Editorial [Hot Topic: Emerging Therapeutic Targets and Agents for Pancreatic Cancer Therapy (Guest Editor: Dr. Felix Ruckert)]

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most malignant tumor diseases exhibiting an unfavorable prognosis. It is well known for its late presentation, the aggressive progression and metastatic spread, along with its poor outcome [1, 2]. In Western countries, PDAC is the fourth leading cause of cancer related death with an overall 5-year survival rate less than 1 % and most patients dying within one year [3]. The management of PDAC patients depends on the stage of disease at time point of diagnosis. Surgical resection followed by adjuvant therapy is the standard treatment for patients with a locally defined tumor stage. Patients undergoing tumor resection have a median survival time of 13-23 months and an overall 5-year-survival of 10-20 % depending on the post-operative treatment [4]. However, 80-85 % of the patients present at an advanced stage, being locally advanced or metastatic, precluding surgical resection [4, 5]. These patients have a very dismal prognosis and the impact of current therapies is very small. Single-agent gemcitabine has been the standard therapy of advanced PDAC over the past decade. Combinations with other cytostatic drugs such as fluorouracil, capecitabine, cisplatin, irinotecan or oxaliplatin did not produce any clear benefit in survival time [6]. Treatment regimens combining 5-fluorouracil, folinic acid and irinotecan (mFOLFIRI.3) or 5-fluorouracil, folinic acid and oxaliplatin (mFOLFOX) offered modest activities as second-line therapy of gemcitabine-refractory PDAC patients and have to be evaluated in further studies [7]. Recently, combinations of gemcitabine and targeted therapies have entered clinical application. However, treatment of advanced PDAC with gemcitabine and the small-molecule EGFR tyrosine kinase inhibitor erlotinib has only marginally improved median survival time compared to gemcitabine monotherapy (6,24 months versus 5,91 months) [8]. Overall, many clinical trials assessing different combinations of chemotherapy with other cytotoxic drugs, radiotherapy or targeted therapies have failed to substantially improve survival times of PDAC patients during the past decade. However, tremendous progresses in treatment of many cancer entities have been made by enabling tumor prevention through early diagnosis and the identification of molecular and cellular targets that are used for combined therapy regimens. Hence, why we have not progressed more in the treatment of PDAC? To achieve a remarkable step forward in the treatment of PDAC patients two main problems have to be solved: i) the late detection of the tumor and its advanced stage of disease at time point of diagnosis and ii) the broad therapy resistance of the tumor. The fact that PDAC causes only unspecific symptoms during tumor development extensively hampers its diagnosis at an early stage. Accordingly, the detection of PDAC at the precursor stage of pancreatic intraepithelial neoplasias (PanINs) is a major aim. Therefore, routine screenings involving abdominal palpations, ultrasonography and determination of serologic markers are discussed at least for high-risk individuals (e.g. with hereditary predisposition) [9]. The identification of markers that are detectable in the serum on the one hand and specifically discriminate between normal pancreatic tissue, chronic pancreatitis and PDAC on the other hand is urgently required allowing a broad screening of even asymptomatic patients. Numerous studies have analyzed the expression profile of PanINs versus normal pancreatic tissues revealing many markers differentiating between normal ducts and PanINs but also between low-grade and “risky” high-grade PanINs [10]. In addition, improvement and usage of novel imaging techniques would also facilitate an early diagnosis of PDAC [11]. Besides the late diagnosis along with a high tumor burden and metastatic spread, the broad failure of PDAC treatment can be related to the pronounced resistance in particular towards chemo- and radiotherapy. To date, these therapies mainly target the tumor cells and often rely on the ability to affect highly proliferating cells. In fact, one hallmark of PDAC is its stroma enriched composition. Besides an intense network of extracellular matrix proteins fibroblasts, myofibroblasts, macrophages and other regulatory immune cells dominate the proportion of tumor cells [9,12-14]. Thus, many promising findings regarding new therapy concepts of PDAC have been made with model systems that have not considered the impact of the stromal compartment providing one explanation for the failure of these strategies in clinical settings. Meanwhile, we and other groups have clearly documented the broad impact of stromal cells on PDAC tumorigenesis and progression e.g. by demonstrating its promoting effect on epithelial-mesenchymal transition (EMT), apoptosis/chemoresistance, migration and invasion [15-18] Preclinical validation of new therapeutic strategies has been often conducted in inappropriate animal models providing an explanation for the diverging results obtained later on in clinical settings. An example is the usage of the VEGF neutralizing antibody bevacizumab which has shown considerable success in the treatment of advanced colorectal cancer [19] and led also to reduction of hypervascularized experimental tumors in PDAC animal models [20] but failed to improve treatment and survival of PDAC patients up to now [21]. Since PDAC is a rather hypovascularized tumor, these findings are comprehensible and point to the need of new preclinical models to better recapitulate aspects of tumorigenesis. Such improved tumor models will allow for new therapeutic concepts involving normalization of tumor perfusion and thereby improving the accessibility of the tumor for drugs. One promising approach was recently published by Olive et al. who use KPC mice as PDAC model systems [22]. These mice develop tumors with pathophysiological and molecular features that resemble those of human PDAC including poor vascularization [23]. Using this PDAC mouse model, a new therapeutic strategy targeting the stroma and tumor compartment by inhibition of Hedgehog signalling was validated demonstrating normalization of the tumor vasculature along with an improved response towards chemotherapy and significant tumor reduction [22]. It will be exciting to see whether these findings can be confirmed in clinical studies. In this review, Assifi and Hines will discuss several strategies of anti-angiogenetic therapies and their potential for clinical application. Since the tumoral stroma essentially promote tumorigenesis of PDAC [13,15-18], its consideration as a therapeutic target is obvious. For the development of an effective PDAC therapy it will be of particular importance to further deepen our understanding of the stromal composition, the tumor stroma interplay and by which therapy stromal cells can be affected. Identification of key players of the tumor stroma interaction will be the most suitable strategy to impair the tumoral microenvironment along with an effective elimination of the PDAC cells. Interdisciplinary initiatives such as the recently founded Pancreatic Cancer Consortium-Kiel (PCC-Kiel) are required to enlarge our knowledge on this highly relevant field of tumor biology. The review by Krautz et al. in this issue will provide an overview on the molecular mechanisms leading to development and progression of PDAC with a special emphasis on the impact of the tumor microenvironment and how this can be therapeutically addressed. Owing to the complex tumor stroma interactions, many signalling pathways are dramatically altered in PDAC cells (and also in stromal cells) implying a deregulated expression of growth factors and their ligands, signalling molecules and transcription factors driving PDAC progression. Targeting of these deregulated signalling pathways offers new strategies to interfere with the tumor stroma interplay and to improve PDAC treatment. In this issue, Falasca et al. will discuss the targeting of the phosphoinositide 3- kinase pathways as therapeutic strategy and Rieder et al. will describe the role of the insulin-like growth factor-I (IGF-1) and its receptor in PDAC, illustrate different strategies by which this interaction can be inhibited and provide an overview on the clinical studies using this therapeutic approach. Further interesting target structures might be the neuropilins and the neuropilin associated molecules. Originally identified as receptors for vascular endothelial growth factors like VEGF-A and VEGF-C, their involvement in different processes of PDAC biology, e.g. chemoresistance, has been widely documented. The review article by Muders will outline the current literature on the neuropilin receptors and their potential as therapeutic target for PDAC treatment....