Current Drug Targets - Volume 13, Issue 6, 2012

Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century [1]. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, incidence rates are virtually identical to mortality rates [2]. The majority of patients is diagnosed with advanced disease and has a median survival with treatment of 6 months. Even for those with early-stage local and resectable disease, the 5-year survival is only 20% after resection. In the advanced setting, the current standard of care was established over a decade ago when gemcitabine improved symptoms and prolonged survival in a phase III trial when compared with 5-fluorouracil [3]. A modest breakthrough occurred when the addition of erlotinib to gemcitabine was shown to prolong survival compared with gemcitabine monotherapy [4]. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer [5], there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. However, this bleak landscape seems to be slowly changing as recent studies are offering new hopes for early detection and prevention [6, 7], and for effective molecularly targeted [8] or novel chemotherapeutic treatments [9] for this devastating disease. This present Hot Topic issue is meant to describe and discuss the most important advances in the comprehension of the complex molecular biology, the standardization of preoperative diagnostic studies, the increasing safety of surgical intervention, and the development of novel targeted agents for pancreatic cancer. Milella and colleagues review the most recent findings in pancreatic cancer biology as sources of novel molecular targets to be exploited therapeutically. Scarpa and colleagues describes the molecular pathology of the cellular components of pancreatic cancer with a special interest not only to the markers for diagnosis but also to the molecular markers with prognostic and predictive value in this disease. De Bellis highlights the role of preoperative endoscopic biliary drainage in the management of jaundiced patients with resectable pancreatic cancer. Kim and colleagues describes recent advances in pancreatic cancer surgery, whereas Bianco and colleagues details the surgical treatment of pancreatic cancer presenting with vascular invasion. Wolff discusses rationale and challenges in using neoadjuvant therapy for upfront resectable or borderline resectable diseases. Reni reviews the most recent evidences for adjuvant chemotherapy and chemo-radiotherapy. Perrone and colleagues summarize the most updated results with conventional chemotherapeutic regimens in the advanced setting. Innocenti and colleagues discuss how the individualization of patient treatment through pharmacogenetics could help improve outcome by maximizing treatment efficacy whilst lowering toxicity. Finally, Ciardiello and colleagues review the role of the epidermal growth factor receptor signaling network and the clinical trials with inhibitors of this pathway in pancreatic cancer. These reports summarize most of the major topics discussed during the First update meeting on pancreatic cancer that was held at the National Cancer Institute of Naples. Participants of this meeting included basic, translational, and clinical investigators, surgeons, radiotherapists, and radiologists in order to facilitate collaboration among these disciplines. With this Hot Topic issue on pancreatic cancer we hope to inform those interested but not expert in this topic, to stimulate the thinking of those working in the field, and to highlight concepts for future research.

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically.

Pancreatic ductal adenocarcinoma (referred here as pancreatic cancer) is a lethal disease with the worst prognosis among all solid tumors. Surgical resection represents the only hope for cure but it is possible only in patients that present with local disease (about 20% of cases). Whether dismal prognosis of pancreatic cancer is a result of late diagnosis or early dissemination to distant organ is still a debate. Moreover, this disease shows an intrinsic chemotherapeutic resistance that has been mainly ascribed to the presence of a dense stromal reaction that significantly impairs drugs delivery. Clinical management of pancreatic cancer patients relies on few molecular markers (e.g., the diagnostic marker CA19-9) that, however, present several limitations to their use. The clinical usefulness of somatic alterations in well-characterized genes (such as KRAS and TP53), whose detection is technically feasible in different biological samples, has been extensively investigated leading to inconsistent results. Furthermore, none of the candidate molecular markers identified in recent years has shown an appropriate clinical performance and therefore none is routinely used. This depicts a scenario where the identification of novel and effective clinical biomarkers is mandatory. Very recent genome-wide comprehensive studies have shed light on the high degree of genetic complexity and heterogeneity of the pancreatic cancers. Although far from being introduced into the clinical settings, results from those studies are expected to change definitively the perspective through which we look at the clinical management of pancreatic cancer patients towards a personalized cancer medicine.

The role of preoperative biliary drainage (PBD) in the management of jaundiced patients with resectable pancreatic cancer (RPC) is controversial. Obstructive jaundice determines hepatic dysfunction which can increase the operative risks. Experimental studies demonstrated that PBD could be associated with improved surgical outcomes. However, clinical studies did not confirm these findings. Initial clinical studies conducted with percutaneous approach failed to demonstrate a real advantage for patients undergoing PBD before pancreaticoduodenectomy. Overall morbidity was higher in patients undergoing PBD, because of procedure-related complications. Similar results were obtained with endoscopic PBD. Six meta-analyses have not clarified the role of PBD in the management of patients with malignant jaundice undergoing pancreaticoduodenectomy, because of lack of uniformity among all the studies published. Recently, the results of a large randomized controlled trial indicated that direct surgery should be the best therapeutic strategy for jaundiced patients with RPC. The debate whether jaundiced patients with RPC should undergo PBD continues and the advent of neoadjuvant chemoradiotherapy added some arguments in favor of PBD. The latter is still considered the first step for jaundiced patients when they present with cholangitis, intense pruritus or severe jaundice; surgery cannot be scheduled within 7-10 days from the diagnosis; neoadjuvant chemoradiation is planned, as part of the treatment. While endoscopic PBD is considered the preferred approach, there is still controversy about the type of biliary stent which should be used. Emerging data support the insertion of short (4-6 cm) biliary self-expandable metallic stent, especially if surgery is not immediately planned.

Pancreatic cancer patients have an extremely poor survival prognosis, and surgical resection remains the only curative treatment. Greater experience in pancreatic surgery and developments in surgical techniques have reduced surgical mortality and morbidity rates. It has been suggested that experienced pancreaticoduodenectomy centers should have mortality rates of less than 5% and major complication rates of less than 40%. Surgical resection followed by combined adjuvant therapy is currently the standard treatment for resectable pancreas cancer. Patients with borderline or marginal resectable tumors are beginning to have favorable outcomes following neoadjuvant chemotherapy or chemoradiation. A number of prospective randomized trials have concluded that “extended” pancreaticoduodenectomy for pancreatic head cancer, involving radical dissection of lymph nodes and peripancreatic soft tissue, does not appear to provide any survival benefits compared with “standard” pancreaticoduodenectomy. Conversely, extensive surgery for pancreatic tail or body cancer (i.e., radical antegrade modular pancreatosplenectomy) can result in favorable R0 resection rates and survival outcomes. However, more prospective randomized trial data are required before these conclusions can be considered established. Laparoscopic approaches are being increasingly used in the field of pancreatic tumor surgery. Moreover, robotic-assisted laparoscopic surgery has also been tried in some expert centers. Again, at present a lack of outcome data prevent any definitive conclusion at this stage on the usefulness of those approaches compared to standard open approaches. Finally, a major problem hindering efforts to identify optimal surgical treatment modalities for pancreas cancer is the lack of a clear definition and standardization of surgical procedures and pathologic descriptions. The American Hepato- PancreatoBiliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract conference on pancreatic cancer held in 2008 resulted in a consensus statement as an important first step in overcoming this fundamental hurdle.

Pancreaticoduodenectomy (PD) is the gold standard treatment for cancer of pancreatic head in all the cases that are supposed to be resectable. Although the overall survival depends on many heterogeneous factors, the main aim of the treatment must be to achieve a R0 resection with microscopically and macroscopically free margins. As in recent reports vascular involvement does not represent anymore a technical limit, it is mandatory pointing out whether or not vascular resection modifies overall survival and if that is the case vascular invasion should not be considered as an exclusion criterion but as part of a standard resection. The review analysis demonstrated a progressive trend of inversion in the treatment of head pancreatic cancer over the last years. Recently, provided that a R0 resection may be performed, a more aggressive surgical approach has led to consider the possibility of venous and arterial resections. The basis for this new approach has been that the superior mesenteric vein or spleno-portal mesenteric vein invasion is not a measure of the tumor malignancy but merely a consequence of the tumor location. On the contrary, the controversial results in terms of overall survival and local recurrences achieved with major arterial resections are more likely due to a biological aggressivity than to the tumor site. The “artery first” technique seems to be the most promising approach to the problem although it needs further trials to determine whether or not this approach may be beneficial for patients in terms of overall survival and local recurrences.

For over 25 years, the standard of care for resectable pancreatic adenocarcinoma has been upfront surgery followed by delivery of post-operative therapy. Until recently however, there has been no consensus as what constituted a standard adjuvant regimen. Data from large phase III studies now support single agent gemcitabine, administered over 6 cycles, as standard. Nevertheless, the overall survival of patients undergoing upfront surgical resection followed by adjuvant therapy remains poor, with no significant improvements in median, or long term survival over the last 3 decades. Surgery as the first intervention for potentially curative pancreatic cancer has some distinct disadvantages and neoadjuvant therapy provides a mechanism to better select patients for subsequent surgical intervention. Current data suggest this approach spares patients from a morbid surgical procedure when it will be of no benefit and improves outcomes for those who do undergo surgery. Furthermore, with the increasing recognition of borderline resectable pancreatic cancer, neoadjuvant treatment should be considered as alternative to upfront surgery for this distinct clinical entity. This has the potential to maximize the chances of a margin-negative resection and minimize the number of patients harboring aggressive disease from undergoing a fruitless surgical procedure. Importantly, as the number of targeted agents available for clinical use expands, more rational, personalized neoadjuvant therapies may emerge.

Pancreatic adenocarcinoma is a rare tumor with a very poor outcome. Even with surgery, 5-year overall survival is less than 10%, due to the propensity of the disease for local and systemic recurrence. Adjuvant chemoradiotherapy and systemic chemotherapy were assessed in prospective trials in order to improve disease control and patients’ prognosis. However, due to the difficulty of performing prospective trials in a rare disease; to the progress in surgical and radiotherapic techniques; and to the availability of novel anti-cancer agents, the existing information on the best possible management of patients with resectable disease is limited and becomes rapidly obsolete. Accordingly and also due to some contradictory findings from randomized trials, the topic of optimal adjuvant therapy for this disease encompasses several areas of controversy. The present review reports the main opinions on the role of adjuvant chemoradiotherapy, adjuvant chemotherapy, best single agent, and combination chemotherapy. Data from randomized trials are presented and critically analyzed to identify the available evidence supporting the different therapeutic choices and the main methodological drawbacks hampering the proper interpretation of results. Single agent chemotherapy yields a clinically significant, albeit modest, improvement in overall survival and may represent a standard option. The role of combination chemotherapy warrants further investigation and the impact of adjuvant chemoradiation both on local control and on the final outcome is uncertain. The need for more active and effective systemic treatments, for a better knowledge of the disease biology, for new therapeutic agents and predictors of pattern of recurrence is evident.

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.

Effective systemic treatment of pancreatic cancer remains a major challenge, with progress hampered by drug resistance and treatment related toxicities. Currently available cytotoxic agents as monotherapy or in combination have provided only a modest survival benefit for patients with advanced disease. Disappointing phase III results with gemcitabine-based combinations in patients with advanced pancreatic cancer might be related to poor efficacy of systemic therapies in unselected patients. Future research strategies should prioritize identification of predictive markers through pharmacogenetic investigations. The individualization of patient treatment through pharmacogenetics may help to improve outcome by maximizing efficacy whilst lowering toxicity. This review provides an update on the pharmacogenetics of pancreatic cancer treatment and its influence on treatment benefits and toxicity.

Statins have been successfully used in patients with hypercholesterolemia and cardiovascular diseases, but there is increasing evidence that they exert effects by much exceeding the lowering of cholesterol levels. Statins have antiatherosclerotic, antiinflammatory, antioxidant, immunomodulatory and antithrombotic effects. These "pleiotropic" effects stem from their inhibition of prenylation of the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins modulate immune responses by altering cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Anti-inflammatory and immunosuppressory properties of statins provide the rationale for their potential application in conditions in which the inflammation and immune response represent key pathogenic mechanisms, such as antiphospholipid syndrome, rheumatoid arthritis and systemic lupus erythematosus. Reduction of atherosclerosis progression in autoimmunity is also a very important effect. Statins pathways of action in systemic autoimmune diseases, and their potential therapeutic use are discussed in this review. The inhibition of mevalonate pathway by statins impairs modification of Ras and Rho GTPases, which play key roles in signaling pathways related to tumor formation, metastasis and cell death. There is experimental and clinical evidence that statins may improve the therapeutic outcome of anticancer drugs. Thus, this review will also discuss recent insights into the molecular mechanisms underlying the anticancer effects of statins and their assessment as promising candidates for inclusion into current therapeutic regimens for the treatment of malignant diseases.

The adenosine pathway is a powerful evolutionarily selected mechanism aimed at a fine modulation of inflammatory responses and protection of tissues from injuries. Adenosine exerts its modulatory effects via interaction with G protein-coupled receptors, designated as A1, A2A, A2B and A3. In this regard, extracellular adenosine concentrations are critical in determining its ability of regulating several biological functions. The levels achieved by adenosine in close proximity of its receptors are strictly regulated by a variety of dynamic mechanisms, including intracellular and extracellular biosynthesis, transport and metabolism, based on tissue energy status. In this context, the catabolic enzyme adenosine deaminase (ADA) represents a critical checkpoint in the regulation of extracellular adenosine levels and, consequently, in the control of receptor stimulation, thus playing a pivotal role in the modulation of purinergic responses to several pathophysiological events, such as chronic pulmonary diseases, rheumatoid arthritis, inflammatory bowel diseases and sepsis. This article reviews current data on the role played by ADA in the regulation of immune system activity through its modulation of adenosine pathways. Particular attention has been paid to the involvement of ADA in the pathophysiology of relevant inflammatory diseases. In addition, the interest in designing and developing novel ADA inhibitors, as new tools potentially useful for the therapeutic management of inflammatory disorders, has been discussed.

Apixaban (BMS-562247-01) is a compound being investigated as an anticoagulant. Apixaban molecule is developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban, a coagulation factor Xa inhibitor, approved in the E.U. in 2011 for the prevention of venous thromboembolic events in adult patients, who have undergone elective hip or knee replacement. The Apixaban based drug will be marketed under the brand name Eliquis® and is expected to rack up annual sales of over $2.5 billion. Apixaban is expected to provide stiff competition to warfarin, a popular blood thinner used in Europe. Warfarin is known to cause some serious side effects in patients. Apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism in patients experiencing atrial fibrillation by more than 50% (from 3.7% per annum with aspirin to 1.6% per annum with apixaban). Apixaban exhibits superiority to enoxaparin in preventing thrombosis in patients undergoing elective hip replacement surgery with similar bleeding rates. Apixaban is a highly selective and potent Factor Xa Inhibitor with Ki=0 8nM to both free as well as prothrombinase bound FXa. In X-ray crystal structure studies indicate that the pyrazole N-2 nitrogen atom interacts with backbone of Gln192 and the carbonyl oxygen of carboxamide interacts with NH of Gly216. The orientation of phenyllactum in the S4 region indiacates an edge to face interaction with Trp215, which is positioned between the Tyr99 and Phe174. In the present review, we have tried to cover comparative study of various FXa-inhibitors and point out apixaban in the various aspect including molecular chemistry, physical properties, commercial synthesis, current patent status, crystalline polymorphic forms, molecular receptor interaction, pharmacophore rational, mechanism of action, clinical studies, preclinical, adverse effect, available formulation, dose regimen and co-therapy, thus giving emphasis on medicinal chemistry aspects.