T-line Treatment of Metastatic Pancreatic Cancer: The Randomised, Open-label Phase II ACCEPT Study of the Arbeitsgemeinschaft Internistische Onkologie With an Integrated Analysis of the ‘Burden of Therapy’ method,” European Journal of Cancer 146 (2021): 95-106.

[137] M. R. Jones, L. M. Williamson, J. T. Topham, et al., “NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma,” Clinical Cancer Research 25, no. 15 (2019): 4674-4681.

[138] Y. Du, Y. Chen, Y. Wang, et al., “HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC That Overcomes Osimertinib-Resistant EGFR Triple Mutations,” Molecular Cancer Therapeutics 21, no. 7 (2022): 1060-1066.

[139] K. Kashima, H. Kawauchi, H. Tanimura, et al., “CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation,” Molecular Cancer Therapeutics 19, no. 11 (2020): 2288-2297.

[140] S. Suzuki, M. Yamamoto, T. Sanomachi, et al., “Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing,” Biomedicines 8, no. 8 (2020): 273.

[141] S. Cascinu, R. Berardi, R. Labianca, et al., “Cetuximab plus Gemcitabine and Cisplatin Compared With Gemcitabine and Cisplatin Alone in Patients With Advanced Pancreatic Cancer: A Randomised, Multicentre, Phase II Trial,” The Lancet Oncology 9, no. 1 (2008): 39-44.

[142] F. Kullmann, S. Hollerbach, M. M. Dollinger, et al., “Cetuximab plus Gemcitabine/Oxaliplatin (GEMOXCET) in First-line Metastatic Pancreatic Cancer: A Multicentre Phase II Study,” British Journal of Cancer 100, no. 7 (2009): 1032-1036.

[143] B. Burtness, M. Powell, P. Catalano, et al., “Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel plus Cetuximab for Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study,” American Journal of Clinical Oncology 39, no. 4 (2016): 340-345.

[144] M. J. Sorich, M. D. Wiese, A. Rowland, et al., “Extended RAS Mutations and Anti-EGFR Monoclonal Antibody Survival Benefit in Metastatic Colorectal Cancer: A Meta-analysis of Randomized, Controlled Trials,” Annals of Oncology 26, no. 1 (2015): 13-21.

[145] S. B. Dreyer, D. K. Chang, P. Bailey, et al., “Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development,” Clinical Cancer Research 23, no. 7 (2017): 1638-1646.

[146] M. Iida, T. M. Brand, M. M. Starr, et al., “Overcoming Acquired Resistance to cetuximab by Dual Targeting HER family Receptors With Antibody-based Therapy,” Molecular cancer 13 (2014): 242.

[147] M. Iida, H. Bahrar, T. M. Brand, et al., “Targeting the HER Family With Pan-HER Effectively Overcomes Resistance to Cetuximab,” Molecular Cancer Therapeutics 15, no. 9 (2016): 2175-2186.

[148] E. Assenat, D. Azria, C. Mollevi, et al., “Dual Targeting of HER1/EGFR and HER2 With Cetuximab and Trastuzumab in Patients With Metastatic Pancreatic Cancer After Gemcitabine Failure: Results of the “THERAPY”Phase 1-2 Trial,” Oncotarget 6, no. 14 (2015): 12796-12808.

[149] D. Su, S. C. Jiao, L. J. Wang, et al., “Efficacy of Nimotuzumab plus Gemcitabine Usage as First-line Treatment in Patients With Advanced Pancreatic Cancer,” Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine 35, no. 3 (2014): 2313-2318.

[150] D. Strumberg, B. Schultheis, M. E. Scheulen, et al., “Phase II Study of nimotuzumab, a Humanized Monoclonal Anti-epidermal Growth Factor Receptor (EGFR) Antibody, in Patients With Locally Advanced or Metastatic Pancreatic Cancer,” Investigational New Drugs 30, no. 3 (2012): 1138-1143.

[151] B. Schultheis, D. Reuter, M. P. Ebert, et al., “Gemcitabine Combined With the Monoclonal Antibody Nimotuzumab Is an Active First-line Regimen in KRAS Wildtype Patients With Locally Advanced or Metastatic Pancreatic Cancer: A Multicenter, Randomized Phase IIb Study,” Annals of Oncology 28, no. 10 (2017): 2429-2435.

[152] S. Qin, J. Li, Y. Bai, et al., “Nimotuzumab plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer,” Journal of Clinical Oncology 41, no. 33 (2023): 5163-5173.

[153] J. Remon, C. E. Steuer, S. S. Ramalingam, and E. Felip, “Osimertinib and Other Third-generation EGFR TKI in EGFR-mutant NSCLC Patients,” Annals of Oncology 29, no. suppl_1 (2018): i20-i27.

[154] M. S. Eno, J. D. Brubaker, J. E. Campbell, et al., “Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer,” Journal of Medicinal Chemistry 65, no. 14 (2022): 9662-9677.

[155] F. Gonzalvez, S. Vincent, T. E. Baker, et al., “Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer,” Cancer discovery 11, no. 7 (2021): 1672-1687.

[156] C. Zhou, S. S. Ramalingam, T. M. Kim, et al., “Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients with EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial,” JAMA oncology 7, no. 12 (2021): e214761.

[157] C. R. Chong and P. A. Jänne, “The Quest to Overcome Resistance to EGFR-targeted Therapies in Cancer,” Nature Medicine 19, no. 11 (2013): 1389-1400.

[158] M. T. Blasco, C. Navas, G. Martín-Serrano, et al., “Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas Upon Combined Inhibition of EGFR and C-RAF,” Cancer Cell 35, no. 4 (2019): 573-587. e6.

[159] K. Suda, H. Mizuuchi, Y. Maehara, and T. Mitsudomi, “Acquired Resistance Mechanisms to Tyrosine Kinase Inhibitors in Lung Cancer With Activating Epidermal Growth Factor Receptor Mutation-diversity, Ductility, and Destiny,” Cancer and Metastasis Reviews 31, no. 3-4 (2012): 807-814.

[160] L. V. Sequist, B. A. Waltman, D. Dias-Santagata, et al., “Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors,” Science Translational Medicine 3, no. 75 (2011): 75ra26.

[161] Z. Zhang, J. C. Lee, L. Lin, et al., “Activation of the AXL Kinase Causes Resistance to EGFR-targeted Therapy in Lung Cancer,” Nature Genetics 44, no. 8 (2012): 852-860.

[162] L. Wang, G. Zhang, L. Qin, et al., “Anti-EGFR Binding Nanobody Delivery System to Improve the Diagnosis and Treatment of Solid Tumours,” Recent Patents on Anti-Cancer Drug Discovery 15, no. 3 (2020): 200-211.

[163] J. Sharifi, M. R. Khirehgesh, F. Safari, and B. Akbari, “EGFR and Anti-EGFR Nanobodies: Review and Update,” Journal of Drug Targeting 29, no. 4 (2021): 387-402.

[164] A. Indini, E. Rijavec, M. Ghidini, A. Cortellini, and F. Grossi, “Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors,” Pharmaceutics 13, no. 5 (2021): 653.

[165] M. Choi, H. Bien, A. Mofunanya, and S. Powers, “Challenges in Ras Therapeutics in Pancreatic Cancer,” Seminars in Cancer Biology 54 (2019): 101-108.

[166] M. R. Lee, S. M. Woo, M. K. Kim, et al., “Application of Plasma Circulating KRAS Mutations as a Predictive Biomarker for Targeted Treatment of Pancreatic Cancer,” Cancer Science 115, no. 4 (2024): 1283-1295.

[167] F. Skoulidis, B. T. Li, G. K. Dy, et al., “Sotorasib for Lung Cancers With KRAS p.G12C Mutation,” New England Journal of Medicine 384, no. 25 (2021): 2371-2381.

[168] J. H. Strickler, H. Satake, T. J. George, et al., “Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer,” New England Journal of Medicine 388, no. 1 (2023): 33-43.

[169] T. S. Bekaii-Saab, R. Yaeger, A. I. Spira, et al., “Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation,” Journal of Clinical Oncology 41, no. 25 (2023): 4097-4106.

[170] A. Sacher, P. LoRusso, M. R. Patel, et al., “Single-Agent Divarasib (GDC-6036) in Solid Tumors With a KRAS G12C Mutation,” New England Journal of Medicine 389, no. 8 (2023): 710-721.

[171] J. Li, L. Shen, Y. Gu, et al., “Preliminary Activity and Safety Results of KRAS G12C Inhibitor glecirasib (JAB-21822) in Patients With Pancreatic Cancer and Other Solid Tumors,” Journal of Clinical Oncology 42, no. 3_suppl (2024): 604-604.

[172] E. Lorthiois, M. Gerspacher, K. S. Beyer, et al., “JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors,” Journal of Medicinal Chemistry 65, no. 24 (2022): 16173-16203.

[173] The KRASG12D Inhibitor MRTX1133 Elucidates KRAS-mediated Oncogenesis. Nature Medicine 2022; 28(10): 2017-2018.

[174] J. Luo, “KRAS Mutation in Pancreatic Cancer,” Seminars in Oncology 48, no. 1 (2021): 10-18.

[175] M. J. Nokin, A. Mira, E. Patrucco, et al., “RAS-ON Inhibition Overcomes Clinical Resistance to KRAS G12C-OFF Covalent Blockade,” Nature Communications 15, no. 1 (2024): 7554.

[176] M. M. Awad, S. Liu, I. I. Rybkin, et al., “Acquired Resistance to KRASG12C Inhibition in Cancer,” New England Journal of Medicine 384, no. 25 (2021): 2382-2393.

[177] J. Y. Xue, Y. Zhao, J. Aronowitz, et al., “Rapid Non-uniform Adaptation to Conformation-specific KRAS(G12C) Inhibition,” Nature 577, no. 7790 (2020): 421-425.

[178] H. S. Solanki, E. A. Welsh, B. Fang, et al., “Cell Type-specific Adaptive Signaling Responses to KRASG12C Inhibition,” Clinical Cancer Research 27, no. 9 (2021): 2533-2548.

[179] Y. Adachi, K. Ito, Y. Hayashi, et al., “Epithelial-to-Mesenchymal Transition Is a Cause of both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer,” Clinical Cancer Research 26, no. 22 (2020): 5962-5973.

[180] J. Dilly, M. T. Hoffman, L. Abbassi, et al., “Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer,” Cancer discovery 14, no. 11 (2024): 2135-2161.

[181] U. Degirmenci, M. Wang, and J. Hu, “Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy,” Cells 9, no. 1 (2020): 198.

[182] C. Guo, M. Chénard-Poirier, D. Roda, et al., “Intermittent Schedules of the Oral RAF-MEK Inhibitor CH5126766/VS-6766 in Patients With RAS/RAF-mutant Solid Tumours and Multiple Myeloma: A Single-centre, Open-label, Phase 1 Dose-escalation and Basket Dose-expansion Study,” The Lancet Oncology 21, no. 11 (2020): 1478-1488.

[183] D. E. Gerber, D. R. Camidge, D. Morgensztern, et al., “Phase 2 Study of the Focal Adhesion Kinase Inhibitor defactinib (VS-6063) in Previously Treated Advanced KRAS Mutant Non-small Cell Lung Cancer,” Lung Cancer 139 (2020): 60-67.

[184] S. N. Banerjee, K. L. Ring, E. V. Nieuwenhuysen, et al., “Initial Efficacy and Safety Results From ENGOT-ov60/GOG-3052/RAMP 201: A Phase 2 Study of Avutometinib (VS-6766) ± Defactinib in Recurrent Low-grade Serous Ovarian Cancer (LGSOC),” Journal of Clinical Oncology 41, no. 16_suppl (2023): 5515.

[185] T. Y. Weng, M. C. Yen, C. T. Huang, et al., “DNA Vaccine Elicits an Efficient Antitumor Response by Targeting the Mutant Kras in a Transgenic Mouse Lung Cancer Model,” Gene Therapy 21, no. 10 (2014): 888-896.

[186] S. Wedén, M. Klemp, I. P. Gladhaug, et al., “Long-term Follow-up of Patients With Resected Pancreatic Cancer Following Vaccination Against Mutant K-ras,” International Journal of Cancer 128, no. 5 (2011): 1120-1128.

[187] M. Jiang, K. Jia, L. Wang, et al., “Alterations of DNA Damage Response Pathway: Biomarker and Therapeutic Strategy for Cancer Immunotherapy,” Acta Pharmaceutica Sinica B 11, no. 10 (2021): 2983-2994.

[188] M. M. Ladan, D. C. van Gent, and A. Jager, “Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation,” Cancers (Basel) 13, no. 5 (2021): 1004.

[189] A. B. Blair, V. P. Groot, G. Gemenetzis, et al., “BRCA1/BRCA2 Germline Mutation Carriers and Sporadic Pancreatic Ductal Adenocarcinoma,” Journal of the American College of Surgeons 226, no. 4 (2018): 630-637. e1.

[190] E. Lai, P. Ziranu, D. Spanu, et al., “BRCA-mutant Pancreatic Ductal Adenocarcinoma,” British Journal of Cancer 125, no. 10 (2021): 1321-1332.

[191] H. Farmer, N. McCabe, C. J. Lord, et al., “Targeting the DNA Repair Defect in BRCA Mutant Cells as a Therapeutic Strategy,” Nature 434, no. 7035 (2005): 917-921.

[192] T. Golan, P. Hammel, M. Reni, et al., “Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer,” New England Journal of Medicine 381, no. 4 (2019): 317-327.

[193] F. Quiñonero, C. Mesas, J. A. Muñoz-Gámez, et al., “PARP1 inhibition by Olaparib Reduces the Lethality of Pancreatic Cancer Cells and Increases Their Sensitivity to Gemcitabine,” Biomedicine & Pharmacotherapy 155 (2022): 113669.

[194] C. Du, Y. Qi, Y. Zhang, et al., “Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer With Breast Cancer 2 (BRCA2) Mutation,” American Chemical Society Nano 12, no. 11 (2018): 10785-10796.

[195] J. Chi, S. Y. Chung, R. Parakrama, F. Fayyaz, J. Jose, and M. W. Saif, “The Role of PARP Inhibitors in BRCA Mutated Pancreatic Cancer,” Therapeutic Advances in Gastroenterology 14 (2021): 17562848211014818.

[196] K. A. Reiss, R. Mick, M. H. O'Hara, et al., “Phase II Study of Maintenance Rucaparib in Patients with Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2,” Journal of Clinical Oncology 39, no. 22 (2021): 2497-2505.

[197] D. Mandelker, A. Marra, B. Zheng-Lin, et al., “Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma,” Journal of Clinical Oncology 41, no. 33 (2023): 5151-5162.

[198] M. J. O'Connor, “Targeting the DNA Damage Response in Cancer,” Molecular Cell 60, no. 4 (2015): 547-560.

[199] S. L. Wethington, P. D. Shah, L. Martin, et al., “Combination ATR (ceralasertib) and PARP (ola parib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer,” Clinical Cancer Research 29, no. 15 (2023): 2800-2807.

[200] C. J. LaFargue, G. Z. Dal Molin, A. K. Sood, and R. L. Coleman, “Exploring and Comparing Adverse Events Between PARP Inhibitors,” The Lancet Oncology 20, no. 1 (2019): e15-e28.

[201] J. Murai, S. Y. Huang, B. B. Das, et al., “Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors,” Cancer Research 72, no. 21 (2012): 5588-5599.

[202] J. Farrés, J. Martín-Caballero, C. Martínez, et al., “Parp-2 Is Required to Maintain Hematopoiesis Following Sublethal γ-irradiation in Mice,” Blood 122, no. 1 (2013): 44-54.

[203] J. Farrés, L. Llacuna, J. Martin-Caballero, et al., “PARP-2 Sustains Erythropoiesis in Mice by Limiting Replicative Stress in Erythroid Progenitors,” Cell Death and Differentiation 22, no. 7 (2015): 1144-1157.

[204] CT014.PETRA: first-in-human Phase 1/2a trial of the first-in-class next-generation poly (ADP-ribose).

[205] K. A. Reiss, R. Mick, U. Teitelbaum, et al., “Niraparib plus nivolumab or niraparib plus ipilimumab in Patients With Platinum-sensitive Advanced Pancreatic Cancer: A Randomised, Phase 1b/2 Trial,” The Lancet Oncology 23, no. 8 (2022): 1009-1020.

[206] M. J. Pishvaian, H. Wang, A. R. He, et al., “A Phase I/II Study of Veliparib (ABT-888) in Combination With 5-Fluorouracil and Oxaliplatin in Patients With Metastatic Pancreatic Cancer,” Clinical Cancer Research 26, no. 19 (2020): 5092-5101.

[207] R. Tuli, S. L. Shiao, N. Nissen, et al., “A Phase 1 Study of veliparib, a PARP-1/2 Inhibitor, With Gemcitabine and Radiotherapy in Locally Advanced Pancreatic Cancer,” EBioMedicine 40 (2019): 375-381.

[208] N. Ferrara, H. P. Gerber, and J. LeCouter, “The Biology of VEGF and Its Receptors,” Nature Medicine 9, no. 6 (2003): 669-676.

[209] J. Garcia, H. I. Hurwitz, A. B. Sandler, et al., “Bevacizumab (Avastin®) in Cancer Treatment: A Review of 15 Years of Clinical Experience and Future Outlook,” Cancer Treatment Reviews 86 (2020): 102017.

[210] H. L. Kindler, G. Friberg, D. A. Singh, et al., “Phase II Trial of Bevacizumab plus Gemcitabine in Patients With Advanced Pancreatic Cancer,” Journal of Clinical Oncology 23, no. 31 (2005): 8033-8040.

[211] H. L. Kindler, D. Niedzwiecki, D. Hollis, 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),” Journal of Clinical Oncology 28, no. 22 (2010): 3617-3622.

[212] E. Van Cutsem, W. L. Vervenne, J. Bennouna, et al., “Phase III Trial of bevacizumab in Combination With Gemcitabine and Erlotinib in Patients With Metastatic Pancreatic Cancer,” Journal of Clinical Oncology 27, no. 13 (2009): 2231-2237.

[213] R. M. Poole and A. Vaidya, “Ramucirumab: First Global Approval,” Drugs 74, no. 9 (2014): 1047-1058.

[214] W. L. Shaib, R. Manali, Y. Liu, et al., “Phase II Randomised, Double-blind Study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus Placebo in Advanced Pancreatic Cancer Patients (HCRN GI14-198),” European Journal of Cancer 189 (2023): 112847.

[215] S. Bozzarelli, L. Rimassa, L. Giordano, et al., “Regorafenib in Patients With Refractory Metastatic Pancreatic Cancer: A Phase II Study (RESOUND),” Future oncology 15, no. 35 (2019): 4009-4017.

[216] V. L. Goodman, E. P. Rock, R. Dagher, et al., “Approval Summary: Sunitinib for the Treatment of imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma,” Clinical Cancer Research 13, no. 5 (2007): 1367-1373.

[217] L. Bergmann, L. Maute, G. Heil, et al., “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,” European Journal of Cancer 51, no. 1 (2015): 27-36.

[218] H. L. Kindler, T. Ioka, D. J. Richel, et al., “Axitinib plus Gemcitabine versus Placebo plus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: A Double-blind Randomised Phase 3 Study,” The Lancet Oncology 12, no. 3 (2011): 256-262.

[219] E. Vakana, S. Pratt, W. Blosser, et al., “LY3009120, a panRAF Inhibitor, Has Significant Anti-tumor Activity in BRAF and KRAS Mutant Preclinical Models of Colorectal Cancer,” Oncotarget 8, no. 6 (2017): 9251-9266.

[220] J. Rinehart, A. A. Adjei, P. M. Lorusso, et al., “Multicenter Phase II Study of the Oral MEK Inhibitor, CI-1040, in Patients With Advanced Non-small-cell Lung, Breast, Colon, and Pancreatic Cancer,” Journal of Clinical Oncology 22, no. 22 (2004): 4456-4462.

[221] H. Oka, Y. Chatani, M. Kohno, M. Kawakita, and O. Ogawa, “Constitutive Activation of the 41- and 43-kDa Mitogen-activated Protein (MAP) Kinases in the Progression of Prostate Cancer to an Androgen-independent state,” International Journal of Urology 12, no. 10 (2005): 899-905.

[222] V. P. Brahmkhatri, C. Prasanna, and H. S. Atreya, “Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies,” BioMed research international 2015 (2015): 538019.

[223] H. Hua, Q. Kong, J. Yin, J. Zhang, and Y. Jiang, “Insulin-Like Growth Factor Receptor Signaling in Tumorigenesis and Drug Resistance: A Challenge for Cancer Therapy,” Journal of hematology & oncology 13, no. 1 (2020): 64.

[224] M. Trajkovic-Arsic, E. Kalideris, and J. T. Siveke, “The Role of Insulin and IGF System in Pancreatic Cancer,” Journal of Molecular Endocrinology 50, no. 3 (2013): R67-74.

[225] E. Karna, A. Surazynski, K. Orłowski, et al., “Serum and Tissue Level of Insulin-Like Growth Factor-I (IGF-I) and IGF-I Binding Proteins as an Index of Pancreatitis and Pancreatic Cancer,” International Journal of Experimental Pathology 83, no. 5 (2002): 239-245.

[226] U. Bergmann, H. Funatomi, M. Yokoyama, H. G. Beger, and M. Korc, “Insulin-Like Growth Factor I Overexpression in human Pancreatic Cancer: Evidence for Autocrine and Paracrine Roles,” Cancer Research 55, no. 10 (1995): 2007-2011.

[227] M. C. Manara, L. Landuzzi, P. Nanni, et al., “Preclinical in Vivo Study of New Insulin-Like Growth Factor-I Receptor-specific Inhibitor in Ewing's Sarcoma,” Clinical Cancer Research 13, no. 4 (2007): 1322-1330.

[228] F. J. Calzone, E. Cajulis, Y. A. Chung, et al., “Epitope-specific Mechanisms of IGF1R Inhibition by Ganitumab,” PLoS ONE 8, no. 2 (2013): e55135.

[229] T. Okusaka, M. Ikeda, A. Fukutomi, et al., “Safety, Tolerability, Pharmacokinetics and Antitumor Activity of ganitumab, an Investigational Fully human Monoclonal Antibody to Insulin-Like Growth Factor Type 1 Receptor, Combined With gemcitabine as First-line Therapy in Patients With Metastatic Pancreatic Cancer: A Phase 1b Study,” Japanese Journal of Clinical Oncology 44, no. 5 (2014): 442-447.

[230] C. S. Fuchs, S. Azevedo, T. Okusaka, 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,” Annals of Oncology 26, no. 5 (2015): 921-927.

[231] E. K. Rowinsky, J. D. Schwartz, N. Zojwalla, et al., “Blockade of Insulin-Like Growth Factor Type-1 Receptor With cixutumumab (IMC-A12): A Novel Approach to Treatment for Multiple Cancers,” Current Drug Targets 12, no. 14 (2011): 2016-2033.

[232] P. A. Philip, B. Goldman, R. K. Ramanathan, et al., “Dual Blockade of Epidermal Growth Factor Receptor and Insulin-Like Growth Factor Receptor-1 Signaling in Metastatic Pancreatic Cancer: Phase Ib and Randomized Phase II Trial of Gemcitabine, Erlotinib, and Cixutumumab versus gemcitabine plus Erlotinib (SWOG S0727),” Cancer 120, no. 19 (2014): 2980-2985.

[233] R. Malaguarnera and A. Belfiore, “The Insulin Receptor: A New Target for Cancer Therapy,” Front Endocrinol (Lausanne) 2 (2011): 93.

[234] X. Li, X. Yan, Y. Wang, B. Kaur, H. Han, and J. Yu, “The Notch Signaling Pathway: A Potential Target for Cancer Immunotherapy,” Journal of hematology & oncology 16, no. 1 (2023): 45.

[235] W. C. Chung and K. Xu, “Notch Signaling Pathway in Pancreatic Tumorigenesis,” Advances in Cancer Research 159 (2023): 1-36.

[236] A. Gurney and T. Hoey, “From Research to the Clinic: Targeting Stem Cell Pathways in Cancer,” Cancer Stem Cells 17 (2016): 441-457.

[237] M. J. McKeage, D. Kotasek, B. Markman, et al., “Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab With Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC,” Targeted Oncology 13, no. 1 (2018): 89-98.

[238] R. L. Coleman, K. F. Handley, R. Burger, et al., “Demcizumab Combined With paclitaxel for Platinum-resistant Ovarian, Primary Peritoneal, and Fallopian Tube Cancer: The SIERRA Open-label Phase Ib Trial,” Gynecologic Oncology 157, no. 2 (2020): 386-391.

[239] D. C. Smith, P. D. Eisenberg, G. Manikhas, et al., “A Phase I Dose Escalation and Expansion Study of the Anticancer Stem Cell Agent demcizumab (anti-DLL4) in Patients With Previously Treated Solid Tumors,” Clinical Cancer Research 20, no. 24 (2014): 6295-6303.

[240] E. M. O'Reilly, L. S. Smith, J. C. Bendell, et al., “Final Results of Phase Ib of Anticancer Stem Cell Antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in Combination With Nab-paclitaxel and Gemcitabine (Nab-P+Gem) in Patients (pts) With Untreated Metastatic Pancreatic Cancer (mPC),” Journal of Clinical Oncology 33 (2015): 278-278.

[241] Z. I. Hu, J. C. Bendell, A. Bullock, et al., “A Randomized Phase II Trial of nab-paclitaxel and gemcitabine With Tarextumab or Placebo in Patients With Untreated Metastatic Pancreatic Cancer,” Cancer medicine 8, no. 11 (2019): 5148-5157.

[242] S. S. Huppert, A. Le, E. H. Schroeter, et al., “Embryonic Lethality in Mice Homozygous for a Processing-deficient Allele of Notch1,” Nature 405, no. 6789 (2000): 966-970.

[243] N. Cook, B. Basu, D. M. Smith, et al., “A Phase I Trial of the γ-secretase Inhibitor MK-0752 in Combination With gemcitabine in Patients With Pancreatic Ductal Adenocarcinoma,” British Journal of Cancer 118, no. 6 (2018): 793-801.

[244] N. Cook, K. K. Frese, T. E. Bapiro, et al., “Gamma Secretase Inhibition Promotes Hypoxic Necrosis in Mouse Pancreatic Ductal Adenocarcinoma,” Journal of Experimental Medicine 209, no. 3 (2012): 437-444.

[245] I. Krop, T. Demuth, T. Guthrie, et al., “Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors,” Journal of Clinical Oncology 30, no. 19 (2012): 2307-2313.

[246] A. De Jesus-Acosta, D. Laheru, A. Maitra, et al., “A Phase II Study of the Gamma Secretase Inhibitor RO4929097 in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma,” Investigational New Drugs 32, no. 4 (2014): 739-745.

[247] J. M. Yingling, W. T. McMillen, L. Yan, et al., “Preclinical Assessment of galunisertib (LY2157299 monohydrate), a First-in-class Transforming Growth Factor-β Receptor Type I Inhibitor,” Oncotarget 9, no. 6 (2017): 6659-6677.

[248] R. B. Holmgaard, D. A. Schaer, Y. Li, et al., “Targeting the TGFβ Pathway With galunisertib, a TGFβRI Small Molecule Inhibitor, Promotes Anti-tumor Immunity Leading to Durable, Complete Responses, as Monotherapy and in Combination With Checkpoint Blockade,” Journal for ImmunoTherapy of Cancer 6, no. 1 (2018): 47.

[249] D. Melisi, R. Garcia-Carbonero, T. Macarulla, et al., “Galunisertib plus Gemcitabine vs. gemcitabine for First-line Treatment of Patients With Unresectable Pancreatic Cancer,” British Journal of Cancer 119, no. 10 (2018): 1208-1214.

[250] D. Melisi, D. Y. Oh, A. Hollebecque, et al., “Safety and Activity of the TGFβ Receptor I Kinase Inhibitor galunisertib plus the Anti-PD-L1 Antibody Durvalumab in Metastatic Pancreatic Cancer,” Journal for ImmunoTherapy of Cancer 9, no. 3 (2021): e002068.

[251] J. C. Morris, A. R. Tan, T. E. Olencki, et al., “Phase I Study of GC1008 (fresolimumab): A human Anti-transforming Growth Factor-beta (TGFβ) Monoclonal Antibody in Patients With Advanced Malignant Melanoma or Renal Cell Carcinoma,” PLoS ONE 9, no. 3 (2014): e90353.

[252] E. Jiggens, M. Mortoglou, and G. H. Grant, “Uysal-Onganer P. The Role of CDK4 in the Pathogenesis of Pancreatic Cancer,” Healthcare (Basel) 9, no. 11 (2021): 1478.

[253] T. Magge, S. Rajendran, A. M. Brufsky, and J. Foldi, “CDK4/6 inhibitors: The Devil Is in the Detail,” Current Oncology Reports 26, no. 6 (2024): 665-678.

[254] FDA. Kisqali FDA Label. 2017. Accessed Dec 16, 2024. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf.

[255] D. Presti and E. Quaquarini, “The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments,” Cancers (Basel) 11, no. 9 (2019): 1242.

[256] B. A. Weinberg, H. Wang, A. K. Witkiewicz, et al., “A Phase I Study of Ribociclib Plus Everolimus in Patients With Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy,” J Pancreat Cancer 6, no. 1 (2020): 45-54.

[257] M. Heckler, L. R. Ali, E. Clancy-Thompson, et al., “Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation,” Cancer discovery 11, no. 10 (2021): 2564-2581.

[258] Q. F. Zhang, J. Li, K. Jiang, et al., “CDK4/6 inhibition Promotes Immune Infiltration in Ovarian Cancer and Synergizes With PD-1 Blockade in a B Cell-dependent Manner,” Theranostics 10, no. 23 (2020): 10619-10633.

[259] R. E. Royal, C. Levy, K. Turner, et al., “Phase 2 Trial of Single Agent Ipilimumab (anti-CTLA-4) for Locally Advanced or Metastatic Pancreatic Adenocarcinoma,” Journal of Immunotherapy 33, no. 8 (2010): 828-833.

[260] J. R. Brahmer, S. S. Tykodi, L. Q. Chow, et al., “Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced Cancer,” New England Journal of Medicine 366, no. 26 (2012): 2455-2465.

[261] A. Marabelle, D. T. Le, P. A. Ascierto, et al., “Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results from the Phase II KEYNOTE-158 Study,” Journal of Clinical Oncology 38, no. 1 (2020): 1-10.

[262] J. Du, C. Lu, L. Mao, et al., “PD-1 Blockade plus Chemoradiotherapy as Preoperative Therapy for Patients With BRPC/LAPC: A Biomolecular Exploratory, Phase II Trial,” Cell Reports Medicine 4, no. 3 (2023): 100972.

[263] Y. Chen, C. Guo, X. Bai, et al., “Randomized Phase II Trial of Neoadjuvant Chemotherapy With Modified FOLFIRINOX versus Modified FOLFIRINOX and PD-1 Antibody for Borderline Resectable and Locally Advanced Pancreatic Cancer (the CISPD-4 study),” Journal of Clinical Oncology 40, no. Suppl 4 (2022): 562.

[264] Z. A. Wainberg, J. M. Link, D. Dawson, et al., “A Pilot Clinical Trial of Neoadjuvant Modified FOLFIRINOX plus nivolumab in Borderline Resectable Pancreas Cancer,” Presented at: American Association for Cancer Research 2024 Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT031.

[265] Z. A. Wainberg, H. S. Hochster, E. J. Kim, et al., “Open-label, Phase I Study of Nivolumab Combined With Nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer,” Clinical Cancer Research 26, no. 18 (2020): 4814-4822.

[266] S. D. Kamath, A. Kalyan, S. Kircher, et al., “Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study,” The Oncologist 25, no. 5 (2020): e808-e815.

[267] A. Wang-Gillam, K. H. Lim, R. McWilliams, et al., “Defactinib, Pembrolizumab, and Gemcitabine in Patients With Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study,” Clinical Cancer Research 28, no. 24 (2022): 5254-5262.

[268] K. Cheng, X. Li, W. Lv, et al., “Spatial Interactions of Immune Cells as Potential Predictors to Efficacy of toripalimab plus Chemotherapy in Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma: A Phase Ib/II Trial,” Signal Transduction and Targeted Therapy 9, no. 1 (2024): 321.

[269] X. Zhu, Y. Cao, W. Liu, et al., “Stereotactic Body Radiotherapy plus Pembrolizumab and Trametinib versus Stereotactic Body Radiotherapy plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection: An Open-label, Randomised, Controlled, Phase 2 Trial,” The Lancet Oncology 23, no. 3 (2022): e105-e115.

[270] I. M. Chen, J. S. Johansen, S. Theile, et al., “Randomized Phase II Study of Nivolumab with or without Ipilimumab Combined with Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC),” Journal of Clinical Oncology 40, no. 27 (2022): 3180-3189.

[271] B. Bockorny, V. Semenisty, T. Macarulla, et al., “BL-8040, a CXCR4 Antagonist, in Combination With pembrolizumab and Chemotherapy for Pancreatic Cancer: The COMBAT Trial,” Nature Medicine 26, no. 6 (2020): 878-885.

[272] M. H. O'Hara, W. Messersmith, H. Kindler, et al., “Safety and Pharmacokinetics of CXCR4 Peptide Antagonist, LY2510924, in Combination With Durvalumab in Advanced Refractory Solid Tumors,” J Pancreat Cancer 6, no. 1 (2020): 21-31.

[273] T. M. Nywening, A. Wang-Gillam, D. E. Sanford, 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,” The Lancet Oncology 17, no. 5 (2016): 651-662.

[274] M. Noel, E. M. O'Reilly, B. M. Wolpin, 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,” Investigational New Drugs 38, no. 3 (2020): 800-811.

[275] S. Das, J. Berlin, and D. Cardin, “Harnessing the Immune System in Pancreatic Cancer,” Current Treatment Options in Oncology 19, no. 10 (2018): 48.

[276] A. M. Wandmacher, A. Letsch, and S. Sebens, “Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer,” Cancers (Basel) 13, no. 16 (2021): 4235.

[277] C. Feig, J. O. Jones, M. Kraman, et al., “Targeting CXCL12 From FAP-expressing Carcinoma-associated Fibroblasts Synergizes With Anti-PD-L1 Immunotherapy in Pancreatic Cancer,” PNAS 110, no. 50 (2013): 20212-20217.

[278] Y. D. Seo, X. Jiang, K. M. Sullivan, et al., “Mobilization of CD8+ T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer,” Clinical Cancer Research 25, no. 13 (2019): 3934-3945.

[279] B. Bockorny, J. E. Grossman, and M. Hidalgo, “Facts and Hopes in Immunotherapy of Pancreatic Cancer,” Clinical Cancer Research 28, no. 21 (2022): 4606-4617.

[280] Y. J. Chen, B. Abila, and Y. Mostafa Kamel, “CAR-T: What Is Next?,” Cancers (Basel) 15, no. 3 (2023): 663.

[281] S. Wöll, A. M. Schlitter, K. Dhaene, et al., “Claudin 18.2 Is a Target for IMAB362 Antibody in Pancreatic Neoplasms,” International Journal of Cancer 134, no. 3 (2014): 731-739.

[282] C. Qi, T. Xie, J. Zhou, et al., “CT041 CAR T Cell Therapy for Claudin18.2-positive Metastatic Pancreatic Cancer,” Journal of hematology & oncology 16, no. 1 (2023): 102.

[283] C. Qi, P. Zhang, C. Liu, et al., “Safety and Efficacy of CT041 in Patients with Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials,” Journal of Clinical Oncology 42, no. 21 (2024): 2565-2577.

[284] K. Takasawa, A. Takasawa, M. Osanai, et al., “Claudin-18 Coupled With EGFR/ERK Signaling Contributes to the Malignant Potentials of Bile Duct Cancer,” Cancer Letters 403 (2017): 66-73.

[285] C. H. Shen, J. Y. Lin, C. Y. Lu, S. S. Yang, C. K. Peng, and K. L. Huang, “SPAK-p38 MAPK Signal Pathway Modulates Claudin-18 and Barrier Function of Alveolar Epithelium After Hyperoxic Exposure,” BioMed Central Pulmonary Medicine 21, no. 1 (2021): 58.

[286] T. Ito, T. Kojima, H. Yamaguchi, et al., “Transcriptional Regulation of Claudin-18 via Specific Protein Kinase C Signaling Pathways and Modification of DNA Methylation in human Pancreatic Cancer Cells,” Journal of Cellular Biochemistry 112, no. 7 (2011): 1761-1772.

[287] N. A. Ullman, P. R. Burchard, R. F. Dunne, and D. C. Linehan, “Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot,” Journal of Clinical Oncology 40, no. 24 (2022): 2789-2805.

[288] H. Jiang, S. Hegde, B. L. Knolhoff, et al., “Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy,” Nature Medicine 22, no. 8 (2016): 851-860.

[289] A. Amedei, E. Niccolai, and D. Prisco, “Pancreatic Cancer: Role of the Immune System in Cancer Progression and Vaccine-based Immunotherapy,” Human vaccines & immunotherapeutics 10, no. 11 (2014): 3354-3368.

[290] B. A. Johnson, M. Yarchoan, V. Lee, D. A. Laheru, and E. M. Jaffee, “Strategies for Increasing Pancreatic Tumor Immunogenicity,” Clinical Cancer Research 23, no. 7 (2017): 1656-1669.

[291] Y. Zhu, B. L. Knolhoff, M. A. Meyer, et al., “CSF1/CSF1R blockade Reprograms Tumor-infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models,” Cancer Research 74, no. 18 (2014): 5057-5069.

[292] A. Voissière, C. Gomez-Roca, S. Chabaud, et al., “The CSF-1R Inhibitor pexidartinib Affects FLT3-dependent DC Differentiation and May Antagonize Durvalumab Effect in Patients With Advanced Cancers,” Science Translational Medicine 16, no. 731 (2024): eadd1834.

[293] D. Raj, M. Nikolaidi, I. Garces, et al., “CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma,” Clinical Cancer Research 27, no. 5 (2021): 1538-1552.

[294] H. Chen, F. Wei, M. Yin, et al., “CD27 enhances the Killing Effect of CAR T Cells Targeting Trophoblast Cell Surface Antigen 2 in the Treatment of Solid Tumors,” Cancer Immunology, Immunotherapy 70, no. 7 (2021): 2059-2071.

[295] H. Zhu, X. Fang, I. J. Tuhin, et al., “CAR T Cells Equipped With a Fully human scFv Targeting Trop2 Can be Used to Treat Pancreatic Cancer,” Journal of Cancer Research and Clinical Oncology 148, no. 9 (2022): 2261-2274.

[296] C. Li, N. Yang, H. Li, and Z. Wang, “Robo1-specific Chimeric Antigen Receptor Natural Killer Cell Therapy for Pancreatic Ductal Adenocarcinoma With Liver Metastasis,” Journal of Cancer Research and Therapeutics 16, no. 2 (2020): 393-396.

[297] M. N. Wente, A. Jain, E. Kono, et al., “Prostate Stem Cell Antigen Is a Putative Target for Immunotherapy in Pancreatic Cancer,” Pancreas 31, no. 2 (2005): 119-125.

[298] K. Y. Teng, A. G. Mansour, Z. Zhu, et al., “Off-the-Shelf Prostate Stem Cell Antigen-Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer,” Gastroenterology 162, no. 4 (2022): 1319-1333.

[299] Fate Therapeutics Announces FDA Clearance for FT536, a First-in-class MICA/B-targeted CAR NK Cell Product Candidate for the Treatment of Solid Tumors. Accessed on Dec 2, 2024. https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-announces-fda-clearance-ft536-first-class.

[300] R. Leidner, N. Sanjuan Silva, H. Huang, et al., “Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer,” New England Journal of Medicine 386, no. 22 (2022): 2112-2119.

[301] H. G. Smeenk, C. H. van Eijck, W. C. Hop, et al., “Long-term Survival and Metastatic Pattern of Pancreatic and Periampullary Cancer After Adjuvant Chemoradiation or Observation: Long-term Results of EORTC Trial 40891,” Annals of Surgery 246, no. 5 (2007): 734-740.

[302] J. M. Herman, M. J. Swartz, C. C. Hsu, et al., “Analysis of Fluorouracil-based Adjuvant Chemotherapy and Radiation After Pancreaticoduodenectomy for Ductal Adenocarcinoma of the Pancreas: Results of a Large, Prospectively Collected Database at the Johns Hopkins Hospital,” Journal of Clinical Oncology 26, no. 21 (2008): 3503-3510.

[303] C. C. Hsu, J. M. Herman, M. M. Corsini, et al., “Adjuvant Chemoradiation for Pancreatic Adenocarcinoma: The Johns Hopkins Hospital-Mayo Clinic Collaborative Study,” Annals of Surgical Oncology 17, no. 4 (2010): 981-990.

[304] W. F. Regine, K. A. Winter, R. Abrams, et al., “Fluorouracil-based Chemoradiation With either Gemcitabine or Fluorouracil Chemotherapy After Resection of Pancreatic Adenocarcinoma: 5-year Analysis of the U.S. Intergroup/RTOG 9704 Phase III Trial,” Annals of Surgical Oncology 18, no. 5 (2011): 1319-1326.

[305] R. A. Abrams, K. A. Winter, K. A. Goodman, et al., “NRG Oncology/RTOG 0848: Results After Adjuvant Chemotherapy ± Chemoradiation for Patients With Resected Periampullary Pancreatic Adenocarcinoma (PA),” Journal of Clinical Oncology 42, no. 16_suppl (2024): 4005.

[306] B. Chauffert, F. Mornex, F. Bonnetain, et al., “Phase III Trial Comparing Intensive Induction Chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) Followed by Maintenance Gemcitabine With Gemcitabine Alone for Locally Advanced Unresectable Pancreatic Cancer. Definitive Results of the 2000-01 FFCD/SFRO Study,” Annals of Oncology 19, no. 9 (2008): 1592-1599.

[307] P. J. Loehrer Sr, Y. Feng, H. Cardenes, et al., “Gemcitabine Alone versus Gemcitabine plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial,” Journal of Clinical Oncology 29, no. 31 (2011): 4105-4112.

[308] C. N. Hurt, S. Falk, T. Crosby, et al., “Long-term Results and Recurrence Patterns From SCALOP: A Phase II Randomised Trial of Gemcitabine- or Capecitabine-based Chemoradiation for Locally Advanced Pancreatic Cancer,” British Journal of Cancer 116, no. 10 (2017): 1264-1270.

[309] M. T. Milano, S. J. Chmura, M. C. Garofalo, et al., “Intensity-modulated Radiotherapy in Treatment of Pancreatic and Bile Duct Malignancies: Toxicity and Clinical Outcome,” International Journal of Radiation and Oncology in Biology and Physics 59, no. 2 (2004): 445-453.

[310] S. Yovino, M. Poppe, S. Jabbour, et al., “Intensity-modulated Radiation Therapy Significantly Improves Acute Gastrointestinal Toxicity in Pancreatic and Ampullary Cancers,” International Journal of Radiation and Oncology in Biology and Physics 79, no. 1 (2011): 158-162.

[311] F. Petrelli, T. Comito, A. Ghidini, V. Torri, M. Scorsetti, and S. Barni, “Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials,” International Journal of Radiation and Oncology in Biology and Physics 97, no. 2 (2017): 313-322.

[312] M. A. Teriaca, M. Loi, M. Suker, F. Eskens, C. H. J. van Eijck, and J. J. Nuyttens, “A Phase II Study of Stereotactic Radiotherapy After FOLFIRINOX for Locally Advanced Pancreatic Cancer (LAPC-1 trial): Long-term Outcome,” Radiotherapy and Oncology 155 (2021): 232-236.

[313] S. Rudra, N. Jiang, S. A. Rosenberg, et al., “Using Adaptive Magnetic Resonance Image-guided Radiation Therapy for Treatment of Inoperable Pancreatic Cancer,” Cancer medicine 8, no. 5 (2019): 2123-2132.

[314] C. Hassanzadeh, S. Rudra, A. Bommireddy, et al., “Ablative Five-Fraction Stereotactic Body Radiation Therapy for Inoperable Pancreatic Cancer Using Online MR-Guided Adaptation,” Advances in Radiation Oncology 6, no. 1 (2020): 100506.

[315] W. Tinganelli and M. Durante, “Carbon Ion Radiobiology,” Cancers (Basel) 12, no. 10 (2020): 3022.

[316] T. D. Malouff, A. Mahajan, R. W. Mutter, et al., “Carbon Ion Radiation Therapy in Breast Cancer: A New Frontier,” Breast Cancer Research and Treatment 181, no. 2 (2020): 291-296.

[317] Y. Guo, R. Shen, F. Wang, et al., “Carbon Ion Irradiation Induces DNA Damage in Melanoma and Optimizes the Tumor Microenvironment Based on the cGAS-STING Pathway,” Journal of Cancer Research and Clinical Oncology 149, no. 9 (2023): 6315-6328.

[318] M. Shinoto, K. Terashima, H. Suefuji, et al., “A Single Institutional Experience of Combined Carbon-ion Radiotherapy and Chemotherapy for Unresectable Locally Advanced Pancreatic Cancer,” Radiotherapy and Oncology 129, no. 2 (2018): 333-339.

[319] S. Kawashiro, S. Yamada, M. Okamoto, et al., “Multi-institutional Study of Carbon-ion Radiotherapy for Locally Advanced Pancreatic Cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) Study 1403 Pancreas,” International Journal of Radiation and Oncology in Biology and Physics 101, no. 5 (2018): 1212-1221.

[320] V. Vitolo, L. Cobianchi, S. Brugnatelli, et al., “Preoperative Chemotherapy and Carbon Ions Therapy for Treatment of Resectable and Borderline Resectable Pancreatic Adenocarcinoma: A Prospective, Phase II, Multicentre, Single-arm Study,” BMC cancer 19, no. 1 (2019): 922.

[321] N. van de Donk and S. Zweegman, “T-cell-engaging Bispecific Antibodies in Cancer,” Lancet 402, no. 10396 (2023): 142-158.

[322] S. Wang, C. Chen, Y. Meng, et al., “Effective Suppression of Breast Tumor Growth by an Anti-EGFR/ErbB2 Bispecific Antibody,” Cancer Letters 325, no. 2 (2012): 214-219.

[323] K. D. Grugan, K. Dorn, S. W. Jarantow, et al., “Fc-mediated Activity of EGFR X c-Met Bispecific Antibody JNJ-61186372 Enhanced Killing of Lung Cancer Cells,” Monoclonal Antibodies 9, no. 1 (2017): 114-126.

[324] D. Seimetz, H. Lindhofer, and C. Bokemeyer, “Development and Approval of the Trifunctional Antibody Catumaxomab (anti-EpCAM x anti-CD3) as a Targeted Cancer Immunotherapy,” Cancer Treatment Reviews 36, no. 6 (2010): 458-467.

[325] M. Umebayashi, A. Kiyota, N. Koya, et al., “An Epithelial Cell Adhesion Molecule- and CD3-bispecific Antibody plus Activated T-cells Can Eradicate Chemoresistant Cancer Stem-Like Pancreatic Carcinoma Cells in Vitro,” Anticancer Research 34, no. 8 (2014): 4509-4519.

[326] Zenocutuzumab Shines in PDAC. Cancer discovery 2021; 11(8): 1864.

[327] A. M. Schram, I. Odintsov, M. Espinosa-Cotton, et al., “Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements,” Cancer discovery 12, no. 5 (2022): 1233-1247.

[328] S. J. Keam, “Cadonilimab: First Approval,” Drugs 82, no. 12 (2022): 1333-1339.

[329] H. Yano, A. Thakur, E. N. Tomaszewski, M. Choi, A. Deol, and L. G. Lum, “Ipilimumab Augments Antitumor Activity of Bispecific Antibody-armed T Cells,” Journal of translational medicine 12 (2014): 191.

[330] Z. Fu, S. Li, S. Han, C. Shi, and Y. Zhang, “Antibody Drug Conjugate: The “Biological Missile” for Targeted Cancer Therapy,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 93.

[331] S. Modi, C. Saura, T. Yamashita, et al., “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer,” New England Journal of Medicine 382, no. 7 (2020): 610-621.

[332] S. A. Hurvitz, R. Hegg, W. P. Chung, et al., “Trastuzumab deruxtecan versus trastuzumab emtansine in Patients With HER2-positive Metastatic Breast Cancer: Updated Results From DESTINY-Breast03, a Randomised, Open-label, Phase 3 Trial,” Lancet 401, no. 10371 (2023): 105-117.

[333] F. Meric-Bernstam, V. Makker, A. Oaknin, et al., “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2-Expressing Solid Tumors: Primary Results from the DESTINY-PanTumor02 Phase II Trial,” Journal of Clinical Oncology 42, no. 1 (2024): 47-58.

[334] M. C. Yang, C. S. Shia, W. F. Li, et al., “Preclinical Studies of OBI-999: A Novel Globo H-Targeting Antibody-Drug Conjugate,” Molecular Cancer Therapeutics 20, no. 6 (2021): 1121-1132.

[335] A. M. Tsimberidou, H. H. Vo, J. Beck, C. S. Shia, P. Hsu, and T. E. Pearce, “First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors,” Journal of Clinical Oncology Precision Oncology 7 (2023): e2200496.

[336] S. Shimoyama, F. Gansauge, S. Gansauge, M. Kaminishi, and H. G. Beger, “Basal Expression and Cytokine Induction of Intercellular Adhesion Molecule-1 in human Pancreatic Cancer Cell Lines,” Journal of Experimental & Clinical Cancer Research 18, no. 1 (1999): 107-110.

[337] G. Y. Liou, H. Döppler, B. Necela, et al., “Mutant KRAS-induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous Lesions,” Cancer discovery 5, no. 1 (2015): 52-63.

[338] J. Huang, A. T. Agoston, P. Guo, and M. A. Moses, “A Rationally Designed ICAM1 Antibody Drug Conjugate for Pancreatic Cancer,” Advanced Science 7, no. 24 (2020): 2002852.

[339] Y. Chen, S. Clark, T. Wong, et al., “Armed Antibodies Targeting the Mucin Repeats of the Ovarian Cancer Antigen, MUC16, Are Highly Efficacious in Animal Tumor Models,” Cancer Research 67, no. 10 (2007): 4924-4932.

[340] J. F. Liu, K. N. Moore, M. J. Birrer, et al., “Phase I Study of Safety and Pharmacokinetics of the Anti-MUC16 Antibody-drug Conjugate DMUC5754A in Patients With Platinum-resistant Ovarian Cancer or Unresectable Pancreatic Cancer,” Annals of Oncology 27, no. 11 (2016): 2124-2130.

[341] X. Yu, J. Zhang, A. Tazbirkova, et al., “Safety and Efficacy of IBI343 (anti-claudin18.2 antibody-drug conjugate) in Patients With Advanced Pancreatic Ductal Adenocarcinoma or Biliary Tract Cancer: Preliminary Results From a Phase 1 Study,” Journal of Clinical Oncology 42, no. 16_suppl (2024): 3037.

[342] A. Beck, L. Goetsch, C. Dumontet, and N. Corvaïa, “Strategies and Challenges for the next Generation of Antibody-drug Conjugates,” Nat Rev Drug Discovery 16, no. 5 (2017): 315-337.

[343] C. X. Dominguez, S. Müller, S. Keerthivasan, et al., “Single-Cell RNA Sequencing Reveals Stromal Evolution Into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy,” Cancer discovery 10, no. 2 (2020): 232-253.

[344] J. W. Purcell, S. G. Tanlimco, J. Hickson, et al., “LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug Conjugates,” Cancer Research 78, no. 14 (2018): 4059-4072.

[345] E. Ben-Ami, R. Perret, Y. Huang, et al., “LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications,” Cancers (Basel) 12, no. 3 (2020): 757.

[346] G. D. Demetri, J. J. Luke, A. Hollebecque, et al., “First-in-Human Phase I Study of ABBV-085, an Antibody-Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors,” Clinical Cancer Research 27, no. 13 (2021): 3556-3566.

[347] P. Müller, M. Kreuzaler, T. Khan, et al., “Trastuzumab Emtansine (T-DM1) Renders HER2+ Breast Cancer Highly Susceptible to CTLA-4/PD-1 Blockade,” Science Translational Medicine 7, no. 315 (2015): 315ra188.

[348] T. N. Iwata, C. Ishii, S. Ishida, Y. Ogitani, T. Wada, and T. Agatsuma, “A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model,” Molecular Cancer Therapeutics 17, no. 7 (2018): 1494-1503.

[349] P. Schmid, S. Im, A. Armstrong, et al., “BEGONIA: Phase 1b/2 Study of Durvalumab (D) Combinations in Locally Advanced/Metastatic Triple-negative Breast Cancer (TNBC)—Initial Results From Arm 1, D+Paclitaxel (P), and Arm 6, D+Trastuzumab Deruxtecan (T-DXd),” Journal of Clinical Oncology 39 (2021): 10231023.

[350] P. H. O'Donnell, M. I. Milowsky, D. P. Petrylak, et al., “Enfortumab Vedotin with or without Pembrolizumab in Cisplatin-Ineligible Patients with Previously Untreated Locally Advanced or Metastatic Urothelial Cancer,” Journal of Clinical Oncology 41, no. 25 (2023): 4107-4117.

[351] D. R. Camidge, F. Barlesi, J. W. Goldman, et al., “A Phase 1b Study of Telisotuzumab Vedotin in Combination with Nivolumab in Patients with NSCLC,” JTO Clinical and Research Reports 3, no. 1 (2021): 100262.

[352] K. N. Moore, K. N. Moore, L. P. Martin, et al., “IMGN853 (mirvetuximab soravtansine), a Folate Receptor Alpha (FRα)-targeting Antibody-drug Conjugate (ADC): Single-agent Activity in Platinum-resistant Epithelial Ovarian Cancer (EOC) Patients (pts),” Journal of Clinical Oncology 34, no. 15_suppl (2016): 5567-5567.

[353] A. R. Yoon, J. Hong, B. K. Jung, H. M. Ahn, and S. Zhang, “Oncolytic adenovirus as Pancreatic Cancer-targeted Therapy: Where Do We Go From Here?,” Cancer Letters 579 (2023): 216456.

[354] M. Bazan-Peregrino, R. Garcia-Carbonero, B. Laquente, et al., “VCN-01 Disrupts Pancreatic Cancer Stroma and Exerts Antitumor Effects,” Journal for ImmunoTherapy of Cancer 9, no. 11 (2021): e003254.

[355] B. L. Musher, E. K. Rowinsky, B. G. Smaglo, et al., “LOAd703, an Oncolytic Virus-based Immunostimulatory Gene Therapy, Combined With Chemotherapy for Unresectable or Metastatic Pancreatic Cancer (LOKON001): Results From Arm 1 of a Non-randomised, Single-centre, Phase 1/2 Study,” The Lancet Oncology 25, no. 4 (2024): 488-500.

[356] Y. Hirooka, H. Kasuya, T. Ishikawa, et al., “A Phase I Clinical Trial of EUS-guided Intratumoral Injection of the Oncolytic Virus, HF10 for Unresectable Locally Advanced Pancreatic Cancer,” BMC cancer 18, no. 1 (2018): 596.

[357] D. Mahalingam, S. Goel, S. Aparo, et al., “A Phase II Study of Pelareorep (REOLYSIN®) in Combination With Gemcitabine for Patients With Advanced Pancreatic Adenocarcinoma,” Cancers (Basel) 10, no. 6 (2018): 160.

[358] D. Mahalingam, G. A. Wilkinson, K. H. Eng, et al., “Pembrolizumab in Combination With the Oncolytic Virus Pelareorep and Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma: A Phase Ib Study,” Clinical Cancer Research 26, no. 1 (2020): 71-81.

[359] S. Nyati, H. Stricker, K. N. Barton, et al., “A Phase I Clinical Trial of Oncolytic adenovirus Mediated Suicide and Interleukin-12 Gene Therapy in Patients With Recurrent Localized Prostate Adenocarcinoma,” PLoS ONE 18, no. 9 (2023): e0291315.

[360] R. Poria, D. Kala, R. Nagraik, et al., “Vaccine Development: Current Trends and Technologies,” Life Sciences 336 (2024): 122331.

[361] E. Lutz, C. J. Yeo, K. D. Lillemoe, et al., “A Lethally Irradiated Allogeneic Granulocyte-macrophage Colony Stimulating Factor-secreting Tumor Vaccine for Pancreatic Adenocarcinoma. A Phase II Trial of Safety, Efficacy, and Immune Activation,” Annals of Surgery 253, no. 2 (2011): 328-335.

[362] J. M. Hardacre, M. Mulcahy, W. Small, et al., “Addition of algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: A Phase 2 Study,” Journal of Gastrointestinal Surgery 17, no. 1 (2013): 94-100. discussion p.100-1.

[363] D. B. Hewitt, N. Nissen, H. Hatoum, et al., “A Phase 3 Randomized Clinical Trial of Chemotherapy with or without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects with Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer,” Annals of Surgery 275, no. 1 (2022): 45-53.

[364] A. A. Wu, K. M. Bever, W. J. Ho, et al., “A Phase II Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) With Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer,” Clinical Cancer Research 26, no. 19 (2020): 5129-5139.

[365] V. Lee, D. Ding, C. Rodriguez, et al., “A Phase 2 Study of Cyclophosphamide (CY), GVAX, Pembrolizumab (Pembro), and Stereotactic Body Radiation (SBRT) in Patients (pts) With Locally Advanced Pancreas Cancer (LAPC),” Journal of Clinical Oncology 39, no. 15_suppl (2021): 4134.

[366] J. Wang, J. Gai, T. Zhang, et al., “Neoadjuvant Radioimmunotherapy in Pancreatic Cancer Enhances Effector T Cell Infiltration and Shortens Their Distances to Tumor Cells,” Science Advances 10, no. 6 (2024): eadk1827.

[367] T. Heumann, C. Judkins, K. Li, et al., “A Platform Trial of Neoadjuvant and Adjuvant Antitumor Vaccination Alone or in Combination With PD-1 Antagonist and CD137 Agonist Antibodies in Patients With Resectable Pancreatic Adenocarcinoma,” Nature Communications 14, no. 1 (2023): 3650.

[368] S. Pant, Z. A. Wainberg, C. D. Weekes, et al., “Lymph-node-targeted, mKRAS-specific Amphiphile Vaccine in Pancreatic and Colorectal Cancer: The Phase 1 AMPLIFY-201 Trial,” Nature Medicine 30, no. 2 (2024): 531-542.

[369] Accessed on Dec 15, 2024. Available at: https://www.globenewswire.com/news-release/2024/12/12/2996042/0/en/Elicio-Therapeutics-Presents-Updated-Results-from-ELI-002-Phase-1-AMPLIFY-201-Study-at-ESMO-Immuno-Oncology-Congress-2024.html.

[370] L. A. Rojas, Z. Sethna, K. C. Soares, et al., “Personalized RNA Neoantigen Vaccines Stimulate T Cells in Pancreatic Cancer,” Nature 618, no. 7963 (2023): 144-150.

[371] X. Wang, W. Wang, S. Zou, et al., “Combination Therapy of KRAS G12V mRNA Vaccine and Pembrolizumab: Clinical Benefit in Patients With Advanced Solid Tumors,” Cell Research 34, no. 9 (2024): 661-664.

[372] FDA approves larotrectinib for solid tumors with NTRK gene fusions. 2018. Accessed on March 15th, 2024. Available at: https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions.

[373] R. C. Doebele, A. Drilon, L. Paz-Ares, et al., “Entrectinib in Patients With Advanced or Metastatic NTRK Fusion-positive Solid Tumours: Integrated Analysis of Three Phase 1-2 Trials,” The Lancet Oncology 21, no. 2 (2020): 271-282.

[374] V. Subbiah, J. Wolf, B. Konda, et al., “Tumour-agnostic Efficacy and Safety of selpercatinib in Patients With RET Fusion-positive Solid Tumours Other Than Lung or Thyroid Tumours (LIBRETTO-001): A Phase 1/2, Open-label, Basket Trial,” The Lancet Oncology 23, no. 10 (2022): 1261-1273.

[375] S. Tao, L. Tian, X. Wang, and Y. Shou, “A Pyroptosis-related Gene Signature for Prognosis and Immune Microenvironment of Pancreatic Cancer,” Frontiers in Genetics 13 (2022): 817919.

[376] C. J. Qiu, X. B. Wang, Z. R. Zheng, et al., “Development and Validation of a Ferroptosis-related Prognostic Model in Pancreatic Cancer,” Investigational New Drugs 39, no. 6 (2021): 1507-1522.

[377] X. Huang, S. Zhou, J. Tóth, and A. Hajdu, “Cuproptosis-related Gene Index: A Predictor for Pancreatic Cancer Prognosis, Immunotherapy Efficacy, and Chemosensitivity,” Frontiers in immunology 13 (2022): 978865.

[378] M. S. Cruz, J. Tintelnot, and N. Gagliani, “Roles of Microbiota in Pancreatic Cancer Development and Treatment,” Gut Microbes 16, no. 1 (2024): 2320280.

[379] A. Sivan, L. Corrales, N. Hubert, et al., “Commensal Bifidobacterium Promotes Antitumor Immunity and Facilitates Anti-PD-L1 Efficacy,” Science 350, no. 6264 (2015): 1084-1089.

[380] B. Routy, E. Le Chatelier, L. Derosa, et al., “Gut Microbiome Influences Efficacy of PD-1-based Immunotherapy Against Epithelial Tumors,” Science 359, no. 6371 (2018): 91-97.

[381] J. Tintelnot, Y. Xu, T. R. Lesker, et al., “Microbiota-derived 3-IAA Influences Chemotherapy Efficacy in Pancreatic Cancer,” Nature 615, no. 7950 (2023): 168-174.

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