Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma.

Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma Amal HI Al Haddad & Thomas E Adrian To cite this article: Amal HI Al Haddad & Thomas E Adrian (2014) Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma, Expert Opinion on Investigational Drugs, 23:11, 1499-1515, DOI: 10.1517/13543784.2014.933206 To link to this article: http://dx.doi.org/10.1517/13543784.2014.933206

Published online: 31 Jul 2014.

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Date: 09 October 2017, At: 04:09

Review

Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma 1.

Introduction

2.

Current therapeutic status of PDAC

3.

Why is PDAC so difficult to

Downloaded by [Australian Catholic University] at 04:09 09 October 2017

treat? 4.

Conclusion

5.

Expert opinion

Amal HI Al Haddad & Thomas E Adrian† †

Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA. The 5-year survival of < 5% has not changed in decades. In contrast to other major cancers, the incidence of PDAC is increasing. Areas covered: The aims of this paper are first to analyze why PDAC is so difficult to treat and, second, to suggest future directions for PDAC therapeutics. The authors provide an article that is based on a comprehensive search through MEDLINE and the clinicalTrials.gov website. Expert opinion: Progress has been made recently. Notably, FOLFIRINOX or nab-paclitaxel plus gemcitabine provide survival benefit over gemcitabine alone, which was previously the mainstay of therapy for PDAC. Most of the current trials are testing combinations of repurposed drugs rather than addressing key targets in the PDAC pathogenesis. It is clear that to really make an impact on this disease, it will be necessary to address three different problems with targeted therapeutics. First, it is important to eradicate PDAC stem cells that result in recurrence. Second, it is important to reduce the peritumoral stroma that provides the tumors with growth support and provides a barrier to access of therapeutic agents. Finally, it is important to address the marked cachexia and metabolic derangement that contribute to morbidity and mortality and further complicate therapeutic intervention. Keywords: cachexia, cancer stem cells, pancreatic cancer, pancreatic ductal adenocarcinoma, therapy, tumor microenvironment Expert Opin. Investig. Drugs (2014) 23(11):1499-1515

1.

Introduction

Around 95% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related deaths in the USA [1]. PDAC has the worst 5-year survival (~ 5%) among all common types of cancer to date, regardless of the stage of the disease at the time of diagnosis [1,2]. Patients with PDAC mostly present with highly infiltrative and metastatic disease at the time of diagnosis. PDAC is the only common cancer where the rate of death is projected to increase by more than twofold by 2030, when it will become the second leading cause of cancer death in the USA [3,4]. The reasons for the increase in incidence are not clear but may result, at least in part, from obesity. In addition to obesity, diabetes, smoking and high-fat -high red meat diets are risk factors [5]. The majority of patients with PDAC are diabetic, but this is usually diagnosed within a year or two or concomitantly with the cancer diagnosis [5]. It is not clear whether diabetes is a risk factor or if the diabetes is a result of the cancer. Obesity, which predisposes to insulin resistance, may provide the link [5]. Chronic pancreatitis is associated with an 10.1517/13543784.2014.933206 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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A. H. I. Al Haddad & T. E. Adrian

paper, however, advances in surgical or radiotherapeutics modalities will not be discussed.

Article highlights. . .

.


.

.

Pancreatic adenocarcinoma has a dismal prognosis and survival has changed little in decades. Recent improvements include therapy with FOLFIRINOX or nab-paclitaxel, but these improve survival by only a few months. The reasons the disease is so difficult to treat include advanced disease at the time of diagnosis, severe cachexia and poor metabolic status, the resistance of cancer stem cells (CSCs) to current drugs and the marked desmoplastic response that facilitates growth and invasion, provides a physical barrier to penetration of therapeutic drugs and prevents immunosurveillance. It is likely that major advances will only be made with combination therapy that will include eradication of the CSCs, disruption of the desmoplastic barrier and also addresses the poor metabolic status of the patients. Review of current clinical trials reveals that novel approaches are being employed to target the CSCs and alter the tumor microenvironment which bodes well for the future.

This box summarizes key points contained in the article.

increased risk of PDAC; the link between chronic pancreatitis and PDAC is strongest in smokers or a small subgroup with hereditary chronic pancreatitis [5]. About 8% of pancreatic cancers occur in families who carry mutations in tumor suppressor genes including P16Ink4a/CDKN2A, BRCA2, MLH1, MSH2, STK1 or VHL [5]. The poor prognosis of PDAC is due to late diagnosis. More than 80% of cases are not eligible for surgical resection of the tumor due to the presence of metastatic spread and/or the local involvement of major blood vessels [6]. A Finnish study reviewed PDAC patient records and tissue blocks to identify the differential features of patients with > 5 years survival in the past 30 years. Out of approximately 150 patients, more than 50% of the cases with 5-year survival were wrongly diagnosed with PDAC [7]. Even for those with correct diagnosis, survival barely exceeded 5 years with the exception of one patient who survived 11 years [7]. These findings suggest that even the poor survival statistics widely reported may be an overestimate. Despite our remarkable improvement in the understanding of cancer biology and the discovery of novel therapies directed to specific targets in other cancers, PDAC therapeutics have shown the least improvement over the past 30 years for any cancer. This review investigates the current challenges and difficulties faced in the discovery of effective agents for novel therapeutic targets for PDAC treatment. Promising approaches are highlighted and discussed. Then, we highlight possible future directions for novel therapeutics for PDAC. In this 1500

2.

Current therapeutic status of PDAC

PDAC is still a significant, unresolved therapeutic challenge. Treatment depends on the stage of the cancer [8]. The gold standard for PDAC treatment is the surgical resection of the tumor using a Whipple procedure for the majority of tumors located in the head of the pancreas or distal pancreatectomy is undertaken for the less frequent lesions in the body or tail region of the pancreas [9] followed by adjuvant chemotherapy [10,11]. The Whipple procedure involves removing the pancreatic head and the curve of the duodenum together (pancreatoduodenectomy), making a bypass for food from stomach to jejunum (gastrojejunostomy) and attaching a loop of jejunum to the cystic duct to drain bile (cholecystojejunostomy) [9]. The pylorus preserving Whipple procedure is also sometimes performed. These surgeries can be only performed if the patient is likely to survive major surgery and if the cancer is not locally invasive or metastasizing and does not involve major blood vessels. On the other hand, the majority of cases undergo palliative chemotherapy treatment, which until recently was with either gemcitabine-based or 5-fluorouracil (5-FU)-based combination therapy for locally advanced and metastatic disease [6]. Gemcitabine results in only a 5-week improvement in median survival duration in patients with advanced pancreatic cancer [6]. The addition of the tyrosine kinase inhibitor erlotinib in combination with gemcitabine as a palliative regimen for pancreatic cancer has demonstrated improved survival [12]. The addition of radiation therapy is controversial [11]. Recently, two new chemotherapy combinations have been introduced as the new standards of care. The first is a drug combination called FOLFIRINOX comprising leucovorin, 5-FU, irinotecan and oxaliplatin. However, because of the side effects, this regimen is reserved for patients who have good performance status. The second is a combination of gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Both FOLFIRINOX and gemcitabine/nabpaclitaxel have shown considerable survival benefit compared with gemcitabine alone [13,14]. The current therapeutic standards for PDAC according to the stage of the disease in addition to the median survival and the 5-year overall survival are summarized in Table 1. These standards are based on the National Comprehensive Cancer Network guidelines and Phase III trials. Although there have been some advances in PDAC therapy, these measures still have a modest effect on life expectancy and the majority of patients will ultimately succumb to the disease. Clearly, we need a major change in strategy if we aim for a real leap in PDAC therapeutics. Thus, addressing major challenges is of paramount importance.

Expert Opin. Investig. Drugs (2014) 23(11)

Challenges and future directions in therapeutics for PDAC

Table 1. Current therapeutic standards for PDAC.


Tumor stage

Standard treatment [12-14,100-110]

Resectable (stage I/II)

Surgery (i.e., Whipple procedure, total pancreatectomy or distal pancreatectomy)

± gemcitabine monotherapy, or 5-FU+ leucovorin, or 5-FU or capecitabine

± gemcitabine/5-FU/ capecitabine-based radiation before or after gemcitabine, or 5-FU or 5-FU+ leucovorin

Locally advanced unresectable (stage III)

Palliative surgery (i.e., biliary bypass, endoscopic stent placement or gastric bypass) Palliative and supportive care

± FOLFIRINOX, or gemcitabine, or gemcitabine + nab-paclitaxel

± 5-FU based radiation

Non-resectable First line or metastatic (stage IV)

Recurrent

Second line Palliative and supportive care ± palliative radiotherapy

± palliative surgery

± palliative surgery

+ palliative and supportive care FOLFIRINOX, or gemcitabine + nab-paclitaxel, or gemcitabine + erlotinib, or gemcitabine + cisplatin, or gemcitabine + capecitabine or gemcitabine monotherapy + capecitabine, or capecitabine + erlotinib or 5-FU + leucovorin + oxaliplatin

Median survival (months) [111]

5-year overall survival (%) [111]

Stage IA: 10 (6.8 -- 24.1) Stage IB: 9.1 (6.1 -- 20.6) Stage IIA: 8.1 (6.2 -- 15.4) Stage IIB: 9.7 (6.7 -- 12.7) 7.7 (7.2 -- 10.6)

Stage IA: 13.6% (3.8 -- 31.4) Stage IB:11.7% (3.4 -- 27.2) Stage IIA: 6.5% (2.4 -- 15.7) Stage IIB: 5.1% (2.0 -- 7.7) Stage III: 2.7% (1.8 -- 6.8)

2.5 (2.5 -- 4.5)

Stage IV: 0.7% (0.6 -- 2.8)

The survival data presented here is based on previous analysis of gemcitabine-based therapies. The survival statistics are expected to markedly improve with the accumulation of survival data since the introduction of FOLFIRINOX and nab-paclitaxel. 5-FU: 5-fluorouracil; FOLFIRINOX: Leucovorin, 5-FU, irinotecan and oxaliplatin; PDAC: Pancreatic ductal adenocarcinoma.

3.

Why is PDAC so difficult to treat?

Generally the disease is advanced at the time of diagnosis

3.1

As pointed out above, < 20% of PDAC patients are candidates for surgical resection, because either they have metastatic disease at the time of diagnosis or they have local invasion involving major blood vessels [6]. The reasons for this late diagnosis are the lack of early symptoms, inaccessibility of the pancreas for evaluation and lack of an early screening method. The lateness of diagnosis clearly contributes massively to the difficulties encountered in treating these patients and this problem can only be solved by development of early diagnostic procedures. 3.2

Metabolic status of PDAC Cachexia and PDAC

3.2.1

In addition to the insulin resistance and high incidence of diabetes, PDAC patients usually exhibit severe cachexia.

Unlike weight loss during dieting or starvation, cachexia is characterized by preferential loss of skeletal muscle, with or without loss of fat, with relative sparing of visceral organs such as the liver, in addition to anorexia. Although cachexia is a major cause of mortality and morbidity in PDAC, the mechanism of muscle wasting and weight loss are poorly understood. The muscle wasting is associated with net protein catabolism, increased hepatic gluconeogenesis from amino acids, an increase in the glucose lactate cycle (Cori cycle) and increases in glucagon and cortisol levels, together with the insulin resistance [15]. Parenteral nutrition can compensate for the loss of energy due to anorexia but cannot reverse the muscle wasting associated with cachexia [16,17]. Cachexia is a complex process, probably driven by inflammatory cytokines such as TNF-a and IL-1b and other circulating factors that may come from the tumor or the surrounding stroma. Whatever the mechanism is, patients in a cachectic state are less able to withstand the rigors of chemotherapy or radiation therapy.


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3.2.2

Insulin resistance and diabetes mellitus in PDAC

There is certainly a relationship between diabetes mellitus and PDAC. Studies have shown that between one-third and two-thirds of patients with PDAC are diabetic at the time of the cancer diagnosis [18-25]. The major question is whether diabetes predisposes the development of the cancer or if the diabetes is a result of the tumor. There is evidence for both. The situation is complex and it may turn out that both are true. The answer to the question is important since the prevalence of diabetes mellitus has increased worldwide and the diabesity epidemic is projected to markedly increase in the future. If diabetes is confirmed to be a predisposing factor to adenocarcinoma then this may at least partially explain the increasing incidence of this cancer. Meta-analysis studies have shown that patients with both type 1 and type 2 diabetes have a modest increased risk of PDAC of about twofold [19-21]. It is apparent from several studies that the strongest association is between diabetes diagnosed within 2 or 3 years prior to, or concomitant with, the cancer diagnosis. This would suggest that, at least in some cases (and perhaps the majority), diabetes is a result of the cancer rather than a predisposing factor [22-26]. Further evidence of this comes from several studies that have shown improvement in the diabetic status, and even complete resolution in some cases, following successful tumor resection [26-29]. As noted above, obesity or prior obesity is a risk factor for PDAC as well as for diabetes [5]. There may be many reasons for the relationship, but insulin resistance is certainly a major factor. Some of the pancreatic blood supply reaches the islets before the exocrine parenchyma, ensuring that the exocrine tissue is bathed in high concentrations of insulin [30]. It has been estimated that periacinar concentrations of insulin are at least 20-fold higher than that of the systemic circulation [30]. Insulin concentrations in the peripheral circulation after food intake are approximately 0.5 -- 1.0 nmol/l, and thus insulin concentrations in the pancreatic parenchyma should peak at 10 -- 20 nmol/l. In a subject who is insulin-resistant, and therefore, hyperinsulinemic, insulin levels within the pancreas may be at least 10-fold higher. Insulin is a potent growth factor for PDAC cells and it may well give a substantial growth advantage to cells in preneoplastic lesions [31]. A further complication has come to light when the influence of different antidiabetic agents is considered. Diabetics treated with metformin have a low risk of development of pancreatic and other cancers [32,33]. Metformin use also increased the 2-year survival rate (from 15.4 to 30.1%) and the median overall survival time (from 11.1 to 15.2 months) and lowered the risk of death by 32% in PDAC patients [32]. Metformin use was significantly associated with longer survival in PDAC patients with nonmetastatic disease [33]. These findings support an earlier animal study that found that metformin completely prevented PDAC development in carcinogen-treated hamsters [34]. In contrast, a more recent study failed to show any survival benefit in PDAC patients treated with metformin 1502

from around the time of the cancer diagnosis [35]. Two recent large meta-analysis studies have also been conducted on the association with metformin and PDAC incidence. One study showed a significant risk reduction of 46% in PDAC [36], whereas the other study just failed to reach statistical significance (p < 0.073) [37], perhaps because of lack of power. Metformin has been shown to induce a striking and sustained increase in the phosphorylation of 5¢-adenosine monophosphate-activated kinase at Thr172 [38], which negatively regulates mammalian target of rapamycin (mTOR) signaling [39]. This may account for its inhibitory effect on pancreatic cancer growth. However, recent studies have shown that metformin has marked growth inhibitory effects on cancer stem cells (CSCs) and this may account for its rather marked effects in pancreatic cancer [40-42]. This raises a question whether metformin can be used as a supplemental therapy in PDAC patients or as a preventive drug in individuals with high risk of developing PDAC. Many experimental and epidemiological studies have supported the above conclusion and have resulted in multiple clinical trials. The antipancreatic cancer effect of metformin is associated with a decrease in expression of CSC markers; CD44, epithelial cell adhesion molecule (EpCAM), histone-lysine N-methyltransferase, Notch-1, transcription factor of undifferentiated embryonic stem cells and octamer-binding transcription factor 4, and induction of expression of microRNAs (let-7a, let-7b, miR-26a, miR-101, miR-200b and miR-200c) that are typically lost in pancreatic cancer [42]. Another study linked the anticancer effects of metformin with decrease expression of sonic hedgehog (Shh) mRNA and protein [43]. Currently, there are multiple ongoing Phase I and Phase II trials of metformin on PDAC patients, which are summarized in Table 2. The results of these should clarify the usefulness of this compound in PDAC therapy. PDAC stem cells The presence of CSCs in most, if not all, cancers has recently come to light. These CSCs are characterized by ability of selfrenewal via asymmetric division, ability to differentiate into diverse phenotypes, ability to initiate tumors from minute numbers and by their chemoresistance [44,45]. By fluorescenceactivated cell sorting analysis, Li et al. isolated CD44+/ CD24+/EpCAM+ (CD326) pancreatic CSCs, which accounted for 0.2 -- 0.8% of total cancer cells, showed stem-cell like properties and had the capability to form tumors in animal models when as few as 100 cells were transplanted [46]. Hermann et al. characterized another subpopulation of pancreatic CSCs expressing the surface marker prominin 1--cell surface antigen (CD133) and described it to be exclusively tumorigenic and highly resistant to standard chemotherapy [47]. Being a viable cause of metastasis, along with their high resistance to conventional chemotherapy, has led to the growing belief that CSCs can be the ultimate foe in the combat against cancer. It is, therefore, becoming the common wisdom that therapies that would specifically eradicate those CSCs are being actively 3.3



Table 2. Ongoing trials of metformin on PDAC patients.


Trial no. (NCT) Phase 01210911 Phase I 01954732 Phase I 01167738 Phase II 02005419 Phase II 01666730 Phase II 01488552 Phase I/II 01971034 Phase II 02048384 Phase Ib

Trial design

Number and types of subjects

Randomized: gemcitabine/erlotinib ± metformin Randomized: neoadjuvant metformin versus surgery alone Randomized: Capecitabine/cisplatin/epirubicin/ gemcitabine ± metformin Randomized: adjuvant gemcitabine ± metformin Open-label single group: Metformin + FOLFOX 6 (leucovorin/calcium/fluorouracil/oxaliplatin) Open-label single group: Gemcitabine + nabpaclitaxel + FOLFIRINOX + metformin + FOLFIRINOX Open-label single group: second-line paclitaxel + metformin Randomized: maintenance metformin ± rapamycin

120 locally advanced or metastatic 39 resectable stage IA/IB/IIA/IIB 82 metastatic 300 resectable stage IA/IB/IIA/IIB 43 metastatic 61 advanced 41 advanced, gemcitabine refractory 22 metastatic

Primary outcome measures

6 months survival Effect on cell proliferation and apoptosis 6 months progression-free survival 1 year recurrence-free survival Median overall survival Complete response rate

Disease control measured by radiological evaluation Safety and feasibility

FOLFIRINOX: Leucovorin, 5-FU, irinotecan and oxaliplatin; PDAC: Pancreatic ductal adenocarcinoma.

investigated [48-52]. CSCs are known to contribute to tumor initiation, self-renewal, chemoresistance and metastasis [45]. Indeed, they are the only cells from a tumor that are capable of recapitulating the disease, indicating that their eradication is essential [45]. Multiple developmental pathways that are involved with growth and differentiation are important for the function of CSCs and thus provide possible targets for their eradication. These include the Hedgehog (Hh), notch, chemokine receptor type 4 (CXCR4) and Wnt/b-catenin (Wnt) pathways. The Hh signaling pathway is known to play a physiological role in embryonic development. However, this pathway also contributes to the formation and maintenance of CSCs as well as the epithelial--mesenchymal transition (EMT) essential for invasion [53]. In the Hh pathway, a seven transmembrane receptor called Smoothened (Smo) drives Hh signaling via the Gli transcription factors (Gli-1 and Gli-2). In the absence of Hh ligand, another protein, Patched (Ptch), suppresses the activity of Smo. Consequently, the downstream transcription factors, the Gli proteins are cleaved by ubiquitin ligases to form isoforms that act as transcriptional repressors. In the presence of Hh ligand, the inhibition of Smo by Ptch is released and Smo is activated and the uncleaved forms of the Gli proteins enter the nucleus and activate transcription of genes, including cyclin D1, Myc and p21. Pancreatic CSCs have increased expression of Shh [46]. Expression of Hh is increased by hypoxia, through hypoxia-inducible factor 1 a (HIF-1a) and by NF-kB. Further, the interplay between the Hh pathway, NF-kB and Akt is essential for cancer initiation and progression [53]. Indeed, the Hh signal was recently found to be essential for induction of EMT and metastasis in gastric carcinoma via the activation of the

phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway and subsequent activation of MMP-9 [53]. Inhibition of Hh signaling inhibits self-renewal of pancreatic CSCs and reverses chemoresistance [54]. The effect of Gli inhibition on CSC growth was investigated using the Gli inhibitor, GANT-61 in vitro and in the mouse xenografts model. GANT-61 inhibited cell viability, spheroid formation, EMT, pluripotency-maintaining factors, Gli--DNA binding and transcriptional activities, induced apoptosis and increased expression of Fas and TRAIL receptors [55]. Knockdown of expression of Gli has similar effects to GANT-61 [55,56]. Other Hh pathway inhibitors produced similar inhibition of growth and EMT and induced apoptosis [57,58]. Further, one Gli inhibitor, perifosine, also enhanced the effect of gemcitabine in the mouse xenograft model [57]. These findings highlight the importance of the Shh pathway for self-renewal and metastases of pancreatic CSCs and indicate that Gli is an important target for elimination of pancreatic CSCs. Hh signaling is also involved in tumor cell/stromal cell interactions as discussed below. Multiple compounds targeting Smo or its receptor are currently under clinical trials. Vismodegib, a Smo inhibitor, has been already approved for basal cell carcinoma since 2012 and is under multiple trials in PDAC patients (Table 3). When one of the five notch ligands (Delta-like 1, 3, 4 or Jagged-1,-2) binds to one of the four notch receptors (Notch 1 -- 4), notch is cleaved through a cascade of proteolytic steps by several enzymes including g-secretase, leading to release of an active notch fragment that leads to activation of notch target genes, including, Akt, mTOR, NF-kB, c-Myc, VEGF and cyclin D [59]. Notch family members have been implicated in the self-renewal of pancreatic CSCs [60]. Thus, several


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Table 3. Investigational drugs targeting stem cell pathways which have progressed to clinical trials. Drug and its characteristic

Phase -- study status -- number of enrolled subjects and types of cancer

Result of published trials/reference or trial number, if unpublished


Targeted pathway: hedgehog signaling pathway -- smoothened inhibitors Saridegib (IPI-926; semisynthetic analog of cyclopamine)

Phase I -- completed -- published -n = 7 PDAC (out of 94 solid tumors)

Gemcitabine ± saridegib

Phase Ib/II -- completed -- awaiting results -n = 122 metastatic PDAC Phase I -- ongoing -n = 21 advanced PDAC Phase I -- completed -- published -n = 8 PDAC (out of 68 solid tumors)

Saridegib + FOLFIRINOX Vismodegib (GDC-0449; artificial cyclopamine-competitive antagonist), (approved in 2012 for BCC)

Vismodegib + erlotinib ± gemcitabine Vismodegib + gemcitabine Gemcitabine ± vismodegib Sirolimus + vismodegib Neoadjuvant tumor perfusion of gemcitabine + vismodegib Gemcitabine + nab-paclitaxel + vismodegib Neoadjuvant vismodegib Neoadjuvant gemcitabine + nab-paclitaxel ± sonidegib or erismodegib (LDE225; artificial selective Smoothened antagonism) Sonidegib Sonidegib + gemcitabine Sonidegib + FOLFIRINOX Sonidegib + BKM120 Sonidegib

LEQ506 (second-generation Smoothened inhibitor) PF-04449913 (orally bioavailable small-molecule Smoothened inhibitor)

Phase I -- Ongoing -n = 70 metastatic PDAC Phase I -- Ongoing -- not recruiting, n = 25 recurrent or metastatic PDAC Phase II -- ongoing -- not recruiting -n = 114 recurrent or metastatic PDAC Phase I -- recruiting -n = 32 various pancreatic cancers Phase 0 -- not yet open for participant recruitment -n = 21 Resectable PDAC Phase II -- recruiting -n = 80 metastatic PDAC Phase II -- terminated -- slow recruitment -n = 3 resectable PDAC Phase I/II -- recruiting -n = 52 resectable PDAC Phase 0 -- recruiting -n = 20 resectable PDAC Phase I -- recruiting -n = 18 locally advanced or metastatic Phase I -- unknown -n = 40 locally advanced or metastatic Phase I -- recruiting -n = 120 advanced PDAC and other solid cancers Phase II -- recruiting -n = 70 Patched 1 or Smoothened-activated solid and hematological tumors Phase I -- ongoing -n = 55 advanced solid tumors Phase I -- completed -- awaiting results -n = 23 solid tumors

Effective in advanced BCC and medulloblastoma, and well tolerated but with no objective response seen in PDAC [71] NCT01130142 NCT01383538 Drug with acceptable safety profile and encouraging antitumor activity in advanced BCC and medulloblastoma only [72] NCT00878163 NCT01195415 NCT01064622 NCT01537107 NCT01713218

NCT01088815 NCT01096732 NCT01431794

NCT01694589 NCT01487785 NCT01485744 NCT01576666 NCT02002689

NCT01106508 NCT01286467

This table includes drugs which have already progressed to clinical trials for PDAC as well as drugs which have entered trials for other solid malignancies that may in the future prove valuable for PDAC. BCC: Basal cell carcinoma; FOLFIRINOX: Leucovorin, 5-FU, irinotecan and oxaliplatin; PDAC: Pancreatic ductal adenocarcinoma.

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Table 3. Investigational drugs targeting stem cell pathways which have progressed to clinical trials (continued). Phase -- study status -- number of enrolled subjects and types of cancer

Drug and its characteristic


Targeted pathway: notch signaling pathway MK-0752 (g-secretase inhibitor) MK-0752 + gemcitabine RO4929097 (g-secretase inhibitor) + gemcitabine


RO4929097 + cediranib maleate RO4929097 OMP-52M51 (humanized Notch1 receptor mAb) OMP-59R5 (notch 2/3 receptors mAb) + nab-paclitaxel and gemcitabine Demcizumab (OMP-21M18; a humanized anti-DLL4 mAb) + gemcitabine ± nab-paclitaxel BMS-906024 (pan-Notch inhibitor)

Phase I -- completed -- published -n = 103 solid tumors Phase I -- recruiting -n = 60 advanced or metastatic PDAC Phase I -- completed -- awaiting results -n = 18 advanced solid tumors Phase I -- ongoing -n = 50 advanced solid tumors Phase II -- ongoing -n = 21 second-line metastatic PDAC Phase I -- recruiting -n = 33 relapsed or refractory solid tumors Phase Ib/2 -- recruiting -n = 154 stage IV PDAC Phase Ib -- recruiting -n = 50 locally advanced or metastatic PDAC Phase I -- recruiting -n = 95 advanced or metastatic solid tumors

Clinical benefit was observed [112] NCT01098344 NCT01145456 NCT01131234 NCT01232829 NCT01778439 NCT01647828 NCT01189929 NCT01292655

Targeted pathway: CXCR4 signaling pathway Plerixafor (AMD3100; JM 3100) + bevacizumab ± surgery Plerixafor or ganetespib + AC220 + chemotherapy Plerixafor + lenalidomide (+ rituximab)

MSX-122 (orally bioavailable inhibitor of CXCR4 inhibitor) POL6326 (potent and selective antagonist of CXCR4) + eribulin

ALX-0651 (nanobody-inhibiting CXCR4)

Phase I -- recruiting -n = 46 recurrent high-grade glioma Phase I/II -- recruiting -n = 90 acute myeloid leukemia and high-risk myelodysplastic syndrome Phase I -- ongoing -n = 21 previously treated chronic lymphocytic leukemia Phase I -- suspended -n = 27 refractory metastatic or locally advanced solid tumors Phase I -- recruiting -n = 24 relapsed, triple negative and hormone refractory estrogen receptor-positive metastatic breast cancer Phase I -- terminated -- proof of principle established -n = 52 healthy volunteers

NCT01339039 NCT01236144

NCT01373229

NCT00591682

NCT01837095

NCT01374503

Targeted pathway: Wnt/b-catenin signaling pathway PRI-724 (CBP/b-catenin antagonist) LGK974 (highly potent, selective porcupine inhibitor) OMP-54F28 (anti-frizzled 8 receptor and the Fc domain of a human IgG1 antibody) + nab-paclitaxel + gemcitabine Vantictumab (OMP-18R5; anti-frizzled 7 mAb) + nab-paclitaxel + gemcitabine

Phase Ia/Ib -- recruiting -n = 54 advanced solid tumors Phase I -- recruiting -n = 80 malignancies dependent on Wnt ligands Phase Ib -- recruiting -n = 20 stage IV PDAC

NCT01302405

Phase Ib -- ongoing -- not recruiting -n = 34 stage IV PDAC

NCT02005315

NCT01351103 NCT02050178

This table includes drugs which have already progressed to clinical trials for PDAC as well as drugs which have entered trials for other solid malignancies that may in the future prove valuable for PDAC. BCC: Basal cell carcinoma; FOLFIRINOX: Leucovorin, 5-FU, irinotecan and oxaliplatin; PDAC: Pancreatic ductal adenocarcinoma.


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compounds targeting g-secretases and biologicals targeting various notch receptors or their ligands are currently under clinical experimentation in PDAC and other solid tumors (Table 3). When stromal cell-derived factor-1 or chemokine 12 (CXCL12 also known as SDF-1) binds to its G-proteincoupled receptor, CXCR4, it activates several signal transduction pathways, including ERK2, Akt, PI3K, MAPK and NF-kB. The CXCR4 pathway is critical for development of metastases, because CXCR4 expression cells migrate to normal tissues expressing CXCL12. A recent study revealed that CXCR4 is involved in pancreatic CSCs [47]. CXCR4 is coexpressed with CD133 in pancreatic CSCs and these cells have a high metastatic potential, whereas depletion of this cell subtype abrogates the development of metastases [47]. At present, there are several trials underway for CXCR4 inhibitors, but these trials target cancers other than PDAC. If positive results are obtained for these trials, it is likely that future trials will involve PDAC subjects. The Wnt/b-catenin signaling pathway is also vital during embryogenesis. Wnt signals are transduced through the frizzled receptor and lipoprotein receptor-related protein to the b-catenin signaling cascade. This Wnt pathway is another critical pathway in defining CSCs in skin, mammary and colon cancers [61,62]. In colon cancer, CSCs are regulated by activating the Wnt pathway through the secretion of growth factors from adjacent stromal myofibroblasts into the tumor’s microenvironment [62]. Although its role has not yet been exploited in pancreatic CSCs per se, the Wnt pathway plays a role in pancreatic cancer formation [46] as well as in the crosstalk with Hh pathway and is thus a potential target in eliminating CSCs [44]. There is evidence for involvement of the Wnt pathway in pancreatic CSCs [63,64]. An important paper recently showed that the CSC phenotype could be influenced by myofibroblasts. When co-cultured, or treated with conditioned media from myofibroblasts, colon cancer cells showed enhanced nuclear b-catenin, increased Wnt activity and enhanced tumorigenicity when transplanted into mice [62]. This indicates that the CSC phenotype is plastic and dependent on the microenvironment. Therefore, targeting the CSC--microenvironmental interface may be an effective treatment strategy [62]. Phase I trials using mAbs targeting frizzled receptors in PDAC are currently underway, whereas other Wnt inhibitors, b-catenin antagonist and selective porcupine inhibitor, are being tested in other cancers (Table 3). A recent paper reported on an extensive high-throughput screening study for compounds that would target CSCs using a platform to reveal differences between neoplastic and normal human pluripotent stem cells and identified compounds in order to induce differentiation to overcome neoplastic self-renewal [50]. The findings surprisingly revealed that the most potent compound with such properties was thioridazine, an antipsychotic drug that acts as a dopamine receptor antagonist [50]. Further, they investigated the presence of dopamine receptors in 13 acute myelocytic leukemia patient samples and found expression of all five receptor subtypes in all 13 samples [50]. 1506

Since the discovery of CSCs, large numbers of agents have been screened in search for those which can eliminate them. Promising ones that entered clinical trials are summarized in Table 3. Theoretically, any drug which effectively eradicates them should be curative. Eventually, potent agents targeting the above pathways will hopefully prove valuable in eradicating pancreatic CSCs. There are currently multiple Phase I and Phase II clinical trials being conducted utilizing compounds that target components in the above pathways; these are summarized in Table 3. Local tumor microenvironment of PDAC One of the features of PDAC is the intense desmoplastic response to the tumors. These infiltrating tumors are surrounded by dense fibrous stroma that contains stellate cell-derived myofibroblast-like cells, inflammatory cells, small blood vessels and atrophied cellular components of the invaded pancreas. Non-cellular components include types I, III and IV collagen, laminin, fibronectin, hyaluronan and osteonectin [65]. Activated stellate cells play a major role in triggering this fibrotic response much in the same way as they trigger fibrosis in the liver disease [66]. There has been much debate over the question of whether the desmoplastic reaction is beneficial for the tumor host by preventing tumor invasion or whether it provides a beneficial environment for the tumor. There is now overwhelming evidence that this microenvironment aids tumor development growth and invasion [67-69]. Further, recent evidence suggests that it acts as an effective barrier to prevent access of chemotherapeutic agents to the tumor [70]. Indeed, concentrations of gemcitabine in tumor tissue have been found to be extremely low, suggesting that the desmoplasia is yet another mechanism of drug resistance in PDAC [70]. This could arise from increased interstitial fluid pressure, from increased extracellular matrix protein deposition or from poor tissue perfusion resulting from disorganized local vasculature [67]. Targeting the desmoplasia is likely to improve the tumor response to chemotherapeutic agents. This could be accomplished by targeting the TGF-b pathway which is involved with activation of the pancreatic stellate cells [67]. TGF-b inhibitors and mAbs are now under Phase I and Phase II trials in PDAC and other solid tumors (Table 4). Ligands from PDAC have also been shown to activate the Hh pathway in the stroma and a Hh inhibitor was able to deplete the stroma and revascularize poorly perfused tumors in a genetic mouse model of the disease [70]. This has led to clinical trials with Hh inhibitors, as discussed in the previous section and summarized in Table 3, although the current results available in pancreatic cancer thus far have been disappointing [71,72]. Albumin-bound paclitaxel (nab-paclitaxel) was developed to increase the solubility of paclitaxel. Osteonectin, a component of the desmoplastic stroma, binds to the albumin and concentrates paclitaxel in the tumor. This appeared to lead to stromal collapse [67]. A clinical trial based on this 3.4



Table 4. Investigational drugs targeting tumor stroma, which have progressed to clinical trials. Phase -- study status -- number of enrolled subjects and types of cancer

Drug and its characteristic


Targeted pathway: TGF-b signaling pathway


Trabedersen (AP 12009; phosphorothioate antisense oligodeoxynucleotide for human TGF-b2 mRNA; TGF-b2 inhibitor) LY2157299 (novel TGF-b inhibitor)

Fresolimumab (GC1008; human anti-TGF-b 1 -- 3 mAb) + local radiotherapy IMC-TR1 (LY3022859; fully human neutralizing mAb binds and blocks signaling through TGF-bRII)

Phase I -- completed -- awaiting results -n = 62 pancreatic neoplasms, melanoma and colorectal neoplasms Phase Ib/II -- recruiting -n = 168 metastatic neoplasm, advanced and metastatic PDAC Phase I -- recruiting -n = 28 metastatic breast cancer Phase I -- recruiting -n = 95 advanced solid tumors

NCT00844064

NCT01373164

NCT01401062 NCT01646203

Targeting hyaluronic acid at the extracellular matrix (tumor stroma) mFOLFIRINOX ± PEGPH20: PEGylated form of rHuPH20 (recombinant human hyaluronidase) Nab-paclitaxel + gemcitabine ± PEGPH20 Gemcitabine ± PEGPH20

Phase I/II -- recruiting -n = 172 metastatic PDAC Phase II -- ongoing -n = 132 metastatic PDAC Phase Ib/II -- ongoing -n = 147 metastatic PDAC

NCT01959139 NCT01839487 NCT01453153

FOLFIRINOX: Leucovorin, 5-FU, irinotecan and oxaliplatin; PDAC: Pancreatic ductal adenocarcinoma.

observation has shown a substantial survival benefit and revealed that the nab-paclitaxel increased gemcitabine concentrations in tumors, explaining the beneficial clinical response [73]. A subsequent Phase III trial confirmed the clinical benefit of this combination [14]. Although studies in a mouse model of PDAC have confirmed the efficacy of nabpaclitaxel, they have questioned the mechanism by which the drug is working. One study showed a synergistic effect of nab-paclitaxel with gemcitabine through reactive oxygen species-mediated degradation of cytidine deaminase, the major gemcitabine degrading enzyme. Thus, the combination of nab-paclitaxel with gemcitabine resulted in higher intratumoral concentrations of gemcitabine [74]. However, the synergistic effect of nab-paclitaxel was not changed in animals with genetic ablation of the osteonectin gene [75]. Although the mechanisms of action may be uncertain, the effectiveness of nab-paclitaxel in combination with gemcitabine is established. Hh signaling in stromal cells also plays a role in tumorigenesis in multiple ways. First, Hh activation in stromal cells leads to paracrine secretion of growth factors that stimulate tumor growth and invasive behavior [76]. Second, the resulting growth factor-mediated activation of ERK and Akt kinases results in increased Hh secretion by the tumor via by NF-kB [77]. Third, NF-kB-activated monocytes, recruited to the stroma produces Shh which is the Hh pathway in the cancer cells via the paracrine route [78]. Fourth, paracrine production of the chemokine, CXCL12 by stromal cells activates NF-kB via the cancer cell CXCR4 receptors and the Erk and

Akt kinase cascades [79]. Because of these paracrine pathways, inhibition of Hh signaling in the stellate cells of the stroma results in reduced growth and invasion of PDAC [80,81]. Hypoxia also plays a role in triggering Hh signaling in PDAC. First, hypoxia upregulates expression of Smo and thereby activates the Hh pathway [82]. The mechanism for this is not clear as some studies have suggested that activation of the Hh pathway is independent of HIF-1a and also ligand-independent [82,83], whereas another study suggested that HIF-1a expression in the stroma leads to activation of the Hh pathway by Shh [84]. Whatever the mechanism, it is clear that activation of Hh signaling results in EMT and progression to more aggressive and chemoresistant malignancies [83-85]. Because of the importance of the Hh pathway in the stroma as well as in CSCs, there have been multiple attempts to target the pathway in preclinical and clinical trials that are discussed above in Section 3.3 and outlined in Table 3. Another therapeutic approach to target the stroma is the enzymatic hydrolysis of the extracellular matrix components using recombinant human hyaluronidase [86,87]. Phase I and Phase II trials in PDAC are currently underway (Table 4). Another feature of the interactions between the tumor and its microenvironment is the evasion of immune surveillance. The understanding of PDAC immunology research lags behind that of other cancers such as melanoma and renal cell carcinomas. However, it is clear that PDAC, like other carcinomas, is able to modulate or manipulate the immune system to evade immune surveillance and thereby prevent


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Table 5. Selected investigational immunotherapy-related drugs utilizing different strategies which have progressed to clinical trials. Agent (target) and its characteristic




Strategy: vaccination trials Adjuvant long synthetic mutant Kras peptides vaccines

Phase I/II -- completed -- published -n = 23 vaccinated resectable

Gemcitabine ± GI-4000; an inactivated recombinant Saccharomyces Cerevisiae-expressing mutant Ras protein Poxviral-based vaccine therapy (targeting CEA and MUC1) plus GM-CSF versus BSC or palliative chemotherapy GVAX (genetically modified pancreatic cancer cells to secrete GM-CSF) given with low-dose cyclophosphamide ± CRS-207 (a live-attenuated Listeria monocytogenes genetically modified that stimulate an immune response against the protein mesothelin) Epitope peptide derived from VEGFR1 and VEGFR2+ gemcitabine

Phase II -- ongoing -n = 176 resectable

Gemcitabine + capecitabine ± telomerase peptide vaccine (GV1001) An alphaviral vector encoding HER2 extracellular domain and transmembrane region (AVX901) Intradermal administration of MUC1-peptide-pulsed DCs

Phase III -- unknown -n = 250 metastatic (stage IV), gemcitabine refractory Phase II -- ongoing -n = 93 metastatic

Phase I/II -- completed -n = 17 unresectable, recurrent or metastatic Phase III -- completed -n = 1110 locally advanced and metastatic Phase I -- recruiting -n = 12 locally advanced or metastatic EGFR2-positive (HER2+) cancers Resectable or metastatic after surgery, and MUC1-positive IHC

Immunological response: 85% (17 of 20 patients) with median survival of 28 months. 5-year survival was 29%. 10-year survival was 20% (4 out of 20 patients); 3 patients with memory response up to 9 years. The vaccination may consolidate the effect of surgery as an adjuvant treatment option [113] NCT00300950

NCT00088660

NCT01417000

NCT00655785

NCT00425360 NCT01526473

The therapy was nontoxic and capable of inducing immunological response to tumor antigen MUC1. Additional studies are necessary to improve tumor rejection responses [114]

Strategy: adoptive cell transfer Cytotoxic T lymphocytes (CTLs) with induced cytotoxicity against 5 MUC1-expressing PDAC cell lines and a breast cancer cell line (adjuvant in resectable patients)

Phase I/II -- completed -- published -n = 28 resectable and unresectable

Median survival was 5 months for unresectable tumors and 17.8 months for 18 of 20 patients with resectable tumors. The 1-, 2- and 3-year survival rates after surgery were 83.3, 32.4 and 19.4%, respectively. Regimen was safe [115]

Strategy: genetically modified T-cell receptors (TCR) T cells modified with chimeric anti-CEA immunoglobulin-TCR

Phase I -- completed -adenocarcinomas including PDAC

NCT00004178

Strategy: chimeric antigen receptors (CAR) Cyclophosphamide and fludarabine + anti-mesothelin CAR lymphocytes + aldesleukin

Phase I/II -- recruiting -n = 136 metastatic cancers including PDAC

NCT01583686

This table includes drugs which have already progressed to clinical trials for PDAC as well as drugs which have entered trials for other malignancies that may in the future prove valuable for PDAC. BSC: Best supportive care; DC: Dendritic cells; IHC: Immunohistochemistry; PDAC: Pancreatic ductal adenocarcinoma.

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Table 5. Selected investigational immunotherapy-related drugs utilizing different strategies which have progressed to clinical trials (continued). Agent (target) and its characteristic



Strategy: mAbs targeting co-stimulatory and inhibitory receptors and ligands


Second-line ipilimumab (antiCTLA-4) + allogeneic pancreatic tumor cells transfected with a GM-CSF gene Ipilimumab (anti-CTLA-4)

Phase I -- completed -- published -n = 30 refractory Phase II -- completed -n = 27 locally advanced or metastatic

The combination has potential for clinical benefit and should be evaluated in a larger study [116] Ipilimumab was ineffective. However, a significant delayed response in one subject suggests that immunotherapeutic approaches deserve further exploration [117]

Strategy: T regulatory cells depletion Recombinant IL 2/diphtheria toxin conjugate (DAB/IL-2)

Phase II -- competed -- published -n = 16 metastatic melanoma

T cells depletion may disrupt the homeostatic control of cognate immunity and allow for the expansion of effector T cells with specificity against neoplastic cells [118]. Similar strategy combining metronomic cyclophosphamide and an anti-CD25 mAb showed success in mouse model of PDAC [119]

This table includes drugs which have already progressed to clinical trials for PDAC as well as drugs which have entered trials for other malignancies that may in the future prove valuable for PDAC. BSC: Best supportive care; DC: Dendritic cells; IHC: Immunohistochemistry; PDAC: Pancreatic ductal adenocarcinoma.

eradication. In recent years, evidence has accumulated on the two-faced role of the immune system during PDAC pathogenesis. First, PDAC produces strong immune suppression signals allowing tumor to evade its immune response. This immune suppression is modulated through several key players such as T regulatory (Treg) cells, myeloid-derived suppressor cells [88] and M2-polarized tumor-associated macrophages [89]. For example, Tregs are abundantly increased in the circulation [90] and the tumor microenvironment [88] in PDAC patients, and this increase is correlated with advanced disease and poor prognosis [91,92]. Tregs normally play an important role in suppressing hyperactivation of the immune response and thereby prevents autoimmune diseases. On the other hand, immune suppression within the tumor microenvironment serves to prevent immune surveillance and to foster tumor growth and progression. The triggered antitumor immune response provides the second immunological mechanism by which PDAC further evades the immune system. The immunosuppressive environment created by PDAC detracts dendritic cells maturation and alter their ability to induce tumor-specific effector T-cell function [93]. Accumulated evidence on the role of the immune system in PDAC pathogenesis has inspired scores of clinical trials so far. However, previously published trials have failed to advance to the clinic, probably because of underdeveloped delivery designs. However, with the advances in strategies, immunotherapy is now looking more promising. Because of the problems in treating PDAC, it is unlikely that immunotherapies will be

successful as stand-alone strategies. On the other hand, including immunotherapy as part of combination therapy regimens may potentiate the effectiveness of these approaches. Various immunotherapy strategies are currently being tested in > 40 active clinical trials in PDAC. Since analyzing the effectiveness of all of these strategies is outside the scope of this review, we have chosen some prominent examples of immunotherapeutic approaches, which are summarized in Table 5. There are two very recent reviews which cover the immunotherapy of PDAC in greater detail [94,95].

Animal models of PDAC to investigate new therapies

3.5

One of the impediments to progress in therapy of PDAC in the past has been the lack of suitable animal models that effectively recapitulate the disease. Over the decades we have gone through carcinogen-induced models, subcutaneous and orthotopic transplants of tumors in immunocompromised mice and most recently a number of genetic models to recapitulate the disease. Mice and rats develop acinar cell tumors in response to carcinogens rather than ductal cell adenocarcinomas and are thus of limited use. Hamsters treated with N-nitrosobis-2-oxypropylamine (BOP) develop ductal cell tumors with k-ras and p53 gene mutations that mimic the disease quite well, but the disease only develops in a proportion of animals and development takes several months and we lack the ability and experience to manipulate the


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background genetics of this species in the way we can in mice [96]. Subcutaneous transplantation of human pancreatic cancer cells into athymic mice has been very widely adopted for investigation of novel therapeutics. It has the advantage of being simple to perform, the tumors form rapidly and tumor growth can be monitored daily if required. However, it has the disadvantage of not having the appropriate host environment for the cells to grow in or having the capability of development of metastases. Orthotopic transplants get around the latter two problems; however, they involve more difficult surgery and monitoring of tumor growth is more challenging. However, if cells are engineered to express luciferase or a fluorescent protein, then tumor growth can be readily monitored in real-time using a number of imaging systems that are now available [97]. Over the past decade, we have seen development of several mouse models which recapitulate the human disease, including development of pancreatic intraepithelial neoplasms -- the major precursor for the development of malignant cancer. These include the pancreatic duodenal homeobox 1 (PDX-1)-Cre:KrasG12D, p53R172H/-; PDX-1-Cre, KrasG12D, Ink4a-/-, p53lox/lox, PDX-1-Cre:KrasG12D, p53Lox/Lox and genetically engineered mouse models [98,99]. All of these genetic models show accelerated development of PDAC and the first two mentioned models also exhibit metastatic disease. The hope is that the use of these models that better recapitulate the human disease process will lead to better information regarding the preclinical efficacy of novel therapeutics in the future. 4.

Conclusion

Pancreatic cancer is a complex disease. The complexities of the genetic mutations and epigenetic events leading to this cancer are slowly being unraveled. Pancreatic cancers have features that set them apart from other malignancies. The tumors are generally considered to be highly aggressive, although autopsy data and other findings suggest that, like other malignancies, these tumors take many years to develop and the major problem is the late diagnosis. The tumors are surrounded by dense desmoplasia which provides growth support, facilitates invasion, prevents immune surveillance and provides a physical barrier against penetration of therapeutic drugs into the tumor. The patients most often exhibit severe cachexia which makes them poor candidates for the rigors of chemotherapy and radiation therapy. Patients are generally severely insulin-resistant and the majority of them are frankly diabetic. Whether the diabetes is a predisposing factor or a result of the tumor is debatable, but it is likely that insulin resistance plays a role in tumor development as well as being tumor-driven as the disease develops. If diabetes really is a predisposing factor, then, with the current worldwide epidemic of obesity and resulting type 2 diabetes, we can anticipate a massive increase in the incidence of this cancer in future years. Indeed, whereas the incidence of most major cancers is declining, the incidence of pancreatic cancer continues to rise 1510

and it has been projected that pancreatic cancer incidence will double by the year 2030. Despite the magnitude of the problem, our ability to make an impact on survival from pancreatic cancer has changed little over several decades. The only potential cure is surgery. Although centralization of surgical procedures and improved techniques have reduced perioperative mortality, even in this preselected group, the majority of patients still succumb to the disease. For many years, gemcitabine was the ‘goldstandard’ of treatment for patients with locally invasive or metastatic pancreatic cancer. Gemcitabine actually has little impact on survival but was approved because it improved quality of life. In 2005, the EGFR tyrosine kinase inhibitor erlotinib was approved because it improved survival in a small percentage of patients. Recently, there have been further therapeutic advances. Notably, both FOLFIRINOX and nab-paclitaxel have shown substantial survival benefit. However, even though these advances are important, they are still relatively small steps forward. If we are to make a major impact on this disease, we must address several problems. These include eradication of the stem cells that will ultimately recapitulate the disease, reduction of the intense desmoplasia that prevents access of therapeutic agents to the tumors and improvement in the metabolic status of the patients.

5.

Expert opinion

Pancreatic adenocarcinoma is clearly a difficult disease to treat. Less than 20% of patients are candidates for tumor resection and, even in this preselected group, the median expectation of life from diagnosis is < 2 years. Patients with unresectable tumors have a worse fate and, even with recent advances in therapy, they have a median expectation of life of < 1 year. Several factors contribute to this, including late diagnosis due to the late onset of symptoms, lack of effective screening tests and the inaccessibility of the organ for screening. After several years with lack of advances in therapy, there has recently been some progress with the recognition that either the FOLFIRINOX combination or addition of nabpaclitaxel to gemcitabine provides substantial survival benefit compared with gemcitabine alone. These advances aside, the vast majority of clinical trials conducted over the past 5 years have failed to show any clinical benefit. This begs the questions of what are we doing wrong and what can be done to correct this situation? When we review the nature of the clinical trials that have been conducted, the vast majority were looking at combinations of gemcitabine with some other agent that has anticancer activity in another situation. Although small steps forward may be gained from this approach, one may argue that the potential gain does not justify the cost. This approach, particularly in the basic scientific aspects that naturally precede the clinical studies, may to some extent be propagated by granting agencies that tend to fund projects considered to be




accomplished readily rather than funding of more novel approaches that may be more likely to fail in their outcome. Clearly innovative approaches are needed and progress with some of these is highlighted in this review. A problem until recent years was the lack of appropriate animal models to recapitulate the disease. Appropriate genetic mouse models are now available and are being used to test novel approaches. This bodes well for the future. It has come to light in recent years that most, if not all, cancers arise in stem cells and that only these CSCs have the capability of recapitulating the tumor. Clearly CSCs have to be a primary target for therapy. If they could be completely eradicated, it is likely that killing the other components of the tumor might not even be necessary in terms of survival, since the outcome would at worst be the presence of a benign tumor. The local tumor microenvironment clearly provides another barrier against therapy, since it has been shown that the dense desmoplasia prevents access of therapeutic agents to the tumors. Thus, disruption of this connective tissue barrier would be another prime target. Since immune evasion is another prominent feature of PDAC, advances in immunotherapeutic approaches may also be of value in treating the disease. Currently, there is intense research to identify genes responsible for development of metastasis. This search may lead to identification of new targets for prevention of metastatic disease, which ultimately kills the majority of patients. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Another problem for therapy is the physical condition of the patients. Most patients with pancreatic cancer develop severe cachexia which makes them less capable of coping with the rigors of chemotherapy. An added problem is that all pancreatic cancer patients are markedly insulin-resistant and the majority of them are frankly diabetic, making treatment of their cancer even more problematic. Cachexia is often the direct cause of mortality and ultimately contributes to the morbidity and mortality in all patients with PDAC. Clearly, a better understanding of the mechanisms of the cachectic state would allow us to better design treatment modalities for this metabolic problem. Combined therapy should be aimed at eradicating the CSCs while disrupting the desmoplastic barrier as well as addressing the metabolic needs of the patient. It is this last area where the least progress has been made as some current clinical trials are certainly targeting the stem cells and the physical barrier against therapeutic intervention.

Declaration of interest The authors are supported by the Terry Fox Cancer Research Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation Amal HI Al Haddad1 RN BSN MSHRM & Thomas E Adrian†2 PhD FRC Path † Author for correspondence 1 PhD student -- Cancer Biology, Researcher, Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, UAE 2 Professor of Physiology, Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, UAE Tel: +971 713 7551; Fax: +971 7671966; E-mail: [email protected]

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State of the art and future directions of pancreatic ductal adenocarcinoma therapy.

Current management and future directions in metastatic pancreatic adenocarcinoma.

Atrial fibrillation: mechanisms, therapeutics, and future directions.

Macrophages and pancreatic ductal adenocarcinoma.

Screening for Barrett's esophagus and esophageal adenocarcinoma: rationale, recent progress, challenges, and future directions.

Laparoscopic distal pancreatosplenectomy for pancreatic ductal adenocarcinoma.

Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future.

Future directions for anti-biofilm therapeutics targeting Candida.

Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size: Positive Implications for Future Targeted Screening.

Genetics and biology of pancreatic ductal adenocarcinoma.

Targeting mTOR in Pancreatic Ductal Adenocarcinoma.

Nondystrophic myotonia: challenges and future directions.

Pediatric cataract: challenges and future directions.

TGFβ signaling in pancreatic ductal adenocarcinoma.

Endoscopic and operative palliation strategies for pancreatic ductal adenocarcinoma.

Video for Adolescent Pregnancy Prevention: Promises, Challenges, and Future Directions.

Surgical techniques for improving outcomes in pancreatic ductal adenocarcinoma.

Radiofrequency ablation of pancreatic ductal adenocarcinoma: The past, the present and the future.

Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.

Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

Interventional Nanotheranostics of Pancreatic Ductal Adenocarcinoma.

Prognostic Fifteen-Gene Signature for Early Stage Pancreatic Ductal Adenocarcinoma.

Immunotherapy for pancreatic ductal adenocarcinoma: an overview of clinical trials.

Association of pancreatic Fatty infiltration with pancreatic ductal adenocarcinoma.