Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches

Radiation Oncology - Tập 14 Số 1 - 2019
Michael Orth1, Philipp Metzger1, S. Gerum1, Julia Mayerle2, Günter Schneider3, Claus Belka1, M. Schnurr4, Kirsten Lauber3
1Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
2Department of Internal Medicine II, University Hospital, LMU Munich, Munich, Germany
3German Cancer Consortium (DKTK), LMU Munich, 81377, Munich, Germany
4Center of Integrated Protein Science Munich (CIPSM) and Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany

Tóm tắt

Từ khóa


Tài liệu tham khảo

Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, Neale RE, Tempero M, Tuveson DA, Hruban RH, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

Quante AS, Ming C, Rottmann M, Engel J, Boeck S, Heinemann V, Westphalen CB, Strauch K. Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med. 2016;5(9):2649–56.

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.

Font-Burgada J, Sun B, Karin M. Obesity and Cancer: The Oil that Feeds the Flame. Cell Metab. 2016;23(1):48–62.

Rahn S, Zimmermann V, Viol F, Knaack H, Stemmer K, Peters L, Lenk L, Ungefroren H, Saur D, Schafer H, et al. Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. Cancer Lett. 2018;415:129–50.

Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91(14):1194–210.

Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni JF Jr. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48(11):3282–7.

Blot WJ. Alcohol and cancer. Cancer Res. 1992;52(7 Suppl):2119s–23s.

Gapstur SM, Jacobs EJ, Deka A, McCullough ML, Patel AV, Thun MJ. Association of alcohol intake with pancreatic cancer mortality in never smokers. Arch Intern Med. 2011;171(5):444–51.

Pelucchi C, Galeone C, Polesel J, Manzari M, Zucchetto A, Talamini R, Franceschi S, Negri E, La Vecchia C. Smoking and body mass index and survival in pancreatic cancer patients. Pancreas. 2014;43(1):47–52.

Olson SH, Chou JF, Ludwig E, O'Reilly E, Allen PJ, Jarnagin WR, Bayuga S, Simon J, Gonen M, Reisacher WR, et al. Allergies, obesity, other risk factors and survival from pancreatic cancer. Int J Cancer. 2010;127(10):2412–9.

Delitto D, Zhang D, Han S, Black BS, Knowlton AE, Vlada AC, Sarosi GA, Behrns KE, Thomas RM, Lu X, et al. Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment. Clin Cancer Res. 2016;22(7):1787–99.

Zhang S, Wang C, Huang H, Jiang Q, Zhao D, Tian Y, Ma J, Yuan W, Sun Y, Che X, et al. Effects of alcohol drinking and smoking on pancreatic ductal adenocarcinoma mortality: A retrospective cohort study consisting of 1783 patients. Sci Rep. 2017;7(1):9572.

Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, Arslan AA, Bueno-de-Mesquita HB, Gallinger S, Gross M, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42(3):224–8.

Pihlak R, Valle JW, McNamara MG. Germline mutations in pancreatic cancer and potential new therapeutic options. Oncotarget. 2017;8(42):73240–57.

Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, Lilyquist J, Na J, Moore R, Antwi SO, et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018;319(23):2401–9.

Gillen S, Schuster T. Meyer Zum Buschenfelde C, Friess H, Kleeff J: Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.

Werner J, Combs SE, Springfeld C, Hartwig W, Hackert T, Buchler MW. Advanced-stage pancreatic cancer: therapy options. Nat Rev Clin Oncol. 2013;10(6):323–33.

Manji GA, Olive KP, Saenger YM, Oberstein P. Current and Emerging Therapies in Metastatic Pancreatic Cancer. Clin Cancer Res. 2017;23(7):1670–8.

Teague A, Lim KH, Wang-Gillam A. Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies. Ther Adv Med Oncol. 2015;7(2):68–84.

Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.

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

Hall WA, Goodman KA. Radiation therapy for pancreatic adenocarcinoma, a treatment option that must be considered in the management of a devastating malignancy. Radiat Oncol. 2019;14(1):114.

Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World J Gastrointest Oncol. 2016;8(2):186–97.

Brunner TB, Scott-Brown M. The role of radiotherapy in multimodal treatment of pancreatic carcinoma. Radiat Oncol. 2010;5:64.

Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, Crosby T, Jephcott C, Roy R, Radhakrishna G, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013;14(4):317–26.

Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, et al. Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018;4(7):963–9.

Reyngold M, Parikh P, Crane CH. Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results. Radiat Oncol. 2019;14(1):95.

Boldrini L, Cusumano D, Cellini F, Azario L, Mattiucci GC, Valentini V. Online adaptive magnetic resonance guided radiotherapy for pancreatic cancer: state of the art, pearls and pitfalls. Radiat Oncol. 2019;14(1):71.

Nanda RH, El-Rayes B, Maithel SK, Landry J. Neoadjuvant modified FOLFIRINOX and chemoradiation therapy for locally advanced pancreatic cancer improves resectability. J Surg Oncol. 2015;111(8):1028–34.

Buwenge M, Macchia G, Arcelli A, Frakulli R, Fuccio L, Guerri S, Grassi E, Cammelli S, Cellini F, Morganti AG. Stereotactic radiotherapy of pancreatic cancer: a systematic review on pain relief. J Pain Res. 2018;11:2169–78.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39.

Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–30.

Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(13):1270–1.

Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.

Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.

Lemery S, Keegan P, Pazdur R. First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med. 2017;377(15):1409–12.

Dougan SK. The Pancreatic Cancer Microenvironment. Cancer J. 2017;23(6):321–5.

Puri S, Folias AE, Hebrok M. Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease. Cell Stem Cell. 2015;16(1):18–31.

Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP, Pan FC, Akiyama H, Wright CV, Jensen K, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22(6):737–50.

Gidekel Friedlander SY, Chu GC, Snyder EL, Girnius N, Dibelius G, Crowley D, Vasile E, DePinho RA, Jacks T. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell. 2009;16(5):379–89.

Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142(4):730–3 e739.

Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10(10):683–95.

Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.

Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.

Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.

Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185–203 e113.

Mueller S, Engleitner T, Maresch R, Zukowska M, Lange S, Kaltenbacher T, Konukiewitz B, Ollinger R, Zwiebel M, Strong A, et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature. 2018;554(7690):62–8.

Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Tanno S, Skele KL, Hoffman JP, Testa JR. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem. 2002;87(4):470–6.

Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016;30(4):355–85.

Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, Salo-Mullen E, Lowery MA, Diaz LA Jr, Mandelker D, Yu KH, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326–36.

Iguchi E, Safgren SL, Marks DL, Olson RL, Fernandez-Zapico ME. Pancreatic Cancer, A Mis-interpreter of the Epigenetic Language. Yale J Biol Med. 2016;89(4):575–90.

Roe JS, Hwang CI, Somerville TDD, Milazzo JP, Lee EJ, Da Silva B, Maiorino L, Tiriac H, Young CM, Miyabayashi K, et al. Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell. 2017;170(5):875–88 e820.

McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49(3):367–76.

Lomberk G, Blum Y, Nicolle R, Nair A, Gaonkar KS, Marisa L, Mathison A, Sun Z, Yan H, Elarouci N, et al. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nat Commun. 2018;9(1):1978.

Connor AA, Denroche RE, Jang GH, Timms L, Kalimuthu SN, Selander I, McPherson T, Wilson GW, Chan-Seng-Yue MA, Borozan I, et al. Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2017;3(6):774–83.

Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47(10):1168–78.

Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17(4):500–3.

Veenstra VL, Garcia-Garijo A, van Laarhoven HW, Bijlsma MF. Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer. Cancers (Basel). 2018;10(2). https://doi.org/10.3390/cancers10020034 .

Muckenhuber A, Berger AK, Schlitter AM, Steiger K, Konukiewitz B, Trumpp A, Eils R, Werner J, Friess H, Esposito I, et al. Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response. Clin Cancer Res. 2018;24(2):351–9.

Aung KL, Fischer SE, Denroche RE, Jang GH, Dodd A, Creighton S, Southwood B, Liang SB, Chadwick D, Zhang A, et al. Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. Clin Cancer Res. 2018;24(6):1344–54.

Nielsen MF, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol. 2016;22(9):2678–700.

Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, Preall J, Tuveson DA. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFbeta to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2019;9(2):282–301.

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579–96.

Melstrom LG, Salazar MD, Diamond DJ. The pancreatic cancer microenvironment: A true double agent. J Surg Oncol. 2017;116(1):7–15.

Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol. 2009;7(11 Suppl):S48–54.

Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, Pirola RC, Wilson JS. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44(4):534–41.

Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):112–20.

Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60.

Erkan M, Kurtoglu M, Kleeff J. The role of hypoxia in pancreatic cancer: a potential therapeutic target? Expert Rev Gastroenterol Hepatol. 2016;10(3):301–16.

Heinemann V, Reni M, Ychou M, Richel DJ, Macarulla T, Ducreux M. Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. Cancer Treat Rev. 2014;40(1):118–28.

Li N, Li Y, Li Z, Huang C, Yang Y, Lang M, Cao J, Jiang W, Xu Y, Dong J, et al. Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci. 2016;17(6). https://doi.org/10.3390/ijms17060799 .

Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, Riches JC, Marshall JF, Chin-Aleong J, Chelala C, Gribben JG, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013;145(5):1121–32.

Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.

Daniel SK, Sullivan KM, Labadie KP, Pillarisetty VG. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin Transl Med. 2019;8(1):10.

Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67(19):9518–27.

Mahajan UM, Langhoff E, Goni E, Costello E, Greenhalf W, Halloran C, Ormanns S, Kruger S, Boeck S, Ribback S, et al. Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. Gastroenterology. 2018;155(5):1625–39 e1622.

Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128–41.

Hu H, Hang JJ, Han T, Zhuo M, Jiao F, Wang LW. The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer. Tumour Biol. 2016;37(7):8657–64.

Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.

Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, Toriola AT, Nieman RK, Worley LA, Yano M, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–62.

Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin JH, Sun YH, Rech AJ, et al. Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity. 2018;49(1):178–193.e177.

Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N, Werba G, Barilla R, Torres-Hernandez A, Hundeyin M, VRK M, et al. gammadelta T Cells Support Pancreatic Oncogenesis by Restraining alphabeta T Cell Activation. Cell. 2016;166(6):1485–99 e1415.

Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, Gorjestani S, Liudahl SM, Truitt M, Olson P, et al. Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov. 2016;6(3):270–85.

Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB, Bar-Sagi D. IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia. Cancer Discov. 2016;6(3):247–55.

Stromnes IM, Hulbert A, Pierce RH, Greenberg PD, Hingorani SR. T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma. Cancer Immunol Res. 2017;5(11):978–91.

Poschke I, Faryna M, Bergmann F, Flossdorf M, Lauenstein C, Hermes J, Hinz U, Hank T, Ehrenberg R, Volkmar M, et al. Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology. 2016;5(12):e1240859.

Johnson BA 3rd, Yarchoan M, Lee V, Laheru DA, Jaffee EM. Strategies for Increasing Pancreatic Tumor Immunogenicity. Clin Cancer Res. 2017;23(7):1656–69.

Yako YY, Kruger D, Smith M, Brand M. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review. PLoS One. 2016;11(5):e0154016.

Roshani R, McCarthy F, Hagemann T. Inflammatory cytokines in human pancreatic cancer. Cancer Lett. 2014;345(2):157–63.

Poruk KE, Firpo MA, Adler DG, Mulvihill SJ. Screening for pancreatic cancer: why, how, and who? Ann Surg. 2013;257(1):17–26.

Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7.

Makohon-Moore AP, Zhang M, Reiter JG, Bozic I, Allen B, Kundu D, Chatterjee K, Wong F, Jiao Y, Kohutek ZA, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet. 2017;49(3):358–66.

Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13.

Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148(1-2):349–61.

Wang S, Huang S, Sun YL. Epithelial-Mesenchymal Transition in Pancreatic Cancer: A Review. Biomed Res Int. 2017;2017:2646148.

Takano S, Reichert M, Bakir B, Das KK, Nishida T, Miyazaki M, Heeg S, Collins MA, Marchand B, Hicks PD, et al. Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev. 2016;30(2):233–47.

Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017;19(5):518–29.

Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol. 2017;44:43–59.

Mees ST, Mardin WA, Wendel C, Baeumer N, Willscher E, Senninger N, Schleicher C, Colombo-Benkmann M, Haier J. EP300--a miRNA-regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas. Int J Cancer. 2010;126(1):114–24.

Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J, Yuan S, Yamazoe T, Black T, Sahmoud A, Furth EE, et al. EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration. Dev Cell. 2018;45(6):681–95 e684.

Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608–20.

Reichert M, Bakir B, Moreira L, Pitarresi JR, Feldmann K, Simon L, Suzuki K, Maddipati R, Rhim AD, Schlitter AM, et al. Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. Dev Cell. 2018;45(6):696–711.e698.

Stratford JK, Bentrem DJ, Anderson JM, Fan C, Volmar KA, Marron JS, Routh ED, Caskey LS, Samuel JC, Der CJ, et al. A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS Med. 2010;7(7):e1000307.

Chaika NV, Yu F, Purohit V, Mehla K, Lazenby AJ, DiMaio D, Anderson JM, Yeh JJ, Johnson KR, Hollingsworth MA, et al. Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma. PLoS One. 2012;7(3):e32996.

Abel EV, Simeone DM. Biology and clinical applications of pancreatic cancer stem cells. Gastroenterology. 2013;144(6):1241–8.

Kruger A. Premetastatic niche formation in the liver: emerging mechanisms and mouse models. J Mol Med (Berl). 2015;93(11):1193–201.

Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816–26.

Grunwald B, Harant V, Schaten S, Fruhschutz M, Spallek R, Hochst B, Stutzer K, Berchtold S, Erkan M, Prokopchuk O, et al. Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. Gastroenterology. 2016;151(5):1011–24 e1017.

Amrutkar M, Gladhaug IP. Pancreatic Cancer Chemoresistance to Gemcitabine. Cancers (Basel). 2017;9(11). https://doi.org/10.3390/cancers9110157 .

Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit Rev Oncol Hematol. 2017;114:139–52.

Morrison AH, Byrne KT, Vonderheide RH. Immunotherapy and Prevention of Pancreatic Cancer. Trends Cancer. 2018;4(6):418–28.

Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M, Izawa T, Mizukami Y, Okumura T, Kohgo Y. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br J Cancer. 2007;96(3):457–63.

Nakahira S, Nakamori S, Tsujie M, Takahashi Y, Okami J, Yoshioka S, Yamasaki M, Marubashi S, Takemasa I, Miyamoto A, et al. Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer. 2007;120(6):1355–63.

Kurata N, Fujita H, Ohuchida K, Mizumoto K, Mahawithitwong P, Sakai H, Onimaru M, Manabe T, Ohtsuka T, Tanaka M. Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil. Int J Oncol. 2011;39(2):473–82.

Valsecchi ME, Holdbrook T, Leiby BE, Pequignot E, Littman SJ, Yeo CJ, Brody JR, Witkiewicz AK. Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma? BMC Cancer. 2012;12:104.

Duxbury MS, Ito H, Benoit E, Waseem T, Ashley SW, Whang EE. RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. Clin Cancer Res. 2005;11(9):3433–8.

Erkan M, Kleeff J, Esposito I, Giese T, Ketterer K, Buchler MW, Giese NA, Friess H. Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene. 2005;24(27):4421–32.

Hessmann E, Patzak MS, Klein L, Chen N, Kari V, Ramu I, Bapiro TE, Frese KK, Gopinathan A, Richards FM, et al. Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer. Gut. 2018;67(3):497–507.

Caparello C, Meijer LL, Garajova I, Falcone A, Le Large TY, Funel N, Kazemier G, Peters GJ, Vasile E, Giovannetti E. FOLFIRINOX and translational studies: Towards personalized therapy in pancreatic cancer. World J Gastroenterol. 2016;22(31):6987–7005.

Huguet F, Mukherjee S, Javle M. Locally advanced pancreatic cancer: the role of definitive chemoradiotherapy. Clin Oncol (R Coll Radiol). 2014;26(9):560–8.

Quintiliani M. Modification of radiation sensitivity: the oxygen effect. Int J Radiat Oncol Biol Phys. 1979;5(7):1069–76.

Matsumoto S, Kishimoto S, Saito K, Takakusagi Y, Munasinghe JP, Devasahayam N, Hart CP, Gillies RJ, Mitchell JB, Krishna MC. Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice. Cancer Res. 2018;78(14):3783–92.

Maacke H, Jost K, Opitz S, Miska S, Yuan Y, Hasselbach L, Luttges J, Kalthoff H, Sturzbecher HW. DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma. Oncogene. 2000;19(23):2791–5.

Mathews LA, Cabarcas SM, Hurt EM, Zhang X, Jaffee EM, Farrar WL. Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas. 2011;40(5):730–9.

Wang F, Xia X, Yang C, Shen J, Mai J, Kim HC, Kirui D, Kang Y, Fleming JB, Koay EJ, et al. SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy. Clin Cancer Res. 2018;24(13):3176–85.

Cordes N, Frick S, Brunner TB, Pilarsky C, Grutzmann R, Sipos B, Kloppel G, McKenna WG, Bernhard EJ. Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1. Oncogene. 2007;26(48):6851–62.

Hehlgans S, Eke I, Storch K, Haase M, Baretton GB, Cordes N. Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells. Radiother Oncol. 2009;92(3):362–70.

Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL. Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2017;23(1):137–48.

Murphy JD, Adusumilli S, Griffith KA, Ray ME, Zalupski MM, Lawrence TS, Ben-Josef E. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007;68(3):801–8.

Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29(31):4105–12.

Chang DT, Schellenberg D, Shen J, Kim J, Goodman KA, Fisher GA, Ford JM, Desser T, Quon A, Koong AC. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009;115(3):665–72.

Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell. 2017;170(6):1062–78.

Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014;13(11):828–51.

Agbunag C, Bar-Sagi D. Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells. Cancer Res. 2004;64(16):5659–63.

Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111(5):817–22.

Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28(22):3605–10.

Kim YJ, Jung K, Baek DS, Hong SS, Kim YS. Co-targeting of EGF receptor and neuropilin-1 overcomes cetuximab resistance in pancreatic ductal adenocarcinoma with integrin beta1-driven Src-Akt bypass signaling. Oncogene. 2017;36(18):2543–52.

Fleming JB, Shen GL, Holloway SE, Davis M, Brekken RA. Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy. Mol Cancer Res. 2005;3(7):413–23.

Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 2011;3(14):1787–808.

Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PI, et al. Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature. 2013;497(7451):638–42.

Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6.

Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, et al. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J Gastroenterol. 2013;48(4):544–8.

Conradt L, Godl K, Schaab C, Tebbe A, Eser S, Diersch S, Michalski CW, Kleeff J, Schnieke A, Schmid RM, et al. Disclosure of erlotinib as a multikinase inhibitor in pancreatic ductal adenocarcinoma. Neoplasia. 2011;13(11):1026–34.

Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22(3):304–17.

Schneeweis C, Wirth M, Saur D, Reichert M, Schneider G. Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes. Small GTPases. 2018;9(6):457–64.

Diersch S, Wirth M, Schneeweis C, Jors S, Geisler F, Siveke JT, Rad R, Schmid RM, Saur D, Rustgi AK, et al. Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. Oncogene. 2016;35(29):3880–6.

Bergmann L, Maute L, Heil G, Russel J, Weidmann E, Koberle D, Fuxius S, Weigang-Kohler K, Aulitzky WE, Wormann B, 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. Eur J Cancer. 2015;51(1):27–36.

Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, et al. Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals. Cancer Res. 2013;73(7):2221–34.

Vaseva AV, Blake DR, Gilbert TSK, Ng S, Hostetter G, Azam SH, Ozkan-Dagliyan I, Gautam P, Bryant KL, Pearce KH, et al. KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell. 2018;34(5):807–22 e807.

Hayes TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, Aziz M, Kassner M, Bryant KL, Pierobon M, et al. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell. 2016;29(1):75–89.

Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, Kabacaoglu D, Gorgulu K, Dantes Z, Wormann SM, Diakopoulos KN, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24(7):954–60.

Zeitouni D, Pylayeva-Gupta Y, Der CJ, Bryant KL. KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment. Cancers (Basel). 2016;8(4). https://doi.org/10.3390/cancers8040045 .

Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles RP, Rabinovich BA, Hann B, Dankort D, et al. A central role for RAF-->MEK-->ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012;2(8):685–93.

Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, Hieber M, Arbeiter A, Klein S, Kong B, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell. 2013;23(3):406–20.

Alagesan B, Contino G, Guimaraes AR, Corcoran RB, Deshpande V, Wojtkiewicz GR, Hezel AF, Wong KK, Loda M, Weissleder R, et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin Cancer Res. 2015;21(2):396–404.

Ischenko I, Petrenko O, Hayman MJ. A MEK/PI3K/HDAC inhibitor combination therapy for KRAS mutant pancreatic cancer cells. Oncotarget. 2015;6(18):15814–27.

Junttila MR, Devasthali V, Cheng JH, Castillo J, Metcalfe C, Clermont AC, Otter DD, Chan E, Bou-Reslan H, Cao T, et al. Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer. Mol Cancer Ther. 2015;14(1):40–7.

Ciuffreda L, Del Curatolo A, Falcone I, Conciatori F, Bazzichetto C, Cognetti F, Corbo V, Scarpa A, Milella M. Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. Ann Oncol. 2017;28(11):2896–8.

Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, Tejani MA, Seery TE, Dy IA, Al Baghdadi T, et al. Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. JAMA Oncol. 2017;3(4):516–22.

Stoy C, Sundaram A, Rios Garcia M, Wang X, Seibert O, Zota A, Wendler S, Mannle D, Hinz U, Sticht C, et al. Transcriptional co-factor Transducin beta-like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy. EMBO Mol Med. 2015;7(8):1048–62.

Fiskus W, Sharma S, Saha S, Shah B, Devaraj SG, Sun B, Horrigan S, Leveque C, Zu Y, Iyer S, et al. Pre-clinical efficacy of combined therapy with novel beta-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia. 2015;29(6):1267–78.

Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886–918.

Wei F, Zhang Y, Geng L, Zhang P, Wang G, Liu Y. mTOR inhibition induces EGFR feedback activation in association with its resistance to human pancreatic cancer. Int J Mol Sci. 2015;16(2):3267–82.

Utomo WK, Narayanan V, Biermann K, van Eijck CH, Bruno MJ, Peppelenbosch MP, Braat H. mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma. Cancer Lett. 2014;346(2):309–17.

Lou HZ, Weng XC, Pan HM, Pan Q, Sun P, Liu LL, Chen B. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun. 2014;450(2):973–8.

Morran DC, Wu J, Jamieson NB, Mrowinska A, Kalna G, Karim SA, Au AY, Scarlett CJ, Chang DK, Pajak MZ, et al. Targeting mTOR dependency in pancreatic cancer. Gut. 2014;63(9):1481–9.

Soares HP, Ni Y, Kisfalvi K, Sinnett-Smith J, Rozengurt E. Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One. 2013;8(2):e57289.

Soares HP, Ming M, Mellon M, Young SH, Han L, Sinnet-Smith J, Rozengurt E. Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2. Mol Cancer Ther. 2015;14(4):1014–23.

O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500–8.

Hassan Z, Schneeweis C, Wirth M, Veltkamp C, Dantes Z, Feuerecker B, Ceyhan GO, Knauer SK, Weichert W, Schmid RM, et al. MTOR inhibitor-based combination therapies for pancreatic cancer. Br J Cancer. 2018;118(3):366–77.

Driscoll DR, Karim SA, Sano M, Gay DM, Jacob W, Yu J, Mizukami Y, Gopinathan A, Jodrell DI, Evans TR, et al. mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer. Cancer Res. 2016;76(23):6911–23.

Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Gunn S, Smetzer L, Mays TA, Kaiser B, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18(8):2316–25.

Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, Enzinger PC, Allen B, Clark JW, Ryan DP, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–8.

Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, Davis D, Zhang Y, Wolff RA, Abbruzzese JL. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.

Iriana S, Ahmed S, Gong J, Annamalai AA, Tuli R, Hendifar AE. Targeting mTOR in Pancreatic Ductal Adenocarcinoma. Front Oncol. 2016;6:99.

Kordes S, Klumpen HJ, Weterman MJ, Schellens JH, Richel DJ, Wilmink JW. Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2015;75(6):1135–41.

Chan J, Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors. Curr Treat Options Oncol. 2014;15(3):365–79.

Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.

Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW, Korc M. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res. 1997;3(8):1309–16.

Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28(22):3617–22.

Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, et al. 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):256–62.

Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.

Craven KE, Gore J, Korc M. Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma. Cancer Lett. 2016;381(1):201–10.

Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 2003;22(37):5784–91.

Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, Aderka D, Paluch-Shimon S, Kaufman B, Gershoni-Baruch R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111(6):1132–8.

Blair AB, Groot VP, Gemenetzis G, Wei J, Cameron JL, Weiss MJ, Goggins M, Wolfgang CL, Yu J, He J. BRCA1/BRCA2 Germline Mutation Carriers and Sporadic Pancreatic Ductal Adenocarcinoma. J Am Coll Surg. 2018;226(4):630–7 e631.

Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5(4):387–93.

Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, Mitchell G, Fried G, Stemmer SM, Hubert A, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.

Bendell J, O'Reilly EM, Middleton MR, Chau I, Hochster H, Fielding A, Burke W, Burris H 3rd. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann Oncol. 2015;26(4):804–11.

Lowery MA, Kelsen DP, Capanu M, Smith SC, Lee JW, Stadler ZK, Moore MJ, Kindler HL, Golan T, Segal A, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19–26.

O'Reilly EM, Lee JW, Lowery MA, Capanu M, Stadler ZK, Moore MJ, Dhani N, Kindler HL, Estrella H, Maynard H, et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018;124(7):1374–82.

Perkhofer L, Schmitt A, Romero Carrasco MC, Ihle M, Hampp S, Ruess DA, Hessmann E, Russell R, Lechel A, Azoitei N, et al. ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. Cancer Res. 2017;77(20):5576–90.

Hessmann E, Johnsen SA, Siveke JT, Ellenrieder V. Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut. 2017;66(1):168–79.

Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21(10):1163–71.

Krantz BA, O'Reilly EM. Biomarker-Based Therapy in Pancreatic Ductal Adenocarcinoma: An Emerging Reality? Clin Cancer Res. 2018;24(10):2241–50.

McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G, Nemirovsky O, Gillespie JA, Karasinska JM, Kalloger SE, et al. Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. Gastroenterology. 2019. https://doi.org/10.1053/j.gastro.2019.05.004 .

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

Sahin IH, Askan G, Hu ZI, O'Reilly EM. Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity? Ann Oncol. 2017;28(12):2950–61.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):512–6.

Bauer C, Kuhnemuth B, Duewell P, Ormanns S, Gress T, Schnurr M. Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer. Cancer Lett. 2016;381(1):259–68.

Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, Eriksen JA, Moller M, Baksaas I, Lothe RA, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer. 2001;92(3):441–50.

Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, Rocha-Lima CS, Safran H, Lenz HJ, Chiorean EG. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013;17(1):94–100 discussion p. 100-101.

Yan J, Pankhong P, Shin TH, Obeng-Adjei N, Morrow MP, Walters JN, Khan AS, Sardesai NY, Weiner DB. Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent antitumor immunity. Cancer Immunol Res. 2013;1(3):179–89.

NewLink Genetics Announces Results from Phase 3 IMPRESS Trial of Algenpantucel-L for Patients with Resected Pancreatic Cancer [ https://globenewswire.com/news-release/2016/05/09/837878/0/en/NewLink-Genetics-Announces-Results-from-Phase-3-IMPRESS-Trial-of-Algenpantucel-L-for-Patients-with-Resected-Pancreatic-Cancer.html ]. Accessed 30 July.

Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, Coxon F, Ross P, Madhusudan S, Roques T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15(8):829–40.

Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–33.

Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015;350(6266):1387–90.

Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016;375(23):2255–62.

Bauer C, Dauer M, Saraj S, Schnurr M, Bauernfeind F, Sterzik A, Junkmann J, Jakl V, Kiefl R, Oduncu F, et al. Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother. 2011;60(8):1097–107.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.

Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229(1):152–72.

Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.

Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.

Jacobs C, Duewell P, Heckelsmiller K, Wei J, Bauernfeind F, Ellermeier J, Kisser U, Bauer CA, Dauer M, Eigler A, et al. An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma. Int J Cancer. 2011;128(4):897–907.

Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner SV, Stieg MR, Grassmann S, Kobold S, Siveke JT, et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. Cell Death Differ. 2014;21(12):1825–37.

Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015;11(7):1018–30.

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439–48.

Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. Int J Mol Sci. 2019;20(6). https://doi.org/10.3390/ijms20061283 .

Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM, et al. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 2016;44(6):1444–54.

Akce M, Zaidi MY, Waller EK, El-Rayes BF, Lesinski GB. The Potential of CAR T Cell Therapy in Pancreatic Cancer. Front Immunol. 2018;9:2166.

Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, Braiteh F, Ritch PS, Zalupski MM, Bahary N, et al. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2018;36(4):359–66.

Doherty GJ, Tempero M, Corrie PG. HALO-109-301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14(1):13–22.

Kanteti R, Mirzapoiazova T, Riehm JJ, Dhanasingh I, Mambetsariev B, Wang J, Kulkarni P, Kaushik G, Seshacharyulu P, Ponnusamy MP, et al. Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biol Ther. 2018;19(4):316–27.

Begum A, Ewachiw T, Jung C, Huang A, Norberg KJ, Marchionni L, McMillan R, Penchev V, Rajeshkumar NV, Maitra A, et al. The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma. PLoS One. 2017;12(7):e0180181.

Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.

Albeituni SH, Ding C, Yan J. Hampering immune suppressors: therapeutic targeting of myeloid-derived suppressor cells in cancer. Cancer J. 2013;19(6):490–501.

Stromnes IM, Brockenbrough JS, Izeradjene K, Carlson MA, Cuevas C, Simmons RM, Greenberg PD, Hingorani SR. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. 2014;63(11):1769–81.

Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19(13):3404–15.

Linehan D, Noel MS, Hezel AF, Wang-Gillam A, Eskens F, Sleijfer S, Desar IME, Erdkamp F, Wilmink J, Diehl J, et al. Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: Correlation with blood monocyte counts. J Clin Oncol. 2018;36(5_suppl):92.

Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.

Schnurr M, Duewell P, Bauer C, Rothenfusser S, Lauber K, Endres S, Kobold S. Strategies to relieve immunosuppression in pancreatic cancer. Immunotherapy. 2015;7(4):363–76.

Vokes EE. Combined modality therapy of solid tumours. Lancet. 1997;349(Suppl 2):SII4–6.

Niyazi M, Maihoefer C, Krause M, Rodel C, Budach W, Belka C. Radiotherapy and “new” drugs-new side effects? Radiat Oncol. 2011;6:177.

Buchsbaum DJ, Bonner JA, Grizzle WE, Stackhouse MA, Carpenter M, Hicklin DJ, Bohlen P, Raisch KP. Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys. 2002;54(4):1180–93.

Morgan MA, Parsels LA, Kollar LE, Normolle DP, Maybaum J, Lawrence TS. The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin Cancer Res. 2008;14(16):5142–9.

Demols A, Mahin C, Maréchal R, Delaunoit T, Borbath I, Hendlisz A, Jacquy C, Mitine C, Laethem JV. Cetuximab plus chemoradiation combined therapy for locally advanced inoperable pancreatic adenocarcima: A phase I study. J Clin Oncol. 2008;26(15_suppl):4629.

Munter M, Timke C, Abdollahi A, Friess H, Jaeger D, Heeger S, Buchler M, Debus J, Huber P, Krempien R. Final results of a phase II trial [PARC-Study ISRCTN56652283] for patients with primary inoperable locally advanced pancreatic cancer combining intensity modulated radiotherapy (IMRT) with cetuximab and gemcitabine. J Clin Oncol. 2008;26(15_suppl):4613.

Arnoletti JP, Frolov A, Eloubeidi M, Keene K, Posey J, Wood T, Greeno E, Jhala N, Varadarajulu S, Russo S, et al. A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2011;67(4):891–7.

Rembielak AI, Jain P, Jackson AS, Green MM, Santorelli GR, Whitfield GA, Crellin A, Garcia-Alonso A, Radhakrishna G, Cullen J, et al. Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer with Concurrent Tissue Sampling Feasibility Study. Transl Oncol. 2014;7(1):55–64.

Hayman TJ, Wahba A, Rath BH, Bae H, Kramp T, Shankavaram UT, Camphausen K, Tofilon PJ. The ATP-competitive mTOR inhibitor INK128 enhances in vitro and in vivo radiosensitivity of pancreatic carcinoma cells. Clin Cancer Res. 2014;20(1):110–9.

Dai ZJ, Gao J, Kang HF, Ma YG, Ma XB, Lu WF, Lin S, Ma HB, Wang XJ, Wu WY. Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells. Drug Des Devel Ther. 2013;7:149–59.

Williams TM, Flecha AR, Keller P, Ram A, Karnak D, Galban S, Galban CJ, Ross BD, Lawrence TS, Rehemtulla A, et al. Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer. Mol Cancer Ther. 2012;11(5):1193–202.

Park JH, Jung KH, Kim SJ, Fang Z, Yan HH, Son MK, Kim J, Kang YW, Lee JE, Han B, et al. Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer. Oncotarget. 2017;8(68):112893–906.

Yang L, Yang G, Ding Y, Dai Y, Xu S, Guo Q, Xie A, Hu G. Inhibition of PI3K/AKT Signaling Pathway Radiosensitizes Pancreatic Cancer Cells with ARID1A Deficiency in Vitro. J Cancer. 2018;9(5):890–900.

Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y. PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis. 2014;5:e1437.

Durrant DE, Das A, Dyer S, Tavallai S, Dent P, Kukreja RC. Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity. Mol Pharmacol. 2015;88(3):512–23.

Lomax ME, Folkes LK, O'Neill P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin Oncol (R Coll Radiol). 2013;25(10):578–85.

O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell. 2015;60(4):547–60.

Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–94.

Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, Muschel RJ, Brunner TB. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012;13(11):1072–81.

Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3:e441.

Wallez Y, Dunlop CR, Johnson TI, Koh SB, Fornari C, Yates JWT, Bernaldo de Quiros Fernandez S, Lau A, Richards FM, Jodrell DI. The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression. Mol Cancer Ther. 2018;17(8):1670–82.

Morgan MA, Parsels LA, Zhao L, Parsels JD, Davis MA, Hassan MC, Arumugarajah S, Hylander-Gans L, Morosini D, Simeone DM, et al. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 2010;70(12):4972–81.

Venkatesha VA, Parsels LA, Parsels JD, Zhao L, Zabludoff SD, Simeone DM, Maybaum J, Lawrence TS, Morgan MA. Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition. Neoplasia. 2012;14(6):519–25.

Engelke CG, Parsels LA, Qian Y, Zhang Q, Karnak D, Robertson JR, Tanska DM, Wei D, Davis MA, Parsels JD, et al. Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin Cancer Res. 2013;19(16):4412–21.

Al-Ejeh F, Pajic M, Shi W, Kalimutho M, Miranda M, Nagrial AM, Chou A, Biankin AV, Grimmond SM, Australian Pancreatic Cancer Genome I, et al. Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma. Clin Cancer Res. 2014;20(12):3187–97.

Tuli R, Surmak AJ, Reyes J, Armour M, Hacker-Prietz A, Wong J, DeWeese TL, Herman JM. Radiosensitization of Pancreatic Cancer Cells In Vitro and In Vivo through Poly (ADP-ribose) Polymerase Inhibition with ABT-888. Transl Oncol. 2014. https://doi.org/10.1016/j.tranon.2014.04.003 .

Rajan A, Carter CA, Kelly RJ, Gutierrez M, Kummar S, Szabo E, Yancey MA, Ji J, Mannargudi B, Woo S, et al. A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res. 2012;18(8):2344–51.

Brix N, Tiefenthaller A, Anders H, Belka C, Lauber K. Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences. Immunol Rev. 2017;280(1):249–79.

Filatenkov A, Baker J, Mueller AM, Kenkel J, Ahn GO, Dutt S, Zhang N, Kohrt H, Jensen K, Dejbakhsh-Jones S, et al. Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clin Cancer Res. 2015;21(16):3727–39.

Lennon S, Oweida A, Milner D, Phan AV, Bhatia S, Van Court B, Darragh L, Mueller AC, Raben D, Martinez-Torrecuadrada JL, et al. Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination. Clin Cancer Res. 2019;25(11):3352-65.

Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015;16(7):795–803.

Shi F, Wang X, Teng F, Kong L, Yu J. Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol Ther. 2017;18(3):137–41.

Azad A, Yin Lim S, D'Costa Z, Jones K, Diana A, Sansom OJ, Kruger P, Liu S, McKenna WG, Dushek O, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017;9(2):167–80.

Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24(5):589–602.

Timke C, Winnenthal HS, Klug F, Roeder FF, Bonertz A, Reissfelder C, Rochet N, Koch M, Tjaden C, Buechler MW, et al. Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer. BMC Cancer. 2011;11:134.

Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014;41(5):843–52.

Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, Inghirami G, Coleman CN, Formenti SC, Demaria S. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618.

Baird JR, Friedman D, Cottam B, Dubensky TW Jr, Kanne DB, Bambina S, Bahjat K, Crittenden MR, Gough MJ. Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors. Cancer Res. 2016;76(1):50–61.

Rech AJ, Dada H, Kotzin JJ, Henao-Mejia J, Minn AJ, Twyman-Saint Victor C, Vonderheide RH. Radiotherapy and CD40 Activation Separately Augment Immunity to Checkpoint Blockade in Cancer. Cancer Res. 2018;78(15):4282–91.

Lee V, Rodriguez C, Shupe E-M, Chen L, Parkinson R, Durham JN, Sugar E, Wilt C, McIntyre KR, Hacker-Prietz A, et al. Phase II study of GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX) with PD-1 blockade antibody and stereotactic body radiation therapy (SBRT) for locally advanced pancreas cancer (LAPC). J Clin Oncol. 2017;35(15_suppl):TPS4154.