Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 5, 2011

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....

Introduction: This review provides an overview of the molecular mechanisms and pathways known to enhance development and progression of pancreatic ductal adenocarcinoma (PDAC). Results: Today, the concept that progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutation in K-ras, p16INK4A, p53 and Smad4 is widely accepted. Multiple signaling pathways that PDAC utilizes to acquire its tumorigenic features have been identified. Recent data suggest that reactivated developmental signaling pathways play a role in oncogenesis of PDAC. Furthermore, it is now clear that the tumor microenvironment actively promotes invasion and tumor growth through a complex of interactions of different cellular components. Conclusion: PDAC is still a challenging entity for physicians and scientists. Despite of recent advances in understanding its molecular biology, treatment options remain limited. Distinct tumor stroma interactions and apoptotic resistance lead to frequent failure of current chemotherapy. An early and aggressive tumor infiltration in combination with a late diagnosis prevents successful surgical therapy. Thus, our primary goal remains to translate the increasing knowledge of molecular pathogenesis of this disease into successful therapeutic strategies. Apart from tumor cell biology, the complex interactions of PDAC cells with their microenvironment have to be focus of future molecular research.

Treatment of pancreatic cancer should be a relatively simple clinical problem, all that is needed is to find the features of pancreatic cancer cells that distinguish them from normal cells and target these differences. This is the basis of current therapies including gemcitabine and 5-FU which target DNA synthesis. Unfortunately, cancer cells become resistant to these therapies: By exclusion of drugs from cancer cells; by changes in enzymes metabolising the drugs; or by becoming more resistant to stress and apoptosis. Increasing levels of the drugs is limited by their somatic toxicity so numerous alternative therapies have been proposed. Testing these alternatives in clinical trials will be difficult unless they work with the standard treatments (e.g. gemcitabine). To date most work has concentrated on combining different S-phase targeting agents. Further incremental increase in survival benefit should be possible by targeting resistance to apoptosis, targeting stroma or even targeting multiple pathways in combination with gemcitabine.

Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

There is an unquestionable need for more effective therapies for pancreatic cancer. Aptamers are single-stranded DNA or RNA oligonucleotide ligands whose 3-dimensional structures are dictated by their sequences. Aptamers have been generated against numerous purified protein targets using an iterative in vitro selection technique known as Systematic Evolution of Ligands by EXponential enrichment (SELEX). Several biochemical properties make them attractive tools for use in an array of biological research applications and as potential pharmacologic agents. Isolated aptamers may directly affect target protein function, or they may also be modified for use as delivery agents for other therapeutic cargo or as imaging agents. More complex selections, using whole cancer cells or tumor tissue, may simultaneously identify novel or unexpected targets and aptamers to inhibit them. This review summarizes recent advances in the field of aptamers and discusses aptamer targets that have relevance to pancreatic cancer.

The Neuropilin receptors are increasingly recognized as receptors for vascular endothelial growth factors like VEGF-A and VEGF-C as well as other important growth factors like HGF and FGF in human vasculature and in tumor cells. More and more studies show an important role of Neuropilin in cancer biology suggesting that these transmembrane proteins might be an emerging target for new therapies in different subsets of cancer. Interestingly, blocking the adaptor protein GIPC1/Synectin that interacts with Neuropilin might be another interesting avenue for therapy. This review summarizes unfolding scientific data on these receptors and its interacting protein GIPC1/Synectin as molecular targets for therapy in pancreatic ductal adenocarcinoma.

Epithelial to mesenchymal transition (EMT) is a biological process that allows well-differentiated, polarized epithelial cells to undergo a conversion to motile, unpolarized mesenchymal cells. EMT plays crucial roles during implantation, embryogenesis, and organ development (Type 1 EMT), is associated with tissue regeneration and organ fibrosis (Type 2 EMT), and involved in cancer invasion, metastasis, and drug resistance (Type 3 EMT). Since aggressiveness and drug resistance are hallmarks of ductal pancreatic cancer, significant effort has been undertaken in recent years to elucidate molecular EMT mechanisms in this dismal malignancy. This represents a formidable challenge for several reasons: EMT is a dynamic process, both with regard to spatial and temporal heterogeneity. Moreover, EMT is induced and regulated by a complex network of traditional signaling pathways and new players like microRNAs. Interestingly, similar molecular characteristics link EMT-type cells also to the concept of cancer stem cells. This review tries to integrate the current knowledge regarding EMT and pancreatic cancer; furthermore to outline not only the perspective on novel EMT-associated therapeutic targets, but also on overcoming drug resistance by interfering with EMT.

Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its silent nature and tendency for late discovery but also because of its persistent resistance to chemotherapy. At present there are very limited treatment alternatives for pancreatic cancer, hence the need to develop novel and more efficient drugs. It is well known that mutations in K-Ras oncogene accumulate early in the disease progression and occur in almost all of pancreatic ductal adenocarcinomas (PDAC). A key downstream target of the Ras family is phosphoinositide 3-kinase (PI3K), the enzyme responsible for generation of 3-phosphorylated phosphoinositides and activation of Akt (Protein Kinase B/Akt). The PI3K/Akt pathway is involved in inhibition of apoptosis and stimulation of cell proliferation and it has been estimated that at least 50% of all cancer types are related to deregulation of this signalling pathway. In this review we will discuss how the PI3K/Akt/mTOR signalling network is altered in pancreatic cancer and further give an overview of preclinical and clinical studies where this pathway has been targeted.

Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with a 5-year survival of less than five percent. Since the majority of patients have locally advanced or metastatic disease at the time of diagnosis, there has been little progress made to extend survival. For over ten years, chemotherapy with gemcitabine has been standard treatment for those patients with advanced pancreatic cancer, prolonging survival by only 5-6 months. To improve upon this modest benefit, several investigations have explored other strategies aimed at curbing pancreatic cancer growth. Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer. This review will discuss these therapies and their potential application in a clinical setting.

Obesity, now a worldwide epidemic, causes myriad medical problems. One of the most significant obesity-related problems is the well-recognized relationship between obesity and various malignancies, including pancreatic cancer. Pancreatic cancer is a devastating disease - the annual death rate nearly approximates its incidence. While surgical extirpation provides the best chance at long term survival, systemic therapy is largely ineffective: even those patients undergoing successful operative resection have only approximately 20% 5-year survival. These poor outcomes are largely a consequence of poor understanding of tumor biology. Clearly, identification of novel treatment strategies is of paramount importance; investigation of pancreatic cancer biology from the novel aspect of obesity offers the potential to identify unique therapeutic targets. This manuscript reviews the epidemiology, clinical findings, and putative basic science mechanisms underlying obesity-related pancreatic cancer.

Resveratrol, a well-know natural product and a major component in grape, has attracted considerable attention as one of the most promising cancer during the past decade. Many studies have established that resveratrol can exert a broad range of biological activities including ceramide-mediated proapoptotic, antineoplastic, apoptosis-inducing, etc. Most important, resveratrol has been identified as an effective candidate for cancer chemoprevention based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This review describes the general properties of resveratrol and its potential effect against cancer including its evidences as an antitumor agent in vitro, in vivo and clinically. In addition, we also summarized the structure-activity relationship of resveratrol and its analogues regarding the antitumor effects.