Shifting paradigm of developing biologics for the treatment of pancreatic adenocarcinoma
Review Article

Shifting paradigm of developing biologics for the treatment of pancreatic adenocarcinoma

Ying Zeng1, Agnieszka A. Rucki2,3, Xu Che2,3,4, Lei Zheng2,3,5,6

1Department of Medical Oncology, Geisinger Medical Center, Danville, PA 17822, USA; 2Department of Oncology, 3The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; 4Department of Abdominal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; 5Department of Surgery, 6The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Contributions: (I) Conception and design: Y Zeng, L Zheng; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Lei Zheng. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Email:

Abstract: Pancreatic adenocarcinoma is still widely considered as a deadly disease even though there are substantial therapeutic developments in the past decade. Using combinational chemotherapy regimens, represented by gemcitabine plus nab-paclitaxel and FOLFIRINOX, was able to improve overall survival in patients with advanced disease to a limited extent. It has been a challenge to develop targeted therapies that are focused on the neoplasm cells of pancreatic adenocarcinoma. Recently, targeting the stroma and immune compartments of pancreatic adenocarcinoma has shown promising results. The paradigm of biologics drug development therefore has been shifted by extending to these exciting areas. Although some of the preclinical and clinical researches in targeting the tumor microenvironment of pancreatic adenocarcinoma have shown promising results, others have resulted in controversial findings. Both comprehensive and in-depth researches on the basic science of the tumor microenvironment of pancreatic adenocarcinoma are thus warranted for the development of effective biologics that target the tumor microenvironment. Moreover, an ideal treatment for pancreatic adenocarcinoma shall be a combination of targeting both neoplastic cells and the tumor microenvironment.

Keywords: Pancreatic adenocarcinoma; chemotherapy; targeted therapy; immunotherapy

Submitted May 16, 2016. Accepted for publication Aug 04, 2016.

doi: 10.21037/jgo.2016.10.02

The landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for four frequently mutated genes (KRAS, TP53, p16/CDKN2A, DPC4/SMAD4). So far, there is no effective targeted therapy for these four driver mutations. It is known over 90 percent of PDACs harbor a KRAS gene mutation. Mutational active oncogenic KRAS engages the PI3K-PDK1-AKT pathway to drive cancer initiation, progression and maintenance. Additionally, activated KRAS signals through the MAPK pathway via RAF-MEK1/2-ERK1/2. However, all attempts to target KRAS directly have failed in the clinic and KRAS is still widely considered to be undruggable (1). Epidermal growth factors receptor (EGFR) is a direct upstream of KRAS (2). It was reported that drugs targeting EGFR will lose efficiency if KRAS is activated (3,4). Although erlotinib, a tyrosine kinase inhibitor of EGFR, is approved by FDA in combination with gemcitabine for the first-line treatment of advanced PDA, it offers minimal clinical benefit (5), likely due to the high prevalence of the KRAS mutation. For the same reason, it is not surprising to see the negative results of the phase III study of testing the combination of gemcitabine and anti-EGFR antibodies. Not until we have more effective therapeutic agents to target the four frequently mutated genes in PDAC, developing targeted therapies that are solely focused on the neoplasm cells of PDAC is unlikely to be successful.

With a better understanding of complex stromal constituents and desmoplastic stromal reaction being crucial to the biology of PDAC, the paradigm of drug development in PDAC has been shifted to focuses on both neoplastic cells and their tumor microenvironment. It first became evident that targeting the stromal components showed a benefit in preclinical mouse models of PDAC (6). Subsequently, clinical developments have been attempted in targeting the following stromal components.

Sonic hedgehog (Shh)

Beneficial effect of Shh pathway inhibition has been demonstrated in the treatment of basal cell carcinoma. Vismodegib (GDC-0449), a small-molecule inhibitor of the hedgehog pathway, showed 30–43% response rate in advanced basal-cell carcinoma and was FDA approved in 2012 (7). Inhibition of Shh in preclinical mouse models showed better gemcitabine delivery, stromal depletion and increased vascularization of PDAC tumors (8). Based on those intriguing results, a few different Shh inhibitors have recently been tested in clinical trials in combination with gemcitabine or FOLFIRINOX (the combination of 5-FU, irinotecan, and oxaliplatin) for metastatic PDACs (9). IPI-926 (Smo inhibitor) given in combination with gemcitabine showed partial responses in three out of nine patients, however the combination of IPI-926 and gemcitabine did not yield any survival benefit comparing to gemcitabine alone (10). Vismodegib is currently being tested in combination with gemcitabine and nab-paclitaxel (human-albumin-bound paclitaxel, ABRAXANE) in a single arm phase II clinical trial in patients with previously untreated metastatic PDA to evaluate disease free survival (DFS) (NCT01088815). Overall, the results from targeting the stroma of PDAC through Shh inhibition have been disappointing. Studies in the mouse models of PDACs are ongoing in an attempt to reveal the underlying mechanisms of the failure in targeting Shh. Given the complexity of the signaling in the stroma, simultaneous modulation of other stromal signaling is perceived as the next step of drug development.

Hyaluronic acid

Hyaluronic acid is another important stromal target in PDAC. It has been demonstrated in mouse models of PDAC, enzymatic degradation of HA resulted in increased gemcitabine tumor cytotoxicity due to relief of vascular collapse (11). Those prove-of-principle experiments led to the development of PEGPH20 (pegylated recombinant human hyaluronidase—an enzyme that degrades HA). In phase Ib clinical trial, PEGPH20 given with gemcitabine in patients with stage IV PDAC resulted partial response in 43% of patients and stable disease in additional 30% patients. Specifically for those patients whose PDACs expressed high level of HA, partial response was seen in 64% patients (12). In the randomized phase II clinical trial, PEGPH20 is given in combination with gemcitabine and nab-paclitaxel, in the subgroup of patients whose PDACs express a high level of HA, gemcitabine and nab-paclitaxel in combination with PEGPH20 yielded a significantly higher objective response rate (52% vs. 24%) and longer (DFS, 9.2 vs. 4.3 months; HR, 0.39; P=0.05) than gemcitabine and nab-paclitaxel. A trend toward improved overall survival was also observed (12 vs. 9 months; HR, 0.62). (ASCO-GI 2016 abstract 439). In light of this result, a phase III study has been initiated to select patients with high HA PDACs for comparing gemcitabine and nab-paclitaxel with PEGPH20 vs. placebo (NCT02715804).


The activation of JAK/STAT pathway is very well known in hematologic malignancies. The JAK family of kinases includes JAK1, JAK2, JAK3 and TYK2. JAK kinases are activated through tyrosine phosphorylation of the cytoplasmic domains of cytokine receptors upon cytokine binding. Activation of JAK promotes recruitment of the transcription factors STAT to the receptor complex, leading to the nuclear translocation of STAT and transcription of genes that regulate cell proliferation, differentiation and apoptosis (13,14).

In addition to the well-studied somatic point mutation in JAK2 gene in myeloproliferative neoplasms, over activation of JAK/STAT pathway with or without JAK2 mutation has been reported in some solid tumors and inflammatory conditions (15,16). Emerging preclinical evidence showed activation of JAK/STAT pathway and related inflammatory process promote development and progression of pancreatic cancer (17,18). In particular, STAT3 plays a critical role and is required for KRAS induced pancreatic tumorigenesis (19-22).

Proinflammatory cytokine activity is associated with weight loss, hypermetabolism, anorexia, cachexia, and it is also strongly implicated in the development and progression of malignancies (23-25). Among the many inflammatory markers studied to date, serum C-reactive protein (CRP) is the most well-characterized inflammation marker in cancer with variety of clinical scenarios including pancreatic cancer (26). The systemic inflammation-based Glasgow Prognostic Score (GPS), the combination of CRP and albumin, is clearly implicated in the prognosis of patients with cancer (27).

The role of ruxolitinib, a potent JAK1/2 inhibitor, in myeloproliferative neoplasms is very well established. Its efficacy in treatment of pancreatic cancer was tested in combination with capecitabine in a randomized, double-blind, phase II clinical trial (the RECAP trial). Patients with metastatic pancreatic cancer who failed gemcitabine based chemotherapy were randomized 1:1 to ruxolitinib plus capecitabine or placebo plus capecitabine. Even though the trial didn’t reach its primary end point for overall survival (HR, 0.79; P=0.25), the pre-specified subgroup analysis of patients with inflammation, defined by CRP greater than the study population median (13 mg/L), overall survival was significantly greater with ruxolitinib compared with placebo (HR, 0.47; P=0.011) (28). Based on these data, two randomized, double-blind, phase III trials (the JANUS 1 and JANUS 2) were undertaken to test ruxolitinib or placebo in combination with capecitabine in patients with advanced or metastatic pancreatic cancer who have failed or are intolerant to first-line chemotherapy (NCT02117479, NCT02119663). However JANUS 1 and JANUS 2 trials were both discontinued after a planned interim analysis of JANUS 1 demonstrated that ruxolitinib plus capecitabine did not show a sufficient level of efficacy to warrant continuation. A more specific biomarker may be needed for selecting patients that may benefit from the treatment with JAK inhibitors.

Transforming growth factor β (TGF-β )

TGF-β expression is increased in PDAC and associated with poor prognosis (29,30). The sources of TGF-β appear to be predominant in the tumor microenvironment. TGF-β is a multifunctional cytokine, including inhibiting cell growth through nuclear SMAD3, activating vascular endothelial growth factor A (VEGF-A) to promote angiogenesis and metastases, and driving a fibrous reaction in the stroma (31). Trabedersen, an antisense molecule against TGF-β2, was tested in a phase I/II study for stage III/IV PDAC, malignant melanoma and metastatic colorectal cancer patients and showed a median overall survival of 13.4 months (32). A humanized monoclonal antibodies against TGF-β, fresolimumab, showed antitumor activity in a phase I study in patients with advanced malignant melanoma and renal cell carcinoma (33). Galunisertib, a small molecule inhibitor of TGF-βR1 serine/threonine kinase, also showed potential antitumor activity in glioma, PDAC and lung cancer (34). As TGF-β is a central molecule mediating multiple immunosuppressive signals, it is more intriguing to target TGF-β for the enhancement of antitumor immune response by combining TGF-β inhibitors with immunotherapy (35).

Immune compartments of the tumor microenvironment

Several approaches to immunotherapy for PDAC have shown promise in early clinical trials. The goal of immunotherapy in PDAC has been focused on inducing tumor infiltration, activation of effector cells (i.e., CD8+ T cells) and consequent CD8+ T cell dependent tumor lysis. Multiple clinical trials demonstrated that enhanced response of interferon-secreting mesothelin-specific CD8+ T cells in peripheral lymphocytes correlated with better survival in patients with resected or metastatic PDAC who received lethally irradiated allogeneic GM-CSF secreting whole cell vaccine (GVAX) (36-38). A trend of improvement in overall survival in heavily treated metastatic PDAC patients was observed in a pilot study testing the combination of GVAX and ipilimumab (an anti-CTLA-4 therapeutic antibody) comparing to ipilimumab alone; it thus supported the role of CTLA-4 blockade in enhancing anti-tumor response of GVAX (39). However, it is still not entirely clear how vaccine-based immunotherapy activates anti-tumor effector cells within the tumor microenvironment, and identification of new targets in tumor microenvironment may help the development of immune modulatory therapies (40).

CD40, a potential immune modulatory target in tumor microenvironment, is a costimulatory molecule found on antigen presenting cells (APCs) that is required for their activation by CD4+ helper cells. Only activated APCs can in turn activate naive CD8+ T cells into cytotoxic effector cells. It was demonstrated in some studies that CD40 activating antibody can effectively stimulate APCs in the absence of CD4+ helper cells, which then can successfully prime and activate CD8+ T cells (41). Those preclinical studies led to development of activating CD40 antibodies, which have been tested in clinical trials. Agonist CD40 monoclonal antibody was shown to induce clinical responses in combination with gemcitabine in patients with surgically incurable PDAC; in addition, in the same study, it demonstrated the antitumor activity of agonist CD40 mAb is T cell-independent, tumoricidal cells were CD40 activated macrophages and not CD8+ T cells as originally expected (42). An agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine was tested in a phase I study in chemotherapy-naive patients with advanced PDAC. The data is promising with four out of 22 patients achieved a partial response (43).

More recently, CCL2/CCR2 chemokine signaling axis has been shown to be a promising target in treatment of PDAC. CCL2/CCR2 facilitates the recruitment of inflammatory monocytes and metastasis-associated macrophages in tumor microenvironment which are crucial for tumor immune evasion, treatment resistance and disease progression (44,45). Human pancreatic cancer produces CCL2, and immunosuppressive CCR2+ macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival (46). It was demonstrated in preclinical study that targeting CCR2 improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses (47). PF-04136309, an oral small-molecule CCR2 inhibitor, in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil) was tested in previously untreated patients with borderline resectable and locally advanced pancreatic cancer in a phase Ib trial. It demonstrated higher objective tumor response in comparison to patients who received FOLFIRINOX alone (48). A phase Ib/II study of PF-04136309 in combination with gemcitabine plus nab-paclitaxel in first-line metastatic pancreatic cancer patients was recently initiated (NCT02732938).

Other targets in the shifted paradigm of drug development

Notch signaling in cancer stem cells

Cancer stem cells are thought to play an important role in the recurrence and metastasis of PDACs, thus, have become a target for the drug development for PDAC. A growing body of evidence suggests that aberrant Notch pathway activation has been implicated in the initiation and progression of different malignancies including pancreatic cancer. Notch pathway components were found to be upregulated in pancreatic cancer stem cells. Activation of Notch signaling contributes to the acquisition of epithelia-mesenchymal transition (EMT) phenotype, and maintaining the cancer stem cell population, therefore increased chemoresistance (49-52). Notch signaling pathway has substantial crosstalk with other signaling pathways that play a significant role in cancer, including PI3K/Akt pathway.

Two main strategies were developed to target the Notch pathway. The inhibitors of the gamma secretase are the first Notch-targeting drugs. Gamma secretase frees up the Notch intracellular domain and allows the subsequent activation of the downstream signaling. A number of preclinical studies revealed gamma secretase inhibitors were effective in inducing apoptosis, tumor regression and controlling metastatic dissemination (53,54). Multiple gamma secretase inhibitors (MK-0752, RO4929097, BMS-906024, PF-03084014) are developed and currently are being evaluated in phase I and I/II clinical trials in metastatic disease including pancreatic cancer. Phase I/II study of PF-03084014 in combination with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic adenocarcinoma is currently undergoing (NCT02109445). Another phase II study of RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma is already completed its first stage, however the development of this drug has been discontinued (55).

Unlike gamma secretase inhibitors which result in pan-Notch inhibition, monoclonal antibody OMP-59R5 (tarextumab) selectively inhibits Notch2/3, and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments (56). Final results of phase Ib of OMP-59R5 in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic cancer was presented at 2015 Gastrointestinal Cancer Symposium. Encouraging anti-tumor activity was observed. A total of 40 patients received treatment at 7 dose levels. Ten patients achieved partial response; stable disease was observed in 17 patients. The main dose limiting toxicity was diarrhea (ASCO-GI 2015 abstract 278). It is currently being examined in phase II ALPINE trial.

Targeting poly(ADP-ribose) polymerase (PARP) and DNA repair mechanism for familial pancreatic cancer

Additional focus of drug development is given toward the genetic defects that cause the familial pancreatic cancer. Studies indicate that about ten percent of patients with pancreatic cancer have a known genetic alteration that predisposes them to the disease. Germline mutations in BRCA1 and especially BRCA2 are associated with an increased risk of pancreatic cancer. About one percent of non-BRCA1/BRCA2 deficient familial breast cancer are contributed by germline defects in PALB2 (partner and localizer of BRCA2) gene. The PALB2 protein binds with BRCA2 protein and stabilizes it in the nucleus; the BRCA2/PALB2 complex is part of the Fanconi anemia DNA repair pathway that acts on double-stranded DNA repair.

BRCA1/BRCA2 encodes proteins critical for homologous recombination-mediated DNA repair which mediates DNA double strand breaks (DSBs). In the absence of functional BRCA1/BRCA2 or PALB2, DSBs are repaired by the error-prone non-homologous end joining pathway which leads to genetic instability.

Tumors with mutations in the BRCA genes are vulnerable to specific DNA-damaging agents and DNA repair inhibitors. Those are the platinum-based chemotherapy agents and the newer class of drugs known as PARP inhibitors. Platinum induces inter-strand DNA cross-link; PARP inhibitors work through several mechanism: inhibition of base excision repair and trapping of PARP which leading to the induction of double-stranded breaks after stalling and collapse of the DNA replication forks (57-59).

Tumor responses and progression-free survival benefit with PARP inhibitor olaparib in breast and ovarian cancers associated with germline BRCA1/2 mutations were demonstrated in multiple clinical trials (60-63). The clinical benefits of using platinum and PARP inhibitors in patients with pancreatic cancer and BRCA1/BRCA2 mutation have been demonstrated in a few retrospective studies. One study included 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1). Median OS for patients with stage III/IV disease was 12 months (95% CI: 6–15 months), and superior OS was observed for patients with stage III/IV treated with platinum vs. those treated with non-platinum chemotherapies (22 vs. 9 months; P=0.039) (64,65). Early phase clinical trials showed some promising results. Olaparib as monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation was tested in a phase II study. A total of 62 patients with pancreatic cancer who had prior gemcitabine treatment were included. The reported tumor response rate was 12.9%, stable disease was observed in 35% patients (66). Large scale prospective trials are still awaited to confirm the clinical benefits of PARP inhibitors in PDACs with BRCA1/BRCA2 mutation.


While the results of targeting the driver mutations in PDACs are disappointing, our understanding of the tumor microenvironment of PDACs has advanced substantially in the last decade. Targeting the stroma and immune compartments of PDACs has shown promising results. The paradigm of biologics drug development thus has been extended to an exciting area. Nevertheless, results from some preclinical and clinical studies targeting the tumor microenvironment were still controversial, suggesting a comprehensive and in-depth research on the basic science of the tumor microenvironment of pancreatic adenocarcinoma are warranted. On another hand, targeting a single aspect of PDACs is unlikely successful. In the future, when the difficulty in targeting tumor cells has also been overcome, the ideal treatment strategy for PDAC shall target tumor cells and the tumor microenvironment simultaneously.


Funding: This work was supported in part by NIH R01 CA169702 (L Zheng), R01 CA19729 (L Zheng), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (L Zheng), and the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (L Zheng).


Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Eser S, Schnieke A, Schneider G, et al. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer 2014;111:817-22. [Crossref] [PubMed]
  2. Raponi M, Winkler H, Dracopoli NC. KRAS mutations predict response to EGFR inhibitors. Curr Opin Pharmacol 2008;8:413-8. [Crossref] [PubMed]
  3. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091-6. [Crossref] [PubMed]
  4. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11:753-62. [Crossref] [PubMed]
  5. Philip PA, Benedetti J, Corless CL, 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;28:3605-10. [Crossref] [PubMed]
  6. Rucki AA, Zheng L. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J Gastroenterol 2014;20:2237-46. [Crossref] [PubMed]
  7. Sobanko JF, Okman J, Miller C. Vismodegib: a hedgehog pathway inhibitor for locally advanced and metastatic basal cell carcinomas. J Drugs Dermatol 2013;12:s154-5. [PubMed]
  8. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457-61. [Crossref] [PubMed]
  9. Liss AS, Thayer SP. Therapeutic targeting of pancreatic stroma. Available online:
  10. Stephenson J, Richards DA, Wolpin BM, et al. The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer. J Clin Oncol 2011;29:abstr 4114.
  11. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418-29. [Crossref] [PubMed]
  12. Strimpakos AS, Saif MW. Update on phase I studies in advanced pancreatic adenocarcinoma. Hunting in darkness? JOP 2013;14:354-8. [PubMed]
  13. Levine RL, Pardanani A, Tefferi A, et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007;7:673-83. [Crossref] [PubMed]
  14. Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 2013;122:893-901. [Crossref] [PubMed]
  15. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9:798-809. [Crossref] [PubMed]
  16. O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013;368:161-70. [Crossref] [PubMed]
  17. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456-69. [Crossref] [PubMed]
  18. Scholz A, Heinze S, Detjen KM, et al. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 2003;125:891-905. [Crossref] [PubMed]
  19. Li Hd, Huang C. STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS One 2011;6:e25941. [Crossref] [PubMed]
  20. Wei D, Le X, Zheng L, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003;22:319-29. [Crossref] [PubMed]
  21. Zhao S, Venkatasubbarao K, Lazor JW, et al. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res 2008;68:4221-8. [Crossref] [PubMed]
  22. Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011;71:5020-9. [Crossref] [PubMed]
  23. Fearon KC, Barber MD, Falconer JS, et al. Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia. World J Surg 1999;23:584-8. [Crossref] [PubMed]
  24. Diakos CI, Charles KA, McMillan DC, et al. Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014;15:e493-503. [Crossref] [PubMed]
  25. Elinav E, Nowarski R, Thaiss CA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013;13:759-71. [Crossref] [PubMed]
  26. Nakachi K, Furuse J, Ishii H, et al. Prognostic factors in patients with gemcitabine-refractory pancreatic cancer. Jpn J Clin Oncol 2007;37:114-20. [Crossref] [PubMed]
  27. Nixon AB, Pang H, Starr MD, et al. Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). Clin Cancer Res 2013;19:6957-66. [Crossref] [PubMed]
  28. Hurwitz HI, Uppal N, Wagner SA, et al. Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed. J Clin Oncol 2015;33:4039-47. [Crossref] [PubMed]
  29. Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology 2007;7:423-35. [Crossref] [PubMed]
  30. Achyut BR, Yang L. Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment. Gastroenterology 2011;141:1167-78. [Crossref] [PubMed]
  31. Zhang H, Liu C, Kong Y, et al. TGFβ signaling in pancreatic ductal adenocarcinoma. Tumour Biol 2015;36:1613-18. [Crossref] [PubMed]
  32. Oettle H, Seufferlein T, Luger T, et al. Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. J Clin Oncol 2012;30:abstr 4034.
  33. Morris JC, Tan AR, Olencki TE, 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 2014;9:e90353. [Crossref] [PubMed]
  34. Fujiwara Y, Nokihara H, Yamada Y, et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2015;76:1143-52. [Crossref] [PubMed]
  35. Soares KC, Rucki AA, Kim V, et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget 2015;6:43005-15. [PubMed]
  36. Lutz E, Yeo CJ, Lillemoe KD, 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 2011;253:328-35. [Crossref] [PubMed]
  37. Laheru D, Lutz E, Burke J, et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 2008;14:1455-63. [Crossref] [PubMed]
  38. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS 207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 2015;33:1325-33. [Crossref] [PubMed]
  39. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013;36:382-9. [Crossref] [PubMed]
  40. Lutz ER, Wu AA, Bigelow E, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2014;2:616-31. [Crossref] [PubMed]
  41. Diehl L, den Boer AT, Schoenberger SP, et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 1999;5:774-9. [Crossref] [PubMed]
  42. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011;331:1612-6. [Crossref] [PubMed]
  43. Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 2013;19:6286-95. [Crossref] [PubMed]
  44. Qian BZ, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011;475:222-5. [Crossref] [PubMed]
  45. Zhao L, Lim SY, Gordon-Weeks AN, et al. Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 2013;57:829-39. [Crossref] [PubMed]
  46. Sanford DE, Belt BA, Panni RZ, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 2013;19:3404-15. [Crossref] [PubMed]
  47. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013;73:1128-41. [Crossref] [PubMed]
  48. Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet oncology 2016;17:651-62. [Crossref] [PubMed]
  49. Güngör C, Zander H, Effenberger KE, et al. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res 2011;71:5009-19. [Crossref] [PubMed]
  50. Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett 2011;307:26-36. [Crossref] [PubMed]
  51. Mazur PK, Einwachter H, Lee M, et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA 2010;107:13438-43. [Crossref] [PubMed]
  52. Abel EV, Kim EJ, Wu J, et al. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One 2014;9:e91983. [Crossref] [PubMed]
  53. Yabuuchi S, Pai SG, Campbell NR, et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer Lett 2013;335:41-51. [Crossref] [PubMed]
  54. Mizuma M, Rasheed ZA, Yabuuchi S, et al. The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. Mol Cancer Ther 2012;11:1999-2009. [Crossref] [PubMed]
  55. De Jesus-Acosta A, Laheru D, Maitra A, et al. A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Invest New Drugs 2014;32:739-45. [Crossref] [PubMed]
  56. Yen WC, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res 2015;21:2084-95. [Crossref] [PubMed]
  57. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012;72:5588-99. [Crossref] [PubMed]
  58. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913-7. [Crossref] [PubMed]
  59. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-21. [Crossref] [PubMed]
  60. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235-44. [Crossref] [PubMed]
  61. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010;376:245-51. [Crossref] [PubMed]
  62. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-92. [Crossref] [PubMed]
  63. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011;12:852-61. [Crossref] [PubMed]
  64. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014;111:1132-8. [Crossref] [PubMed]
  65. Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist 2011;16:1397-402. [Crossref] [PubMed]
  66. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and germline BRCA1/2 mutation. J Clin Oncol 2015;33:244-50. [Crossref] [PubMed]
Cite this article as: Zeng Y, Rucki AA, Che X, Zheng L. Shifting paradigm of developing biologics for the treatment of pancreatic adenocarcinoma. J Gastrointest Oncol 2017;8(3):441-448. doi: 10.21037/jgo.2016.10.02