Current concepts and noveltargets in advanced pancreatic cancer
Current concepts and novel targets in advanced pancreatic cancer Patrick Michl,Thomas M Gress
Department of Gastroenterology,Endocrinology and Metabolism,Philipps University Marburg,Marburg, Germany Correspondence to Professor Dr Thomas Gress, Division of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldinger Strasse,
Marburg35043,Germany; gress@med.uni-marburg.de ABSTRACT
Pancreatic cancer remains one of the most aggressive
tumours with a5-year survival rate of less than5%.The
dismal prognosis of this tumour entity that is associated
with a high degree of drug resistance has not changed
over the past decades.Since1997,gemcitabine-based
regimens have been the therapy of choice for advanced
pancreatic cancer.Recently,however,new combination
chemotherapy regimens achieved a signi?cant survival
bene?t compared to gemcitabine-based therapies.In
addition,novel approaches to improve drug delivery are
currently being developed,and new drugs targeting
signalling pathways both within the tumour cells and the
tumour microenvironment are undergoing preclinical and
clinical validation.Furthermore,efforts are being made to
identify predictive markers for individualised treatment
approaches based on molecular tumour characteristics.
This review provides an overview on current and
emerging concepts as well as novel targets for systemic
treatment of advanced pancreatic https://www.wendangku.net/doc/7f11408523.html,bination
therapies incorporating drugs directed against these new
targets may open new avenues for improving the ef?cacy
of current treatment approaches and overcoming the
devastating prognosis of pancreatic cancer patients.
INTRODUCTION
Pancreatic ductal adenocarcinoma(PDAC)is asso-
ciated with a5-year survival rate of less than5%
and a median survival of6months after diagnosis,
thereby exhibiting the poorest prognosis of all
solid tumours.12It is characterised by a high pro-
pensity for local invasion and distant metastasis as
well as a largely drug-resistant phenotype.At pres-
entation,only approximately20%of PDAC
patients qualify for surgical resection in curative
intent.Even for those,the5-year survival rate
rarely exceeds20%due to early relapse or meta-
static spread of the disease.The vast majority of
patients,however,already present with locally
advanced or metastatic disease,which is associated
with an extremely poor prognosis.3
The current management of PDAC is guided by
tumour stage,comorbidities and performance
status of the patients.Surgical resection followed
by a6-month-course of adjuvant gemcitabine-
based chemotherapy is the standard of care for
early-stage disease(?gure1).3In contrast,patients
with metastatic disease are candidates for systemic
palliative chemotherapy.For patients with locally
advanced disease without evidence of metastasis,
optimal treatment remains to be de?ned,with
chemotherapy alone as well as chemoradiation to
be considered(?gure1).
This review focuses on current and emerging
therapeutic concepts for patients presenting with
metastatic or locally advanced disease,for which
surgery in curative intent is not an option.
CURRENT MANAGEMENT
Metastatic disease
Since1997,the nucleoside analogue gemcitabine
has been established as standard of care in meta-
static PDAC.Burris et al4published the results of a
phase III trial comparing5-?uorouracil(5-FU),
which had been used frequently by that time,
with gemcitabine as a single agent administered as
a weekly intravenous injection.T reatment with
gemcitabine resulted in a superior clinical response
compared to5-FU and was associated with a sig-
ni?cant,but modest survival bene?t(median sur-
vival5.65vs4.41months).In addition,the clinical
bene?t response,a composite score for pain(anal-
gesic consumption and pain intensity),Karnofsky
performance score and weight,was in favour of
gemcitabine leading to US Food and Drug
Administration approval and the establishment of
gemcitabine as standard of care in?rst-line pallia-
tive therapy for advanced PDAC.3
Over the past decade,numerous trials have been
conducted to improve the outcome in patients
with metastatic disease by combination therapies
using gemcitabine as backbone.Most trials used a
second cytotoxic agent such as5-FU,5capecita-
bine,6oxaliplatin,78cisplatin,910irinotecan,11
exatecan12or pemetrexed13administered in com-
bination with gemcitabine.However,despite a
modest improvement in progression-free survival
in some trials,a signi?cant bene?t in overall sur-
vival could not be demonstrated for any of these
combination therapies.3
Despite these discouraging results of single
trials,a recent meta-analysis by Heinemann et al14
suggests a bene?t of combination therapies in
patients with good performance status.By analys-
ing15randomised trials of combination therapies,
the authors showed a signi?cant survival bene?t
when gemcitabine was combined with either a
platinum derivative or?uoropyrimidines.This
was,however,restricted to patients with good per-
formance status.Another meta-analysis by
Sultana et al15con?rmed the bene?t of combin-
ation therapy with gemcitabine and a platinum
compound.In that meta-analysis,however,com-
bination with?uoropyrimidines only resulted in
improved survival when the oral analogue capeci-
tabine was used as the partner drug.T aken
together,these data indicate that there might be a
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signi?cant,albeit small,survival bene?t for gemcitabine-based combination therapies in patients with good performance status.
Conroy et al16recently reported the?rst signi?cant improve-ment in overall survival using a gemcitabine-free combination therapy regimen.In the landmark PRODIGE trial published in 2011,the authors used the FOLFIRINOX protocol(folinic acid,?uorouracil,irinotecan and oxaliplatin),which resulted in a remarkably improved overall survival of11.1months compared to6.8months in the control arm using gemcitabine alone.16As expected,the side effects of this new combination regimen were signi?cant,including a grade3and4neutropenia rate of 45.7%.Interestingly,pancreatic head tumours requiring biliary stents accounted for only14.3%of all patients,which might explain the low observed incidence of cholangitis.T aken together,this new regimen represents a new treatment stand-ard for patients with metastatic PDAC that should be preferred to gemcitabine-based combination regimens in carefully selected patients with good performance status and without contraindications.
Second-line therapy in metastatic disease
Only a few trials have evaluated the use of second-line regi-mens after the failure of?rst-line therapy.The only randomised trial in this context tested the combination of oxaliplatin and 5-FU versus best supportive care after failure of gemcitabine-based?rst-line therapy.Although the trial was prematurely ter-minated due to insuf?cient accrual,the oxaliplatin and5-FU protocol resulted in a signi?cantly prolonged median second-line survival of4.82months compared to2.30months with best supportive care.317This suggests that a sequential admin-istration of a5-FU and platinum-based combination regimen after gemcitabine-based monotherapy is able to provide a sur-vival bene?t.3
Targeted therapies in metastatic disease
During the past decade,numerous targeted agents have been evaluated alone or in combination with chemotherapy in meta-static PDAC.Unfortunately,most agents have so far failed to improve patient survival signi?cantly.The long list of agents tested in trials as futile include antiangiogenic drugs such as the vascular endothelial growth factor(VEGF)antibody bevazi-cumab and multikinase inhibitors with antiangiogenic activity such as axitinib,sunitinib and sorafenib.18–20The same applies for various other targeted agents directed against secreted matrix proteases21or against intracellular targets such as farne-syl transferase inhibitors.22
T o date,inhibition of the epidermal growth factor receptor (EGFR)pathway by the small molecule inhibitor erlotinib represents the only targeted therapy approved for metastatic PDAC.A trial conducted by the National Cancer Institute of Canada Clinical T rials Group demonstrated a small,but signi?-cant bene?t in median overall survival of approximately 2weeks in patients receiving erlotinib in combination with gemcitabine compared to patients treated with gemcitabine plus placebo.23This marginal bene?t clearly raises questions about the clinical signi?cance of erlotinib.However,in a small subgroup of patients who developed grade II or more skin rash as a side effect of erlotinib treatment,a prolonged median survival of10.5months was observed—almost the median sur-vival that has been described with FOLFIRINOX treatment.23 The underlying molecular mechanisms behind this striking observation remain to be fully elucidated.At this point,it is not entirely clear whether the erlotinib-induced rash is predict-ive of treatment response to erlotinib or serves merely as a prognostic factor re?ecting a more favourable tumour biology.24 In view of these data,it is presently recommended to stop erlo-tinib and to continue gemcitabine as monotherapy in the absence of skin toxicity.
Locally advanced pancreatic cancer
Locally advanced pancreatic cancer(LAPC)is de?ned as surgi-cally unresectable disease without evidence of distant metasta-ses.25The optimal treatment for these patients remains to be de?ned.In addition to systemic chemotherapy,chemoradiation has to be considered in order to achieve locoregional control.26 In contrast,radiotherapy alone has been largely abandoned since early studies demonstrated a lack of bene?t from radiation
Figure1Overview on current stage-dependent treatment strategies and new approaches for improvement of pancreatic cancer
therapy.
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alone compared to chemoradiation.2728The impact of chemor-adiation versus chemotherapy alone on the survival of patients presenting with locally advanced disease still has to be clari?ed. Several small early studies using older radiation techniques and chemotherapy regimens resulting in high toxicities may no longer be representative of state-of-the-art clinical care.29–31 However,recent studies continue to produce con?icting data.
A randomised trial conducted by French groups used a fairly aggressive regimen including60Gy of radiation combined with simultaneous continuous infusions of5-FU and cisplatin. Compared with gemcitabine alone,survival was signi?cantly inferior in the chemoradiation group(8.6vs13months).32In contrast,a recent trial conducted by the Eastern Cooperative Oncology Group compared a less toxic regimen consisting of radiotherapy(50.4Gy)and gemcitabine(600mg/m2per week) with gemcitabine alone.In that study,radiochemotherapy resulted in a slight,but signi?cant,survival bene?t (11.1months(95%CI7.6to15.5months)vs9.2months(95% CI7.9to11.4months),one-sided p=0.017).33
In light of these con?icting data,it has to be taken into account that approximately30%of the patients treated with chemoradiation for LAPC develop metastatic disease soon after diagnosis and may thus have little bene?t from this type of therapy.34Therefore,a sequential approach has been proposed consisting of an initial chemotherapy regimen followed by restaging and subsequent chemoradiation only for those patients with no evidence of early metastatic progression,thus avoiding unnecessary toxic treatment.34
The ongoing GERCOR LAP-07study,a multi-institutional phase III trial,was designed to test the impact of this sequen-tial approach on survival(https://www.wendangku.net/doc/7f11408523.html,,identi-?er code NCT00634725).Patients are randomly assigned to receive either gemcitabine alone or gemcitabine/erlotinib.After 4months of chemotherapy,patients with stable disease are ran-domly assigned a second time either to continue their chemo-therapy or to receive chemoradiation to54Gy with concurrent capecitabine.The results of this largest randomised trial in LAPC are eagerly awaited.35
Current trial concepts are not only aiming to identify the optimal sequence of radiation and chemotherapy but also to de?ne the most ef?cient chemotherapy regimens in LAPC. Given the profound impact of the FOLFIRINOX regimen in metastatic PDAC,it may be speculated that an intensi?ed chemotherapy preceding chemoradiation might also be of bene?t to patients with locally advanced tumours.
In addition,it remains unclear to date which drug is most effective as radiosensitiser given concurrently with radiation. Earlier studies have established chemoradiation with5-FU as standard.Based on in-vitro data indicating that gemcitabine is a more potent radiosensitiser compared to5-FU,several smaller trials using gemcitabine together with radiotherapy revealed a trend towards better survival compared to5-FU;36however,at the cost of a higher systemic toxicity.Therefore,efforts have been made to decrease toxicity by reducing the dose of gemci-tabine37or by improving the radiotherapy techniques.2638 Currently,5-FU or gemcitabine at a reduced dose are equally applied as radiosensitiser.
Neoadjuvant therapy in LAPC
Radiochemotherapy as well as intensi?ed chemotherapy with or without subsequent chemoradiation are concepts that may offer the possibility of downstaging patients to achieve second-ary resectability in locally advanced or borderline resectable cases.Several retrospective and small prospective trials indicate that a subgroup of patients who are initially unresectable can successfully undergo resection after neoadjuvant therapy. According to recent meta-analyses by Gillen et al39and Assi?et al40approximately one-third of pancreatic cancer patients initially staged as unresectable or borderline resectable had resectable tumours following neoadjuvant chemoradiation, with survival rates comparable to initially resectable patients. Chemotherapeutic regimens included gemcitabine,5-FU(and oral analogues),mitomycin C and platinum compounds.In the meta-analysis by Gillen et al,39however,neither increased resec-tion frequencies nor improved survival by neoadjuvant therapy were observed in patients with initially resectable tumours. These meta-analysis data demonstrating a survival bene?t of neoadjuvant chemoradiation in patients with LAPC could be corroborated by a recent large retrospective series reported on 215patients with LAPC at a single institution.41In that series, radiotherapy was delivered with a median dose of52.2Gy in single fractions of1.8Gy,with gemcitabine being applied con-comitantly at a dose of300mg/m2weekly.Following radioche-motherapy,26%of the patients could be resected and had a median overall survival of22months,which was similar to patients with primary resection.41
As discussed above,a sequential approach with upfront chemotherapy followed by radiochemotherapy after restaging might prevent unnecessary radiotherapy in patients with early metastatic disease.However,evidence for this approach is limited and further trials for patients with locally advanced tumours are urgently required(NCT01359007).
EMERGING CONCEPTS
Improving drug delivery
The impact of current chemotherapeutic regimens on the overall survival of pancreatic cancer patients is clearly unsatis-fying.Several new approaches aim to improve the delivery of known chemotherapeutic agents into the tumour.Based on recent preclinical data in mouse models that will be discussed below in detail,it has been hypothesised that currently avail-able cytotoxic drugs can not access tumour cells at an effective concentration due to the extensive hypovascular stroma reac-tion that acts as a fence around tumour cells protecting them from therapeutic agents administered to the systemic circula-tion.42Therefore,numerous efforts have been made to improve drug formulations in the aim of enhancing accessibility to the tumour cells.
Nanoparticle albumin-bound(nab)-paclitaxel is an albumin-stabilised paclitaxel formulation that was initially developed to avoid toxicities associated with oil-based solvents required to solubilise paclitaxel.Nab-paclitaxel has been approved in patients with metastatic breast cancer.In addition,it has shown promising activity in a recent phase I/II trial with pan-creatic cancer patients,43and several trials using nab-paclitaxel in combination chemotherapies are currently ongoing (NCT01161186,NCT01470417,NCT01010945).The molecular mechanism of nab-paclitaxel has not been fully elucidated.In addition to the hypothesis that the tumour cells themselves are albumin-avid leading to enhanced tumoral concentration,it has been hypothesised that secreted protein,acidic and rich in cyst-eine,also known as osteonectin,which is highly expressed and secreted by pancreatic peritumoral?broblasts,may serve as an albumin-binding protein that sequesters nab-paclitaxel and con-centrates the drug intratumorally.44Interestingly,a recent pre-clinical study that used a combination of nab-paclitaxel and gemcitabine in a genetic mouse model of pancreatic cancer45 showed that coadministration of nab-paclitaxel and gemcitabine
Recent advances in clinical practice
uniquely led to tumour regression that was associated with increased intratumoral gemcitabine levels and a marked decrease in cytidine deaminase,the primary gemcitabine metabolising enzyme.The authors could demonstrate that paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species-mediated degradation,45which suggests a synergistic effect of(nab)paclitaxel and gemcitabine in com-bination regimens.
In addition to(nab)paclitaxel,several other formulations have been developed in order to facilitate drug delivery to the tumour, among them coating drugs with liposomal phospholipid vesi-cles:EndoTAG-1is a novel cationic liposomal formulation of paclitaxel,which targets tumour endothelial cells that express negatively charged cell-surface molecules.Therapy with cationic liposomal paclitaxel led to reduced tumour vessel density and endothelial cell mitosis resulting in diminished tumour perfu-sion and growth.46A randomised phase II trial showed signi?-cantly improved survival in patients treated with liposomal paclitaxel in combination with gemcitabine compared to gemci-tabine alone.47Similarly,a liposomal formulation of irinotecan (PEP02)has shown activity in gemcitabine-refractory pancreatic cancer.48Further trials are warranted to investigate the activity of liposomal formulations and other modi?cations aiming to improve drug delivery in pancreatic cancer.
Novel targeted approaches
In addition to improving drug delivery,novel targeted therapies are urgently needed.So far,targeted agents have largely failed to provide a substantial survival bene?t in advanced pancreatic cancer.Therefore,it is of utmost importance to identify novel candidates for drug development that are able to impact signi?-cantly on the outcome of this disease.Most novel compounds can be classi?ed functionally into four main groups:(1)drugs interfering with downstream signalling cascades within the tumours cells;(2)drugs targeting the stromal response;(3)drugs modulating tumour vasculature thereby enhancing drug delivery; and(4)drugs targeting the immune response(?gure2).Targeting survival and angiogenesis pathways
Therapeutic inhibition of receptor tyrosine kinases such as EGFR and VEGFR regulating tumour cell survival,proliferation and angiogenesis both by monoclonal antibodies and small molecule inhibitors has been evaluated extensively and approved for clinical use in several solid tumours including colon cancer.49In pancreatic cancer,however,EGFR inhibition with the small molecule inhibitor erlotinib is the only targeted approach that has been approved for clinical use,but only pro-vides a marginal survival bene?t,as discussed above.23 Although robust data on the role of activating K-Ras mutations as predictors of response to EGFR inhibitors in pancreatic cancer are missing,it may be speculated that due to the high percentage of activating K-Ras mutations occurring in up to 90%of pancreatic cancer patients,pharmacological inhibition of EGFR upstream of K-Ras remains only marginally effective in this cancer type.
T argeting VEGF by the monoclonal antibody bevacizumab has also been demonstrated as ineffective in pancreatic cancer.18In addition,antiangiogenic multikinase inhibitors such as axitinib targeting the VEGF family,50sorafenib target-ing VEGF receptor,platelet-derived growth factor receptor and Raf51as well as the VEGF inhibitor a?ibercept52have all shown negative results in recent randomised trials.It can be speculated that the futility of all antiangiogenetic approaches tested so far is due to the largely hypovascular nature of the stroma sur-rounding cancer cells in this disease.In line with the disap-pointing clinical data,recent reports in genetically engineered mouse models suggest that decreasing the stromal density by the inhibition of stromal signalling pathways leads to enhanced intratumoral perfusion.This improves rather than impairs the ef?cacy of chemotherapy by facilitating drug accessibility to the tumour cells.53
Despite these disappointing results with anti-EGFR and anti-VEGR approaches,several novel targets within receptor tyrosine kinase signalling cascades are under evaluation in clinical trials.Among those are components of the insulin-like
Figure2Schematic overview of different therapeutic approaches for advanced pancreatic cancer.CTLA-4, cytotoxic T lymphocyte-associated antigen4;ECM,extracellular matrix; IGFR,insulin-like growth factor receptor;IL2,interleukin2;nab, nanoparticle albumin-bound;mTOR, mammalian target of rapamycin; PEGPH20,PEGylated human recombinant PH20hyaluronidase; TGFβ,transforming growth factorβ
.
Recent advances in clinical practice
growth factor 1receptor (IGF1R)pathway.IGF1R mediates a strong survival effect through both K-Ras-dependent and inde-pendent downstream signalling cascades and is highly expressed in pancreatic cancer tissues (?gure 3).IGF1R there-fore represents a promising survival target,which might be functionally relevant even in K-Ras mutated tumours.54Currently,several monoclonal antibodies targeting IGF1R,among them AMG-479,are under investigation in clinical trials (table 1).Unfortunately,the IGF1R inhibitor cixutumumab (IMC-A12)has already failed to show an effect on progression-free or overall survival in a recent randomised phase II trial when administered in combination with erlotinib and gemcita-bine.55In addition,another trial exploring the IGF1R inhibitor AMG-479has very recently been stopped after an interim ana-lysis revealed that the trial was unlikely to meet its ef ?cacy endpoint.
Activated K-Ras belongs to the predominant oncogenes in pancreatic adenocarcinomas that are mutated in a high percent-age of cases.This mutation can already be detected in early pre-invasive lesions during pancreatic carcinogenesis.56Earlier efforts to target K-Ras by farnesyltransferase inhibitors have failed.22In addition to preclinical research evaluating K-Ras as target using newer molecules,numerous trials are currently investigating kinases acting downstream of mutant K-Ras as therapeutic targets to overcome K-ras-induced drug resistance.The mitogen-activated protein kinase MEK belongs to the most important downstream effectors of K-Ras signalling,and has been shown to mediate K-Ras induced effects on proliferation and survival (?gure 3).MEK inhibition therefore represents an innovative therapeutic avenue particularly in tumours carrying an activating K-Ras mutation.Several small molecule inhibitors have been developed and have been validated in vitro for their therapeutic ef ?cacy in pancreatic cancer cells,including the compounds GSK1120212,BAY86-9766,MSC1936369B and AZD6244.Based on promising preclinical data,phase II trials with GSK1120212and MSC1936369B in combination with gemcitabine in advanced pancreatic cancer are currently in pro-gress (table 1).In addition,AZD6244is being tested in
combination with the EGFR inhibitor erlotinib in patients with pancreatic cancer refractory to gemcitabine (table 1).
The PI3K/Akt signalling pathway represents another promis-ing candidate whose inhibition might offer a signi ?cant thera-peutic potential.57PI3K/Akt is implicated in the progression of numerous human malignancies including pancreatic cancer by enhancing tumour cell proliferation,survival and metabolism.Activation of PI3K/Akt by upstream signals through receptor tyrosine kinases such as IGF1R has been reported in a high pro-portion of pancreatic cancers and serves as an independent negative prognostic factor (?gure 3).58In addition,its activity may be dependent on the phosphatase and tensin homologue,which normally inactivates Akt but whose expression is fre-quently lost in pancreatic cancers.59
V arious small molecules have been identi ?ed as potential inhibitors of PI3K/Akt signalling,some of which are being eval-uated in clinical trials as monotherapy or in combination with chemotherapeutic agents.Among them,the Akt antisense oligonucleotide RX-0201is being tested in a phase I/II trial in patients with metastatic pancreatic cancer 60(table 1).PI3K inhibitors such as BKM120or the combined PI3K/mammalian target of rapamycin (mTOR)inhibitor BEZ235are currently being evaluated in phase I trials in combination with two dif-ferent MEK inhibitors GSK1120212and MEK162in advanced solid tumours including pancreatic cancer carrying K-Ras,N-Ras and/or B-Raf mutations (table 1).This approach aims to overcome drug resistance mediated by upstream mutations of Ras and/or Raf through simultaneous blockade of the two major downstream cascades,MEK/ERK and PI3K/Akt signal-ling.The results of this combined approach are eagerly awaited.mTOR represents another promising target for therapeutic intervention.A serine/threonine kinase like Akt,it is
activated
Figure 3Schematic overview of major survival and proliferation
pathways and targeted agents currently evaluated in pancreatic cancer.mTOR,mammalian target of rapamycin;PTEN,phosphatase and tensin homologue;RTK,receptor tyrosine kinase.
Table 1Overview of selected targeted therapies currently under investigation in clinical trials
Compound
Clinical trial Survival signalling IGF1R AMG-479NCT01231347MEK
GSK1120212NCT01231581MSC1936369B NCT01016483AZD6244NCT01222689MEK162NCT01363232PI3K BKM120NCT01571024BEZ235NCT01337765AKT/PKB RX-0201NCT01028495mTOR RAD001
NCT00560963NCT01077986Immune response CTLA-4
Ipilimumab NCT01473940Tremelimumab NCT00556023CD40
CP870,893NCT01456585Stromal response Fibronectin ED-B L19-IL2NCT01198522TGF βRI LY2157299NCT01373164Hyaluronan
PEGPH20NCT01453153Oncofetal pathways
γ-Secretase (Notch pathway)RO4929097NCT01232829MK0752NCT01098344Epigenetics HDAC
Vorinostat NCT00948688DNA methyltransferase
5-Azacitidine
NCT01167816
CTLA-4,cytotoxic T lymphocyte-associated antigen 4;HDAC,histone deacetylases;IGF1R,insulin-like growth factor 1receptor;mTOR,mammalian target of rapamycin;TGF βRI;transforming growth factor βtype I receptor.
Recent advances in clinical practice
by PI3K/Akt signalling and is known as a regulator of gene tran-scription and cell cycle progression(?gure3).Although a recent phase II trial using the mTOR inhibitor RAD001as monother-apy had minimal clinical activity in patients with gemcitabine-refractory metastatic pancreatic cancer,61trials testing the effect of mTOR inhibition in combination with cytotoxic drugs or EGFR inhibitors are currently ongoing(table1).Interestingly, metformin,a commonly used antidiabetic drug,is known to inhibit the mTOR pathway through activation of the AMP-activated protein kinase(AMPK)that negatively regulates mTOR activity via phosphorylation and stabilisation of the tumour suppressor gene TSC2.62Based on these preclinical?nd-ings and supported by epidemiological studies suggesting that use of the antidiabetic drug metformin might be associated with a reduced life-time risk of developing cancers,6364metfor-min is currently being tested in a randomised phase II trial together with gemcitabine and erlotinib in patients with advanced pancreatic cancer(NCT01210911).In this context, tumour cell metabolism has gained increasing interest as a potential therapeutic avenue with several preclinical studies investigating the feasibility of interfering with glucose and glu-tamine utilisation,65and trials aiming to investigate interference with tumour cell metabolism and to use metabolic pro?les to predict therapeutic outcome(NCT01196247).
Poly(ADP-ribose)polymerase(PARP)is a family of proteins involved in a number of cellular processes mainly involving DNA repair and apoptosis.Sensitivity to therapeutic PARP inhibition is known to be associated with defects in the breast cancer DNA repair pathway.A subset of pancreatic cancer patients including a proportion of patients with familial pan-creatic cancer,have defects in the breast cancer DNA repair pathway or other defects in homologous repair.These cancers might respond to PARP inhibitors when given in combination with the DNA damaging agents.One ongoing trial is currently evaluating the PARP inhibitor olaparib in combination with cis-platin and irinotecan(NCT01296763).Moreover,several groups are investigating another PARP inhibitor,veliparib,with differ-ent drug combinations for advanced pancreatic cancer (NCT01489865,NCT01585805).
Targeting the immune response
In recent years,evidence has accumulated indicating that local and systemic immune response represents a major determinant of tumour resistance and progression.66In contrast to targeted approaches that aim to inhibit molecular pathways crucial for tumour growth and maintenance,immunotherapy endeavours to stimulate a host immune response that results in long-term tumour destruction.67The stroma of pancreatic cancer is par-ticularly rich in in?ammatory cells that are proposed to mediate drug resistance and tumour progression.68Therefore, immune cells such as T cells and macrophages in?ltrating the peritumoral stroma represent a promising target for immu-notherapeutic approaches.
T-cell-mediated immunity includes multiple sequential steps that are regulated by counterbalancing stimulatory and inhibi-tory signals that?ne-tune the response.66Inhibitory pathways are referred to as immune checkpoints that are crucial for main-taining self-tolerance and modulating the duration and ampli-tude of physiological immune responses.It has been recognised that many tumours co-opt certain immune checkpoint path-ways as a major mechanism of immune resistance,particularly against T cells that are speci?c for tumour antigens.66 Cytotoxic T-lymphocyte-associated antigen4(CTLA-4)is one of these immune checkpoints that plays a critical role in regulating and limiting immune responses and can be blocked by speci?c antibodies such as ipilimumab,a fully human anti-body.Binding to CTLA-4blocks its activity,thereby sustaining an active immune response in its attack on cancer cells.After successful clinical trials and approval of ipilimumab for advanced melanoma,early phase trials are currently underway in pancreatic cancer for ipilimumab and a second monoclonal antibody targeting CTLA-4,tremelimumab(table1).It remains to be seen whether the therapeutic ef?cacy of this immu-notherapeutic approach demonstrated in melanoma can be extended to pancreatic cancer.
Another promising target in this context was recently pub-lished in a study by Beatty et al.69In this paper,the authors tested the combination of an agonist CD40antibody with gem-citabine in a phase I trial with patients with advanced pancre-atic cancer.CD40is a tumour necrosis factor receptor superfamily member that has been shown to be a key regulatory step in the development of T-cell-dependent antitumor immun-ity,which relies on CD40-mediated‘licensing’of antigen-presenting cells for tumour-speci?c T-cell priming and activa-tion.69T reatment with the CD40agonist CP870,893resulted in tumour regression in some patients,in particular in those with macrophage-dominated in?ammatory tumour in?ltrates. The authors reproduced this treatment effect in a genetically engineered mouse model of pancreatic cancer and found unex-pectedly that CD40-induced tumour regression required macro-phages rather than T cells or gemcitabine.CD40-activated tumoricidal macrophages rapidly in?ltrated tumours and facili-tated the depletion of tumour stroma.69Following these results, the effect of the CD40agonist CP870,893is currently being tested in a neoadjuvant and adjuvant setting in patients with resectable pancreatic cancer(table1).
In addition to enhancing the systemic immune response, attracting selected antitumour cytokines to the site of the tumour is a promising concept that is currently under intense preclinical and clinical investigation.One of the most tumour-selective antigens that can be used to guide cytokines to the site of the tumour is the extradomain B(ED-B)of?bronectin. Expression of ED-B itself is associated with neoangiogenesis and tumour growth.A human single-chain Fv antibody frag-ment L19has recentlyb been generated,which displays high binding af?nity for ED-B.70This antibody fragment can be linked to interleukin(IL)-2,one of the most potent antitumor cytokines,which is,however,too toxic for systemic administra-tion and is only suitable for local therapy.71The fusion product consisting of the ED-B antibody fragment L19and IL-2 (L19-IL2)is currently being tested in a phase I/II trial in pancre-atic cancer(table1).The targeted accumulation of IL-2to the tumour microenvironment by conjugating it to the tumour-selective L19antibody appears to be an attractive concept to enhance the therapeutic index of IL-2.70
Targeting the stromal reaction
The extensive desmoplastic reaction that comprises up to90% of the tumour volume is the predominant histological feature of pancreatic cancer.The stroma consists of a variety of cellular components such as in?ammatory cells,stellate cells and acti-vated?broblasts that are embedded within a dense extracellular matrix.7273Over decades,the majority of research efforts had focussed on the tumour cells thereby largely neglecting the impact of the stromal response.Only recently,the role of the stroma as a barrier fencing off the tumour cells against system-ically applied drugs has been recognised.73Furthermore,it was hypothesised that inef?cient drug delivery due to the intense
Recent advances in clinical practice
stromal reaction may be an important contributor to chemore-sistance in pancreatic cancer.5373
During recent years,several landmark papers have investi-gated the impact of stroma-related signalling pathways on des-moplastic reaction,tumour progression and drug resistance in genetically engineered mouse models.Inhibition of these path-ways is considered a promising tool to decrease stromal density and to facilitate the access of cytotoxic drugs to the tumour cells.The sonic hedgehog pathway is one of the predominant signalling cascades known to stimulate stromal reaction.In a genetic mouse model,systemic administration of the hedgehog inhibitor IPI926resulted in a signi?cant depletion of tumour-associated stroma.This was associated with an increase in the intratumoral vascular density,enhanced concentration of the coadministered cytotoxic agent gemcitabine and increased sur-vival of the animals.53Based on these preclinical data,trials investigating hedgehog inhibitors have been initiated in patients with advanced pancreatic cancer,among them trials evaluating the hedgehog inhibitor IPI926.Recently,however, this trial was stopped.According to a preliminary press release, an interim analysis found that overall survival in patients on the gemcitabine plus IPI926arm was inferior compared to gem-citabine plus placebo(https://www.wendangku.net/doc/7f11408523.html,).Despite these sobering results,further clinical trials evaluating other hedgehog inhibitors such as GDC-0449in combination with gemcitabine or LDE225in combination with FOLFIRINOX or gemcitabine are still ongoing(table1).
The transforming growth factorβ(TGFβ)-dependent signal-ling cascade is known as another key pathway implicated in stromal reaction.74TGFβplays a crucial role in promoting stroma production and invasion,metastasis,angiogenesis and escape from immunosurveillance in pancreatic cancer.75Several drugs have been developed to target TGFβsignalling,among them the antisense oligodeoxynucleotide trabedersen(AP 12009),which speci?cally inhibits TGFβ2expression.This compound demonstrated an excellent safety pro?le and encour-aging survival results when administered as monotherapy in refractory solid tumours including pancreatic cancer76(table1). TGFβsignalling is induced after TGFβbinds as dimers to the TGFβtype II receptor,which recruits and phosphorylates the TGFβtype I receptor.During recent years,efforts have been made to develop compounds that bind to and inhibit TGFβreceptors.A phase I/II trial is currently ongoing that tests the impact of LY2157299,a small molecule that has been designed to inhibit TGFβtype I receptor selectively,in combination with gemcitabine for patients with advanced or metastatic pancreatic cancer(table1).
In addition to targeting stromal-related signalling pathways, acellular matrix components are currently being evaluated as targets for therapeutic intervention:T wo groups recently iden-ti?ed hyaluronan,a non-sulphated glycosaminoglycan,as highly abundant in the extracellular matrix of both human and murine pancreatic cancer tissues.7778In a genetically engi-neered mouse model the authors could show that a PEGylated human recombinant PH20hyaluronidase(PEGPH20)enzymati-cally depletes hyalouronan,thereby inducing re-expansion of tumour blood vessels and increasing the concentration of gem-citabine within the tumour,which resulted in signi?cantly diminished tumour growth and prolonged survival in mice. Based on these promising preclinical data,a phase1b/2trial comparing PEGPH20combined with gemcitabine versus gemci-tabine alone is currently recruiting to evaluate the impact of depleting hyaluronan in patients with metastatic pancreatic cancer(table1).Targeting oncofetal signalling
Signalling pathways that are essential for embryonic develop-ment and tissue homeostasis are frequently reactivated in cancers.These developmental or oncofetal signals have been demonstrated to accelerate tumour progression and mediate resistance to chemotherapy in pancreatic cancer.79A recent study by Jones et al80using a comprehensive genome sequen-cing approach revealed12major signalling pathways that are genetically affected in pancreatic cancer.Interestingly,four of them have been implicated in embryonic development:Notch, Hedgehog,TGFβand Wntβ–catenin pathways are altered in the majority of cases.80Accumulating evidence indicates that these genetic alterations translate into functional reactivation of these pathways in both human tumours and murine models.8182
The Hedgehog and TGFβsignalling pathway are also major determinants of the stromal reactions and have been discussed above.The Notch pathway is thought to maintain pancreatic progenitor cells in an undifferentiated state by enhancing their survival and persistence,in analogy to its function during embryogenesis.81Both the Notch ligand and receptor are highly expressed in pancreatic cancer.83In a genetic mouse model,Notch activation has been shown to synergise with K-Ras in inducing pancreatic intraepithelial neoplasias and invasive carcinoma,84making the Notch pathway a promising therapeutic target.V arious inhibitors have been developed at different levels of the pathway,including inhibitors of the enzymeγ-secretase that plays a key role in the activation of Notch signalling by proteolytic cleavage and release of the intracellular domain of Notch.81Currently,trials evaluating the γ-secretase inhibitors RO4929097and MK0752in patients with metastatic pancreatic cancer are ongoing(table1).
Targeting epigenetic changes
In contrast to genetic alterations leading to altered expression or activity of proteins,epigenetic alterations are heritable,yet not accompanied by changes in DNA sequence.In contrast to genetic mutations,epigenetic changes are potentially reversible and therefore amenable to therapeutic interventions.During recent years,various epigenetic mechanisms affecting gene expression at the chromatin level have been implicated in car-cinogenesis and tumour progression of many human malignan-cies including pancreatic cancer,among them DNA methylation and histone acetylation as most prominent and therapeutically exploitable features.85
Acetylation of histones removes the positive charge on the histones,leading to a more relaxed chromatin structure (euchromatin)that is associated with transcriptionally active DNA.This relaxation can be reversed by histone deacetylases (HDAC).HDAC activity leads to reduced transcription of mul-tiple genes,among them several crucial tumour suppressor genes.This results in enhanced proliferation,resistance to apop-tosis and tumour progression.In pancreatic cancer,several members of the HDAC family such as HDAC2and HDAC6are highly expressed and are known to mediate resistance to apop-tosis.8687Several drugs inhibiting HDAC such as vorinostat have been developed and demonstrate signi?cant antitumor activity in a variety of malignancies.88In pancreatic cancer,vor-inostat is currently being evaluated in combination with radi-ation therapy and chemotherapy in two trials enrolling patients with locally advanced disease(table1).
In contrast to histone acetylation that activates gene tran-scription,DNA methylation is associated with gene silencing.
Recent advances in clinical practice
Globally,the DNA of cancer cells is considered to be hypo-methylated.This is associated with genomic instability and transcription of silenced transposable sequences.89However, the CpG islands of multiple promoter regions of tumour sup-pressor genes frequently undergo DNA hypermethylation, leading to gene silencing and promotion of cancer develop-ment.89DNA hypermethylation of tumour suppressor genes is therefore an attractive target for therapeutic intervention. 5-Azacitidine is a chemical cytosine analogue known to inhibit DNA methyltransferase at low doses.Based on promising in-vitro data,90a phase I trial of5-azacitidine plus gemcitabine in patients with advanced pancreatic cancer is currently recruit-ing(table1).It remains to be determined whether the net effect of a drug like5-azacitidine on hypermethylated tumour suppressors outweighs potentially harmful interference with methylation signatures of other genes in humans.
THE CHALLENGE:DEFINING PERSONALISED THERAPIES The ultimate goal to overcome the appalling resistance of pan-creatic cancer to numerous systemic therapeutic approaches may be achieved not only by successfully developing new tar-geted agents but also by de?ning which patient subgroups might obtain the greatest bene?t from them.Accumulating evi-dence indicates that PDAC is characterised by a marked genetic heterogeneity.By combining comprehensive transcriptional and genomic analyses,Jones et al80de?ned a core set of12cellular signalling pathways and processes that were each genetically altered in the majority of investigated PDAC cases.However, for each individual case,the genes and pathways affected varied considerably,suggesting that an individualised approach to therapy is likely to be required.3
Facing the long list of futile clinical trials using targeted ther-apies,it may be speculated that some of the agents that failed to bene?t unselected populations of patients with PDAC might have had an impact in a more individualised strategy using selected patients with distinct molecular subtypes responsive to a given targeted agent.
Based on transcriptional pro?les of PDAC tissues,Collisson and coworkers91recently de?ned three PDAC subtypes(classic, quasimesenchymal and exocrine-like),which differed signi?-cantly in clinical outcome and therapeutic response to gemcita-bine and erlotinib.Although currently not ready for routine clinical use,the gene signatures for these subtypes may have utility in stratifying patients for subtype-speci?c therapies. CONCLUSIONS
Numerous novel therapeutic avenues targeting tumour cells, tumour vasculature or stromal response are currently under evaluation in clinical trials.T o date,it is unclear which of these avenues—if any—can be translated into clinical routine care for patients with advanced pancreatic cancer.Generally,clinical trials for pancreatic cancer face several obstacles such as short overall survival time and heterogeneity of the disease.Apart from the marginal bene?t demonstrated by erlotinib,all trials testing novel targeted approaches have failed so far.The advent of the FOLFIRINOX regimen has signi?cantly widened the armamentarium of chemotherapeutic options that had been largely restricted to gemcitabine-based regimens before.In clin-ical practice,treatment choice between aggressive combination therapy and gemcitabine has to be made individually depending on the patient’s performance status and comorbidities.For locally advanced disease,chemoradiation is an option to improve local control although data in this regard are con?icting.In addition,the right timing of chemoradiation remains to be de?ned(?gure1).
Despite some improvements in chemotherapeutic strategies, the prognosis of advanced pancreatic cancer still remains appal-ling.In order to develop new therapeutic strategies successfully for this disease,preclinical and clinical research has to focus on three main areas essential to overcome drug resistance:(1)opti-misation of drug delivery;(2)identi?cation of novel targets; and(3)identi?cation of molecular markers to individualise therapy decisions.
Numerous novel compounds with promising preclinical ef?-cacy data are currently being evaluated in clinical trials.Given the long list of futile trials with novel targeted agents in the past,it remains speculative at present which—if any—of these agents will be able to make a difference in improving the prog-nosis of patients with advanced pancreatic cancer.Most of the drugs that are currently in clinical evaluation have been identi-?ed and preclinically validated in xenograft models using human pancreatic cancer cell lines injected orthotopically or subcutaneously into immune-de?cient mice.However,given the high stroma content and the strong immune in?ltration fre-quently detected in endogenous pancreatic tumours,the trans-ferability of most in-vitro data and xenograft studies to the human situation is very limited.Therefore,future preclinical testing of therapeutic strategies should be performed in appro-priate genetically engineered mouse models that recapitulate the genetic and morphological characteristics of the human https://www.wendangku.net/doc/7f11408523.html,ing these models,the impact of novel agents not only on tumour cells but also on the tumour microenviron-ment can be evaluated in detail in a preclinical setting. Finally,molecular markers are urgently needed that are able to predict therapeutic responsiveness or resistance to a given drug in an approach towards a personalised medicine.In con-trast to other solid tumours,predictive biomarkers suitable for use in clinical routine are largely missing in pancreatic cancer. All future trials evaluating novel agents should be accompanied by comprehensive translational programmes aiming to identify predictive biomarkers,either in the tissue or in body?uids that are easier to access and to monitor during therapy.
It will be the combination of innovative therapeutic strat-egies and optimised patient selection that hopefully will be able to make a difference and?nally translate into a clinically signi?cant bene?t for patients with advanced pancreatic cancer. Contributors PM drafted the manuscript,TG critically revised the manuscript.
Competing interest None.
Patient consent Obtained.
Provenance and peer review Commissioned;externally peer reviewed. REFERENCES
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Recent advances in clinical practice
doi: 10.1136/gutjnl-2012-303588
2013 62: 317-326 originally published online October 30, 2012
Gut
Patrick Michl and Thomas M Gress
advanced pancreatic cancer
Current concepts and novel targets in
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