A Shining Light in the Darkness for the Treatment of Pancreatic Neuroendocrine Tumors

MINI REVIEW

Jaume Capdevila and Josep Tabernero

ABSTRACT Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebo- controlled phase III trials using 2 drugs—everolimus and sunitinib—with distinct molecular ratio- nales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defin- ing the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting.

Summary : Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summa- rize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies. Cancer Discovery; 1(3); 213–21. ©2011 AACR.

INTRODUCTION The medical treatment of advanced PNETs has included somatostatin analogs, interferon, and cytotoxic agents. Gastroenteropancreatic neuroendocrine tumors (GEPNET) This latter group of drugs has limited activity in PNETs for constitute a heterogenic group of neoplasms derived from the many reasons, including the fact that they usually have a Kultchitzky cells of the diffuse neuroendocrine system located low mitosis rate and also because of their particular biologi- in the gastrointestinal tract (origin of carcinoid tumors) and cal properties, such as the presence of biologic markers re- pancreatic islet cells (origin of pancreatic endocrine tumors). lated to chemoresistance (i.e., Akt expression) (2 ). The lack of Although GEPNETs represent less than 2% of all gastroin- effectiveness of conventional cytotoxic agents has prompted testinal cancers, they constitute the second most prevalent exploration of new targeted drugs exploiting phenotypical advanced tumor of the gastrointestinal tract after colorec- features of PNETs. Nevertheless, the development of targeted tal cancer (1 ). The biological behavior of well-differentiated therapies in this field has been limited by a number of factors. pancreatic neuroendocrine tumors (PNET) depends mainly First, PNETs are extremely heterogeneous with very different on their histologic characteristics, such as differentiation characteristics in highly and poorly differentiated tumors. grade, Ki67 expression, or angioinvasion, and the propor- Second, the preclinical development of drugs directed against tion of malignant tumors developing metastases varies widely these tumors is limited because very few in vitro and in vivo between tumor types (from 10% of insulinomas to 90% of models exist. And last, but not least, the frequent shortage glucagonomas). of resources has impacted strongly on rare neoplasms that require international efforts to design and implement sci- Authors’ Affiliation: Medical Oncology Department, Vall d’Hebron University entifically valid studies. In-depth characterization of mo- Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain lecular features and pathways of cell growth, apoptosis, Corresponding Author: Josep Tabernero, MD, Medical Oncology angiogenesis, and invasion are still lacking in this group of Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron tumors, particularly concerning genetic mutations or epigen- University Hospital, Universitat Autònoma de Barcelona, Pg Vall d’Hebron 119-129, Barcelona 08035, Spain. Phone: 34-93-2746085; Fax: 34-93- etic alterations that generate oncogenic dependency or even 2746059; E-mail: [email protected] addiction. This is the concept behind an ideal target; un- doi: 10.1158/2159-8290.CD-11-0151 fortunately, however, the majority of new developments are ©2011 American Association for Cancer Research. based only on phenotypic overexpression of pathways with

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The (over)expression of some factors has been associated MANAGEMENT OF PNET with poor prognosis and decreased progression-free survival (PFS), as well as with tumor growth, aggressiveness, and dis- • Management of advanced PNETs is based on a ease extent in patients with PNETs ( 4 ). multidisciplinary approach that includes surgery, Currently, the medical management of functional PNETs liver-directed treatments, radionuclide and almost invariably involves the use of somatostatin analogs biological therapies, chemotherapy, and targeted to control the symptoms related to hormone secretion. agents. Interferon-α is added when patients develop resistance. • Strong molecular rationale supports antiangio- Although both treatments provide up to 70% to 80% of hor- genic and mTOR-directed therapies for the treat- mone syndrome control and relief of induced symptoms, an- ment of PNETs, with a favorable toxicity profile tiproliferative effects are far from impressive, ranging from compared with standard chemotherapy. 5% to 10% at best. Cytotoxic chemotherapy is a treatment op- • After decades of slight improvement, sunitinib tion in patients with PNETs, given that these tumors typically and everolimus have demonstrated a significant have intermediate cell proliferation rates (2% to 20% mea- benefit in progression-free survival and response sured by Ki67 immunohistochemistry index). Combination rate in the largest ever completed phase III stud- regimens containing streptozocin, dacarbazine, epirubicin, ies in PNETs. lomustine, cisplatin, doxorubicin, etoposide, and 5-fluoro- • No predictive biomarkers have been characterized uracil have shown the best efficacy, with overall response so far for better patient selection. PTEN and rates (ORR) of 20% to 60%, and a median overall survival TSC1/2 downregulation have been suggested to (mOS) ranging from 15 to 26 months ( 5 ). be prognostic factors in PNETs and their potential Surgery, the mainstay of treatment for localized tumors, predictive value in the treatment with PI3K path- can be considered in patients with metastatic disease, to re- way inhibitors is being evaluated. duce tumor mass, before or concomitantly with systemic • Gene expression profiling and tumor sequencing therapy, and to palliate symptoms. Other approaches to re- studies have confirmed the relevance of the PI3K- duce tumor burden or to contribute to hormone syndrome AKT-mTOR pathway in the pathogenesis of PNETs, control include hepatic artery (chemo)embolization, radio- and have highlighted other significant pathways frequency ablation, and somatostatin receptor-targeted less known in the PNET molecular profile, but with radionuclide therapy ( 6 ). enough preclinical data to be assessed in the Several targeted agents have been studied in the treatment future, such as Wnt/β-catenin, Hedgehog, Notch, of GEPNETs including antiangiogenic compounds (e.g., bev- or TGF-β. acizumab), inhibitors of multiple receptors with kinase activ- • The prolonged survival of patients with PNETs ity (e.g, sunitinib), and inhibitors of intracellular downstream requires that they sequentially receive all the effector proteins such as mTOR (e.g., everolimus). Two phase available treatment options. It is anticipated that III studies with everolimus and sunitinib were recently con- ongoing and next-generation studies will clarify ducted in patients with PNETs and demonstrated significant whether the best approach is to combine some clinical activity increasing PFS, and results were published in active cytotoxic drugs with targeted agents or to the New England Journal of Medicine. The last publication of a sequentially administer all available treatment chemotherapy combination in this disease in this prestigious options. In this regard, predictive and prognostic journal was two decades ago, and that treatment became the biomarkers will likely be useful to better define standard of care of patients with advanced well-differentiated the most appropriate sequence. PNETs (7 ).

ANTIANGIOGENESIS TREATMENT IN ADVANCED PNETs moderate signaling repercussions in cell growth and survival, PNETs are some of the most vascularized tumors iden- which limit their therapeutic potential. Emerging studies are tified to date. Currently, a number of antiangiogenic com- providing insights into specific deregulation in proliferative pounds are being evaluated in the clinic, and can be divided and growth signaling pathways of various PNET subsets ( 3 ). into 3 groups: (i) drugs targeting VEGF, such as the VEGF- PNETs are characterized by being remarkably vascular and directed monoclonal antibody bevacizumab; (ii) small mol- expressing several growth factors, including vascular endo- ecules that inhibit the receptor tyrosine kinase domains thelial growth factor (VEGF), platelet-derived growth factor of VEGFR and other related receptors, such as sunitinib, (PDGF), insulin-like growth factor 1 (IGF-1), basic fibro- sorafenib, and pazopanib; and (iii) other compounds with blast growth factor (bFGF), and transforming growth fac- different antiangiogenic mechanisms, such as thalidomide or tor (TGF)-α and TGF-β. In addition, expression of several endostatin (Table 1). receptors of these growth factors and ligands has been de- The first evidence of activity of bevacizumab in GEPNETs scribed, including stem cell factor receptor (c-KIT), epidermal was reported by Yao and colleagues (8 ) in a phase II study growth factor receptors (EGFR), VEGF receptors (VEGFR)-2 with 44 patients randomly assigned to receive bevacizumab and 3, IGF receptors (IGF-R), and PDGF receptors (PDGFR). (15 mg/kg every 3 weeks) or weekly pegylated interferon α-2b

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Table 1. Main antiangiogenic compounds in clinical development for advanced neuroendocrine tumors

Agent(s) Target(s) Phase Tumor ORR PFS (m) Comments Reference Bevacizumab VEGF Phase II Carcinoid 18% 16.5 Ongoing phase III 8 BV + CHT FOLFOX GEPNET 20%–33% Ongoing 31 XELOX PNETs 31% Ongoing 32 Temozolomide GEPNET 0%–24% Ongoing 33 BV + everolimus VEGF + mTOR GEPNET 21% 14 Ongoing 41 Sunitinib VEGFR1-3, PDGFR, Phase II Carcinoid 2% 10.5 10 RET, FLT3, KIT PNETs 17% 7.7 Phase III PNETs 9% 11.4 Positive phase III 11 Sorafenib VEGFR2-3, PDGF, Phase II Carcinoid 7% 7.8 Completed 34 Raf, KIT, RET PNETs 17% 11.9 Sorafenib + BV VEGFR2-3, PDGF, GETNET 10% 12.4 Completed 35 Raf, KIT, RET + VEGF Vatalanib VEGFR1-3, PDGFR, KIT Phase II GEPNET 0% NR Withdrawn — Pazopanib VEGFR1-3, PDGFR, Phase II Carcinoid 0% 12 Ongoing 36 PNETs 19% 14.2 Motesanib VEGFR1-3, PDGFR, RET Phase II GEPNET — — Ongoing — Atiprimod Inhibits VEGF secretion Phase II GEPNET 0% 76% at 6 m Ongoing 37 Deactivates Akt and STAT3 Thalidomide VEGF and bFGF Phase II GEPNET 0% — 80% SD 38 Thalidomide + CHT Temozolomide + 7%–45% 39 VEGF and bFGF rH-Endostatin Endogenous endothelial Phase II Carcinoids 0% 5.8 80% SD 40 inhibition PNETs 0% 7.6

Abbreviations: BV, bevacizumab; CHT, chemotherapy; NR, not reached; PFS, progression-free survival; STAT, signal transducers and activators of transcription; rH, recombinant human; m, months.

(PIF; 0.5 μg/kg, for 18 weeks). After 18 weeks of treatment or carcinoid tumors and 66 with PNETs) with documented in the event of disease progression, patients could receive the disease progression. The authors reported an ORR of 16.7% combination of the 2 drugs. The bevacizumab arm showed in PNETs with 68% of patients presenting stable disease a higher ORR (18% vs. 0%), a lower progression rate (5% vs. (SD). In patients with carcinoid tumors, the ORR and SD 27%), and therefore a better PFS rate after 18 weeks of treat- rates were 2.4% and 83%, respectively. A pharmacodynamic ment (95% vs. 68%). Bevacizumab treatment was also associ- study of potential soluble surrogate biomarkers was also ated with a significant tumor blood decrease measured by done and identified sVEGFR-3 as a potential biomarker functional computed tomography (CT) scans compared with of the biological effect of sunitinib and interleukin-8 as a PIF (P < 0.01). The toxicity profile was manageable with hy- potential predictor of response (10 ). These results led to pertension as the main adverse event. A larger phase III study the design of a double-blind, placebo-controlled phase III (SWOG S0518) is currently recruiting patients to confirm study in advanced PNETs (11 ). The initial design planned to these promising results. Bevacizumab is being evaluated in recruit 340 patients with disease progression documented combination with cytotoxic chemotherapy and also with by Response Evaluation Criteria in Solid Tumors (RECIST) other targeted therapies, including sorafenib and everolimus in the 12 months prior to trial enrollment. The study was (Table 1). prematurely stopped following a recommendation of the Sunitinib malate (SU-11248) is a highly potent, ATP- Data Monitoring Committee due to significant differences competitive binding small molecule capable of inhibiting in disease progression and deaths in the placebo arm. A several tyrosine kinase membrane receptor proteins in- total of 171 patients were enrolled in the trial, 86 receiv- volved in the main angiogenic and proliferative pathways, ing sunitinib (37.5 mg daily) and 85 receiving placebo. The such as VEGFR-1 to 3, PDGFR, FLT-3, c-KIT, and RET. The results of the study regarding ORR, median PFS (mPFS), first evidence of activity of sunitinib in advanced GEPNETs and estimated mOS significantly favored the sunitinib was reported in a first-in-man phase I study (9 ), which arm. Patients treated with sunitinib achieved mPFS of 11.4 was followed by a phase II trial with 107 patients (41 with months compared with 5.5 months in the placebo arm

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(HR: 0.42; 95% CI, 0.26–0.66; P = 0.0001), with a probabil- regulator of the cytoskeleton and also phosphorylates ity of being event free at 6 months of 71.3% versus 43.2%. the serine-threonine protein kinase AKT when mTOR is In the subgroup analysis, all groups showed benefit with blocked, through the use of an mTOR inhibitor. Activation sunitinib regardless of age, Eastern Cooperative Oncology of mTORC1 by positive regulators induces the phosphoryla- Group (ECOG) performance status (PS), previous therapies, tion of 2 of the main downstream effectors, the eukaryotic tumor burden, time since diagnosis, concomitant treat- translation initiation factor 4E–binding protein-1 (4E-BP1) β ment with somatostatin analogs, or Ki67 levels. Patients and the ribosomal protein S6 kinase -1 (S6K1). The ac- treated with sunitinib presented an ORR of 9% compared tivation of these effectors leads to the enhancing of the with no responses in the placebo arm (P = 0.007). The tox- translation of essential mRNAs involved in the cell cycle pro- icity profile was as expected for sunitinib with diarrhea, gression through G1 to S1 phase (12). Several targets of the fatigue, nausea, and vomiting being the main side effects PI3K-AKT-mTOR signaling pathway have been identified in observed. The most frequent grade 3-4 adverse events were PNETs, and several genetic disorders that have constitutive neutropenia (12% vs. 0%), hypertension (10% vs. 1%), hand- activation of this pathway along with increased incidence of foot syndrome (6% vs. 0%), and leukopenia (6% vs. 0%). neuroendocrine tumors have been well defined, such as the Benefit data in mOS (HR: 0.41; 95% CI, 0.19–0.89; P = 0.02) tuberous sclerosis complex (TSC), neurofibromatosis type should be considered with caution because no crossover was I, Von Hipple-Lindau (VHL) disease, or multiple endocrine planned in the design of the protocol, and although 69% of neoplasia type I (MEN1) (13). patients received sunitinib after progression with placebo, Two rapamycin inhibitors have been evaluated in neuroen- not all of them received the drug immediately after tumor docrine tumors: temsirolimus and everolimus. Temsirolimus progression. The trial also included quality of life (QoL) was only studied in a multicenter phase II trial with assessment, and sunitinib provided clinical benefit while 37 advanced GEPNETs; although the therapy was generally maintaining global QoL. In conclusion, sunitinib demon- well tolerated, the drug showed modest antitumor activity strated a significant benefit in mPFS and response rate in with only 2 confirmed responses (5.6%). The activity was patients with radiologically progressive well-differentiated similar between carcinoid and PNETs: mPFS was 6 months PNETs compared to placebo. and OS at 1 year was 71.5%. The authors considered the activity was not sufficiently clinically meaningful for further development. INHIBITION OF mTOR IN PNETs Everolimus has been intensively developed in GEPNETs. The first study in this disease, conducted at the MD mTOR is an intracellular serine-threonine kinase down- Anderson Cancer Center, included 30 patients with carci- stream of the phosphatidyl inositol 3′ kinase (PI3K)-AKT noid tumors and 30 patients with PNETs in 2 consecutive signaling pathway. Under physiologic conditions the PI3K- cohorts (14). The first cohort treated 30 patients with the AKT-mTOR signaling pathway plays a major role in regu- combination of depot octreotide (30 mg intramuscularly lating cell growth, proliferation, motility, and survival, and every 28 days) plus everolimus (5 mg daily). The second cellular nutrient and energy levels, protein synthesis, autoph- cohort included 30 patients treated with octreotide at the agy, transcription, and redox status. mTOR integrates mul- same doses and everolimus (10 mg daily). The authors re- tiple upstream signals, including growth factors (e.g., EGF ported encouraging antitumor activity with an ORR of 17% and IGF-1/2), and mitogens. Interestingly, mTOR is also in- in carcinoid tumors and 27% in islet cell carcinomas, with volved in angiogenesis, regulating the translation and activity mPFS of 63 and 50 weeks, respectively. Moreover, patients of hypoxia-inducible factor 1α (HIF1α), which is related to included in the cohort receiving everolimus (10 mg) ob- VEGF expression under hypoxic conditions. tained a higher ORR (30% vs. 13%) and prolonged mPFS Hyperactive mTOR signaling is a key participant in (72 vs. 50 weeks). Overall, everolimus showed an acceptable development, growth, and proliferation in about 50% of all toxicity profile, the most frequent grade 3-4 adverse events human tumors. mTOR acts as the catalytic subunit of 2 being aphthous ulcers, fatigue, diarrhea, hyperglycemia, and distinct complexes. mTOR complex 1 (mTORC1) consists of hypophosphatemia. mTOR, the target of the rapamycin complex subunit LST8 After these encouraging results, the RAD001 in Advanced (LST8, also known as GβL), the proline-rich Akt substrate Neuroendocrine Tumors (RADIANT) trials were designed 1 (AKT1S1, also named PRAS40), and its main partner, the to explore the efficacy of everolimus in neuroendocrine regulatory associated protein of mTOR (RAPTOR). mTOR tumors of different origins. The RADIANT-1 study was a complex 2 (mTORC2) is composed of mTOR, LST8, the tar- confirmatory international phase II trial in progressive get of rapamycin complex 2 subunit MAPKAP1 (SIN1), the chemotherapy-refractory islet cell carcinomas divided into proline-rich protein 5 (PRR5, or PROTOR1), and its most 2 strata: the first included 115 patients with advanced important partner, rapamycin-insensitive companion of PNETs treated with everolimus (10 mg daily) and the sec- mTOR (RICTOR). mTORC1 is characterized by the classic ond had 45 patients with the combination of depot octreo- features of mTOR, functioning as a nutrient-energy-redox tide (30 mg intramuscularly every 28 days) plus everolimus sensor and controlling protein synthesis. The activity of this (10 mg daily) (15). The ORR was 7.8% in stratum 1 and 4.4% complex is stimulated by several growth factors, hormones, in stratum 2, with SD rates of 68.7% and 77.8%, respectively. nutrients (amino acids, glucose), cellular energy status, The mPFS was 9.3 months in stratum 1 and 12.9 months and stress conditions. mTORC2 functions as an important in stratum 2. Additionally, 49% and 56% of patients with

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Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2011 American Association for Cancer Research. Treatment of Pancreatic Neuroendocrine Tumors MINI REVIEW increased chromogranin A levels in stratum 1 and 2, respec- concerns with everolimus therapy, were typically grade 1-2 tively, achieved either normalization or a reduction greater and generally managed with antibiotics and steroids. Results than 50%. Moreover, the authors reported a statistically sig- of further secondary analyses of the RADIANT-3 study are nificant relationship between the decrease in chromogranin expected in the near future, such as possible predictive bio- A levels and mPFS (decrease ≥30%, mPFS 13.3 months vs. markers that may guide clinicians in the selection of patients nonresponders, 7.5 months). The treatment was generally who are more likely to respond to everolimus therapy. In well tolerated with few grade 3-4 adverse events, mainly fa- summary, the RADIANT trials are the largest studies in tigue, diarrhea, and stomatitis. advanced neuroendocrine tumors ever conducted and, as a RADIANT-2 and RADIANT-3 studies are 2 interna- result, everolimus will become a new standard of care in ad- tional, double-blind, placebo-controlled phase III trials in vanced well-differentiated PNETs and probably a new ther- advanced clinically functional extrapancreatic neuroendo- apy option in advanced carcinoid tumors in combination crine tumors and advanced PNETs, respectively. The initial with somatostatin analogs. report of the RADIANT-2 trial was presented at the 35th European Society for Medical Oncology (ESMO) Congress (Milan, Italy, October 8–12, 2010). In this trial, the efficacy KEY UNMET NEEDS AND FUTURE and safety of everolimus (10 mg/d) plus octreotide LAR DIRECTIONS (30 mg every 28 days) was compared to that of placebo plus octreotide LAR (30 mg every 28 days) in 429 patients with Almost half a century has elapsed since the most widely advanced carcinoid tumors and a history of hormone-re- used neuroendocrine tumor classification, which was lated symptoms. Although the study did not meet its pri- developed according to embryologic origin, was proposed mary endpoint based on central radiologic review of data, by Williams and Sandler. Since then, various systems of the results showed that everolimus plus octreotide LAR sig- nomenclature based on site of origin, tumor stage, histo- nificantly improved mPFS by 5.1 months (HR: 0.77; 95% CI, logic, or functionality classifications have been introduced, 0.59–1.00; P = 0.026) when compared with placebo. After causing much confusion. These terminology issues have adjusting for imbalances in baseline characteristics between jeopardized not only the creation of a worldwide prog- the 2 treatment arms, and inconsistencies between radiology nostic classification of neuroendocrine tumors but also scans to assess disease progression, the results also showed the development of well-designed clinical trials, where the that everolimus plus octreotide LAR significantly reduced inclusion of tumors with different behavior has compro- the risk of disease progression by 40% (HR: 0.60; 95% CI, mised interpretation of the results, such as happened in the 0.44–0.84; P = 0.0014) when compared to octreotide LAR RADIANT-2 study. alone (16). Fortunately, in recent years, gene expression profiling and The results of the RADIANT-3 study were recently pub- surface sequencing have shown promising potential in the lished, showing the efficacy of everolimus in advanced molecular features of neuroendocrine tumors. The key role of PNETs (17). A total of 410 patients with disease progres- the PI3K-Akt-mTOR pathway in the pathogenesis of PNETs sion documented prior to inclusion were randomly assigned was known from phenotypes of hereditary syndromes, such to receive either daily oral everolimus (10 mg/d) or placebo as TSC, neurofibromatosis, VHL disease, or MEN1 syn- (1:1). Treatment with everolimus demonstrated a significant dromes, where constitutive activation of the PI3K-Akt-mTOR increase in mPFS by central radiological review, more than pathway leads to an increased incidence of PNETs (18–20). double that of placebo, from 4.6 to 11.0 months (HR: 0.35; Data from tumor expression profiling in PNETs has also 95% CI, 0.27–0.45; P < 0.0001) fulfilling the primary end- shown that the downregulation of PTEN and TSC2 corre- point. At 18 months, PFS in the everolimus arm was 34%, lates with poorer prognosis (3), but also microRNA expres- with a subgroup of patients who obtained prolonged clinical sion profiling has demonstrated that the expression level of benefit of everolimus treatment with an acceptable safety miR-21 is strongly associated with liver metastases, and a profile. The benefit in PFS was observed in all subgroups high Ki67 index and miR21 levels are inversely proportional of patients regardless of previous therapies, ECOG PS, age, to PTEN levels (Fig. 1) (21, 22). The significance of HIF/p53 tumor burden, time since diagnosis, treatment with soma- pathway in the development and progression of PNETs has tostatin analogs, and tumor grade. Although the response also been highlighted and the protein encoded by the MEN1 rate was relatively low—but significantly higher in the evero- gene, Menin, has altered distribution and intensity in 80% limus arm (5% vs. 2%, P = 0.001)—64.4% of patients had of PNETs, leading to the inhibition of AKT activation by decreases of between 1% and 29% in target lesion size. Thus, regulating its cellular location (23, 24). Moreover, activation the main benefit of everolimus in PFS was seen due to minor of the PI3K-Akt-mTOR pathway in PNETs is also led by the responses and tumor stabilizations. No differences in OS (over)expression of membrane tyrosine kinase receptors that were observed due to the preplanned crossover at disease trigger this pathway, such as IGF-1R, fibroblast growth factor progression defined in the protocol (73% of patients in the receptor 3 (FGFR3), or in the companion vasculature with placebo arm received open-label everolimus at progression). mutations in the FLT1 gene, which encodes VEGFR1 (25). The most common grade 3-4 adverse events were stomatitis Furthermore, expression of EGFR has been widely described (observed in 7% of patients), anemia (6%), and hyperglycemia in PNETs, but no meaningful activity has been observed (5%). Infections (23%), pneumonitis (12%), and interstitial with EGFR inhibitors. Preclinical data with the most used lung disease (2%), which often represent the main clinical transgenic mouse model, RIP-Tag2, have demonstrated that

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IGF-1R VEGFR FGFR3 EGFR

NOTCH

SSTR1-5

P13K RAS NICD Wnt PTEN

miR-21 AKT BRAF

PLC Hedgehog SHP1 MENIN GSK-3␤ mTOR MAPK

␤-catenin

Caspase 8 Smoothened p53 Bax GLi2/3A

DAXX/ATRX ATM

HIF1 SMADs

TGF-␤

VHL MGMT

Figure 1. Schematic of intracellular signaling pathways involved in pancreatic neuroendocrine tumor differentiation and proliferation, of intranuclear transcription factors, and DNA repair enzymes involved in tumor carcinogenesis and cytotoxic therapy resistance. ATM, ataxia telangiectasia mutated; ATRX, X-linked mental retardation and a-thalassemia syndrome protein; Bax, Bcl-2–associated X protein; DAXX, death domain-associated protein; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; GSK-3b, glycogen synthase kinase-3b; HIF1, hypoxia-inducible factor 1; IGF-1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; MGMT, O6- methylguanine DNA methyltransferase; miR21, microRNA-21; mTOR, mammalian target of rapamycin; NICD, intracellular domain of Notch; PI3K, phosphatidylinositol-3-kinase; PLC, phospholipase C; PTEN, phosphatase and tensin homolog deleted; SHP1, Src homology region 2 domain- containing phosphatase-1; SSTR1-5, somatostatin receptors 1-5; TGF-b, transforming growth factor-b; VEGFR, vascular endothelial growth factor receptor; VHL, Von Hippel-Lindau.

EGFR inhibition with erlotinib is able to abrogate the poten- of MEN1 and the PI3K-Akt-mTOR pathways, but has also tial resistance mediated by Akt upregulation after mTORC1 highlighted the importance of several transcription factors, inhibition (26). such as DAXX (death domain-associated protein), ATRX Deep sequencing of the entire neuroendocrine tumor (X-linked mental retardation and α-thalassemia syndrome genome could be expected to provide not only instrumental protein), or ATM (ataxia telangiectasia mutated), which knowledge for prognostic classification but also a “biotype” may open new target opportunities for the treatment of characterization that would allow assessment of potential PNETs (13). drug pathways for individual patients. Currently, within The next step after this characterization is the design the International Cancer Genome Consortium, there is a of molecularly guided clinical studies that could help to task force to perform deep sequencing of GEPNETs. Recent determine the best treatment combinations for PNETs. In data based on deep sequencing have confirmed the key role order to counter escape mechanisms along with primary

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Table 2. Main planned/ongoing clinical trials with targeted therapies in advanced pancreatic neuroendocrine tumors

Agent (s) Target(s) Phase Protocol ID Everolimus + erlotinib mTOR + EGFR Phase II NCT00843531 AMG479 IGFR Phase II NCT01024387 Bevacizumab + pertuzumab + octreotide LAR VEGF + HER1/HER2 + SSRT Phase II NCT01121939 Everolimus +/– bevacizumab mTOR + VEGF Phase II NCT01229943 LY2584702 + everolimus p70 S6 Kinase + mTOR Phase Ib NCT01115803 Cixutumumab + everolimus + octreotide LAR IGFR + mTOR + SSRT Phase Ib NCT01204476 Everolimus + pasireotide mTOR + SSRT Phase Ib NCT01263353 Phase II SOM230I2201 Everolimus + sorafenib mTOR + VEGFR2-3, PDGF, Raf, KIT, RET Phase Ib NCT00942682 FR901228 Histone deacetylase Phase II NCT00084461 MK-2206 Akt Phase II NCT01169649 Bortezomib Proteasome Phase II NCT00017199

Abbreviations: HER, human epithelial growth factor receptor; SSRT, somatostatin receptors.

and secondary resistance to mTOR inhibition, several com- In April 2011, everolimus and sunitinib were presented bined approaches are being evaluated, including mTOR to the Food and Drug Administration for approval in the and IGF-1R inhibition, mTOR inhibition plus pan-analog treatment of advanced PNETs, and everolimus for tumors of of somatostatin receptors (SOM230), mTOR and EGFR gastrointestinal and lung origin, based on the RADIANT-2 inhibition, and dual mTORC1 and mTORC2 and dual results. Selection of one of these drugs for the treatment of PI3K and mTORC1/2 inhibition. Some studies are already advanced PNETs will be based mainly on their toxicity pro- in early recruitment (Table 2; also see clinicaltrials.gov). files because both drugs are able to double mPFS. Only the Nonetheless, despite the strong molecular rationale for sunitinib study has assessed the QoL profile of these patients. this approach, it seems very unlikely that combination of Nonetheless, QoL is an important objective in this particular targeted agents will displace the use of cytotoxic agents. group of tumors because most are pauci- or asymptomatic We should keep in mind that PNETs are not completely and therefore drug side effects could jeopardize compliance resistant to chemotherapy. Moreover, recent data suggest with long-term treatment. Tumor response does not facilitate that temozolamide, a cytotoxic agent approved for the the choice between these new drugs because both give less treatment of glioblastoma, may be active in patients with than 10% ORR. Moreover, ORR with these drugs compares PNETs. Encouragingly, the patients most sensitive to this unfavorably with those of older studies of cytotoxic therapies treatment may be characterized by O6 -methylguanine DNA in PNETs, which achieved rates of up to 60%. In this regard, it methyltransferase (MGMT) expression using immunohis- is suggested that these new targeted therapies are reserved for tochemistry (27 ). slow-growing tumors and that we should continue using tra- Another approach uses the abrogation of other signaling ditional chemotherapy in those patients for whom reduction pathways such as Wnt/β-catenin, Hedgehog, Notch, or TGF-β, of tumor burden is the main objective. The vast population known to be critical in processes of epithelial-mesenchymal that achieves SD in these studies constitutes the main objec- transition, and regulation of neuroendocrine differentiation tive of prolonging mPFS, and the real benefit of these stabi- and cancer stem cell proliferation and survival. Limited pre- lizations can only be assessed in placebo-controlled phase III clinical data support the evaluation of drugs targeting these studies with documented disease progression before therapy pathways in patients with advanced PNETs (28–30 ). begins. Furthermore, no relationship has been established between mPFS increase and prolongation of OS. The cross- CONCLUSIONS over design in placebo-controlled studies, although ethically The future management of advanced neuroendocrine mandatory, increases the difficulty of survival interpretation. tumors finally appears to be changing after decades of gen- Despite this, the sunitinib study showed OS gain reflecting erally ineffective chemotherapy and limited usefulness of the value of stabilizations in heavily pretreated PNET patients. somatostatin analogs in hormone-related syndromes. Better With this scenario, sunitinib and everolimus will be- knowledge of molecular mechanisms related to carcinogen- come new treatment options for PNETs but are far from esis, angiogenesis, and tumor progression have led to the becoming the new standard of care for all patients, in development of specific targeted therapies that will change whom medical therapy, surgery, and locoregional ablations the armamentarium of treatment of neuroendocrine tumors. will continue to play the main role. The development of

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Jaume Capdevila and Josep Tabernero

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