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Abstract

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 (p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy.

Keywords

Neuroendocrine Carcinoid Pancreatic Everolimus mTOR Tumor NETs RADIANT Afinitor Sunitinib

Introduction

Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal (GI) tract have classically been identified as either carcinoid or pancreatic (‘islet cell’) NETs (pNETs). NETs commonly known as carcinoids generally originate from luminal organs, such as the small bowel, appendix, rectum, duodenum, stomach, and lungs, while pNETs arise in the pancreas. pNETs are a fairly rare class of tumors that have a wide spectrum of symptomatology, tumor biology, and prognosis [Leung et al. 2013; Peng and Schwarz, 2013]. Functional pNETs are often classified by the peptide hormones that they secrete, the most common being insulin, gastrin, glucagon, or vasoactive intestinal peptide (VIP), all of which result in a unique clinical syndrome when hypersecreted. However, up to 75% of pNETs are nonfunctional and are therefore not associated with a particular endocrine syndrome [Hochwald et al. 2002; Klimstra et al. 2010].

Overall pNETs are relatively uncommon malignancies, affecting about 0.32 in 100,000 people per year and currently account for less than 3% of all primary pancreatic neoplasms. However, their incidence has increased sharply over the last three decades, likely due to increased detection of asymptomatic disease and greater standardization of the pathological diagnosis [Yao et al. 2008a; Oberstein and Saif, 2012]. Although pNETs are generally considered a more indolent disease than the more common ductal adenocarcinoma, and surgery can provide curative treatment in some cases of pNETs, the majority (64%) of patients present in a late stage with locally advanced disease or distant metastases [Strosberg et al. 2009]. In these patients, curative resection is frequently impossible and median survival time is only 24 months. Therefore, systemic therapy is indicated for symptom control, palliation, slowing tumor progression, and potentially causing tumor regression, with the goal of improving quality of life and prolonging survival [Weber, 2013].

Current systemic antitumor therapies available for the treatment of disseminated NETs include somatostatin analogs (SSAs), interferon, cytotoxic chemotherapeutics, systemic radionuclide therapy, and molecular targeted therapy. However, efficacy is highly dependent on tumor type and grade, requiring experience and knowledge in selecting the proper therapy. Although NETs occur throughout the body and share similar histologic characteristics, it has become increasingly clear that pNETs have markedly different pathogenesis and molecular biology, and tend to respond differently to therapeutic agents than other NET subtypes. Systemic therapy for pNETs was limited to streptozotocin-based regimens as it was the only treatment approved by the US Food and Drug Administration since 1983. However, at the end of 2011, two agents received approval for the treatment of unresectable pNETs: everolimus and sunitinib. We will describe the data on everolimus and interpret its place in the treatment of advanced pNETs.

Mammalian target of rapamycin pathway

mTOR is a central protein kinase in the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway that regulates multiple cellular functions and has been identified as a commonly mutated or unregulated pathway in many cancers, including pNETs [Grozinsky-Glasberg and Shimon, 2010]. The mTOR pathway is part of a larger complex of intracellular pathways involved in cell signaling and transduction. As part of the PI3K pathway, it helps to regulate cell growth, autophagy, protein translation and transcription, cell survival, and cell proliferation [Wullschleger et al. 2006; Liu et al. 2009]. It integrates input from upstream signaling pathways, including insulin, insulin-like growth factor 1 (IGF-1), IGF-2, and amino acids, as well as sensing intracellular nutritional and oxidation-reduction status to regulate its various downstream pathways [Hay and Sonenberg, 2004; Tokunaga et al. 2004; Beevers et al. 2006].

mTOR exists in two discrete multiprotein complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2), that are activated by distinct upstream signals and regulate different intracellular processes [Sabatini, 2006]. mTORC1 is sensitive to rapamycin and is regulated by numerous upstream signaling pathways, including PI3K/Akt [Liu et al. 2009]. Activation of PI3K by growth factors (or activating mutations, in the case of some cancers) results in the activation of Akt which causes phosphorylation and dissociation of the inhibiting tuberous sclerosis complex 2 (TSC2), and ultimately increased activity of mTORC1 [Ballou and Lin, 2008]. mTORC1 is also regulated by cellular energy levels. When the cellular energy stores are depleted, TSC2 activity is increased, causing downregulation of mTORC1 activity and ultimately decreased cell growth and proliferation [Bai and Jiang, 2010]. mTORC1 activation leads to downstream activation of multiple effector proteins through phosphorylation, leading to cell proliferation, cell survival, and angiogenesis. mTORC1 also acts as a negative feedback mechanism for its own expression through phosphorylation of insulin receptor substrate 1 (IRS-1). Activation of IRS-1 prevents insulin-induced signaling to Akt via the PI3K pathway, and thus provides negative feedback to the mTOR activation pathway [Wullschleger et al. 2006; Meric-Bernstam and Gonzalez-Angulo, 2009] (Figure 1).

Figure 1.

Schematic drawing of a phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. eNOS, endothelial nitric oxide synthase; HSP, heat shock protein; MAPK, mitogen-activated protein kinase; mTORC1, mTOR Complex 1; mTORC2, mTOR Complex 2; NF-κB, nuclear factor κB; NO, nitric oxide; PKC, protein kinase C; PTEN, phosphatase and tensin homolog.

Less is known about mTORC2. Rapamycin and its analogs do not bind directly to mTORC2 as they do to mTORC1, and its activity is not impaired by short-term rapamycin exposure [Rosner and Hengstschlager, 2008]. Prolonged rapamycin treatment reduces mTORC2 levels and inhibits Akt activation in some cell lines [Zeng et al. 2007]. Two major functions have been attributed to mTORC2: organization and regulation of the actin cytoskeleton and Akt regulation through phorphorylation of its carboxyl terminal. Phosphorylation of Akt by mTORC2, along with phosphorylation through the PI3K pathway, is required for full Akt activation. Therefore, Akt is both upstream and downstream of mTOR.

Evidence for mammalian target of rapamycin pathway in pathogenesis of pancreatic neuroendocrine tumors

A trial examining global gene expression in 72 primary pNETs, 7 matched metastases, and 10 normal pancreatic samples implicated the PI3K/Akt/mTOR pathway in pNETs. Patients with low TSC2 expression by immunohistochemistry staining showed an overall worse prognosis with shorter overall survival, time to progression, and disease-free survival (DFS), and low levels of TSC2 expression was significantly correlated with functional status and tumor aggressiveness [Missiaglia et al. 2010].

This same study implicated another important inhibitor of the Akt/mTOR pathway, phosphatase and tensin homolog (PTEN), in the pathogenesis of pNETs. Over 60% of samples examined by immunohistochemistry in this trial showed altered PTEN expression in either the nuclear or cytoplasmic compartments, or both. Although a low level of nuclear PTEN was found in 58% of pNETs, only those tumors with diminished cytoplasmic expression of PTEN showed a significant correlation with clinicopathologic parameters, including diminished functional status and more aggressive tumors, shorter time to progression and DFS.

Overall, 85% of the primary pNETs examined in this study showed altered expression of TSC2, PTEN, or both, and patients with altered TSC2/PTEN expression demonstrated more aggressive tumors and increased rate of metastasis as well as local invasion. This finding supported the idea that the Akt/mTOR pathway is central to the pathogenesis of pNETs. However, neither TSC2 nor PTEN were found to be independent prognostic indicators in this analysis.

However, in contrast to the idea that mTOR alteration occurs in the majority of pNETs, Jiao and colleagues suggested that only a subset of pNETs have mutations in this pathway. They examined DNA from neoplastic and matched non-neoplastic tissue samples from 10 patients with sporadic pNETs and compared them through parallel genomic sequencing. Multiple genes were examined, including PTEN and TSC2, as well as PIK3CA, as its product is part of the mTOR pathway. In total, somatic mutations in PTEN, TSC2, and PIK3CA were identified in 7.3%, 8.8%, and 1.4% of pNET samples respectively. Although this study excluded pNETs associated with familial syndromes and examined only a small number of individual tumors, the authors suggested that these results might have direct clinical application through prioritization of mTOR-directed therapy [Jiao et al. 2011].

Mammalian target of rapamycin inhibitors

The first efforts to modulate mTOR pathway activity in cancer utilized rapamycin, a macrolide antibiotic that binds to FK binding protein 12 (FKBP-12). FKBP-12 is a cytosolic protein that interacts downstream with the mTOR complex and prevents signal propagation [Gingras et al. 2001]. Preclinical trials utilized gene knockout mice that were susceptible to malignancy due to deficiency in the tumor suppressor gene PTEN. In this model, rapamycin was shown to reduce the rate of tumor development and progression [Podsypanina et al. 2001].

mTOR inhibitors have been studied in a variety of human cancers, including breast cancer, head and neck malignancies, and lymphoma. A preclinical study published in 2005 showed that utilizing rapamycin to target the mTOR pathway in carcinoid cell lines significantly inhibited cell proliferation, further supporting the idea that mTOR inhibitors may have significant clinical potential [Yee et al. 2006; Patel et al. 2011; Baselga et al. 2012; Nakabayashi et al. 2012].

The first rapamycin analog used for mTOR inhibition in NETs was temsirolimus. It was evaluated in 36 patients with unresectable NETs, 21 with carcinoids and 15 with pNETs. However, only three patients (5.6%) experienced an objective response to therapy [Duran et al. 2006].

Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor that blocks the activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12 [Boulay et al. 2004]. Preclinical trials show the efficacy of everolimus in inhibiting proliferation in a number of solid tumors in vitro as well as in vivo, including renal cell carcinoma [Easton and Houghton, 2006; Motzer et al. 2008]. A phase I trial examining the safety of everolimus in 92 patients with a variety of solid tumors suggested that doses up to 10 mg/day were tolerated and that trials should begin at doses of at least 5 mg/day [O’Donnell et al. 2008].

Yao and colleagues conducted the first phase II clinical trial examining the efficacy of everolimus in advanced NETs based on the preclinical evidence discussed above. Sixty patients with NETs (30 with carcinoids and 30 with pNETs) were treated with 5 or 10 mg/day everolimus plus long-acting octreotide (Sandostatin long acting release (LAR), 30 mg every 28 days, Novartis, Basel, Switzerland). Partial response was seen in 22% of patients and 70% of patients demonstrated stable disease. Although there were no patients that demonstrated complete response to treatment, median progression-free survival (PFS) was 60 weeks (95% confidence interval 54–66 weeks) [Yao et al. 2008b]. The promising results of this single institution phase II trial led to the design of the RAD001 in advanced NETs (RADIANT) trials that further explored the efficacy of everolimus in NETs and pNETs in a series of phase II and phase III clinical trials.

Results from RADIANT studies

RADIANT-1

RADIANT-1 was a multinational, single-arm phase II trial that examined 160 patients with advanced pNETs refractory to cytotoxic chemotherapy. Patients who were previously on SSAs were continued on this regimen, and all patients were started on 10 mg/day of everolimus. This trial demonstrated an 8.7% objective response rate and 84.7% of patients demonstrated at least stable disease. Median PFS was 9.7 months in patients receiving everolimus alone and 16.7 in patients receiving everolimus and octreotide. Median overall survival was 24.9 months in the everolimus group and had not yet been reached at the time of publication in the everolimus plus octreotide group [Yao et al. 2010]. Results from this phase II trial confirmed results from prior studies indicating the high rates of disease stabilization with everolimus treatment, and led to the design and initiation of two large randomized, multicenter phase III trials.

RADIANT-2

The RADIANT-2 trial was a multicenter, randomized, placebo-controlled phase III trial looking at the role of adding 10 mg/day everolimus or placebo to octreotide LAR 30 mg intramuscularly every 28 days in patients with advanced NETs and carcinoid syndrome. There were 429 patients enrolled, 6% of whom had a pancreatic primary. Median PFS was 16.4 months in the everolimus group compared with 11.3 months in the placebo group [Pavel et al. 2011]. Although this trial demonstrated that treatment with everolimus was associated with a reduced risk of progression of 23% compared with placebo, the hazard ratio (0.77, p = 0.026) fell short of achieving statistical significance based on the prespecified cutoff value (p = 0.0246). Some problems with this trial were that the two arms were not well balanced, with more severe cases in the everolimus arm. Furthermore, several types of NETs were included, not only classical carcinoids but lung, pancreatic carcinoids as well as paragangliomas.

RADIANT-3

RADIANT-3 was a multicenter, double-blind, randomized phase III trial looking at 410 patients with unresectable or metastatic low- or intermediate-grade pNETs that showed significant improvements in PFS associated with everolimus [Yao et al. 2011]. Patients in this study could have received chemotherapy or other systemic treatment prior to study enrollment, but could not have received prior treatment with mTOR inhibitors. Patients received either 10 mg/day everolimus or placebo in addition to best supportive care, including SSAs in 40% of cases. The patient’s treatment group was concealed until progression of disease was detected, at which point patients who were previously receiving placebo were allowed to cross over into the everolimus group. PFS was 11 months for the everolimus group versus 4.6 months in the placebo group, with a hazard ratio for disease progression or death with everolimus of 0.35 (p < 0.001).

As was demonstrated with earlier studies, response rates were low for both everolimus and placebo groups (5% versus 2% respectively), with most patients experiencing stable disease as their best response (73% versus 51%). Unfortunately, 14% of patients in the everolimus group had progression of disease as their best response compared with 42% of patients in the placebo group.

There was significant crossover of the placebo arm patients into the everolimus treatment group, with 148 of 203 (73%) crossing over after progression of disease. The mean duration of treatment in the placebo group was 3.74 months compared with 8.79 months in the everolimus group. There has been no significant difference in overall survival demonstrated between the two treatment arms of the RADIANT-3 trial, presumably because the trial design allows crossover into the treatment arm with progression of disease.

Limitations

Although everolimus is generally well tolerated, with the majority of patients reporting grade 1 or 2 toxicities, a few grade 3 and 4 toxicities have been described and may have contributed to discontinuation of therapy in a number of patients. In the RADIANT-2 trial, grade 1 or 2 toxicities were frequent and included stomatitis (62% versus 14%), rash (37% versus 12%), and fatigue (31% versus 23%). The most frequent drug-related grade 3 or 4 events were fatigue, diarrhea, and hyperglycemia, and pneumonitis was observed in 12% of patients on everolimus versus 0% in the placebo arm.

Similar toxicity was noted in the RADIANT-3 trial, with 64% of patients reporting stomatitis (versus 17% in placebo group), 49% with rash (versus 10%), 34% with diarrhea (versus 10%), 23% with infections (versus 6%), and 12% with pneumonitis (versus 0%). Atypical infections such as pulmonary tuberculosis, bronchopulmonary aspergillosis, and reactivation of latent hepatitis B were all seen in a single patient on everolimus therapy, and five patients (2%) were thought to have grade 3 or 4 noninfectious pneumonitis or interstitial lung disease.

In addition to toxicities, the low objective tumor response rates seen in the above clinical trials reflect an inability of everolimus to cure unresectable or metastatic pNET disease. This may be in part related to the drug’s inability to block mTORC2. Everolimus is active against mTORC1 only, and when mTORC1 activity is inhibited by everolimus, its negative feedback onto mTORC2 is blocked in addition to the blocking of its downstream effector molecules that give the drug its tumor stabilization efficacy. This indicates that everolimus is not able to block the mTORC2-mediated Akt activation, which may be leading to the therapeutic limitations of the drug to achieve tumor regression as a monotherapy [Markman et al. 2010]. Another explanation for the lack of response might be mutation in the FGFR4 gene. A single nucleotide polymorphism (FGF4-G388R) alters pNET progression and response to mTOR inhibition therapy [Serra et al. 2012].

Conclusion and next steps

Strong evidence supports the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy and targeted therapies. mTOR inhibitors have been found to be additive or synergistic with paclitaxel, carboplatin, cisplatin, vinorelben, doxorubicin and camtotecin [Grunwald et al. 2002; Chiu et al. 2010]. Compared with single-agent therapy, the combination of mTOR inhibitors and chemotherapy enhances apoptosis in vitro and enhances antitumor efficacy in vivo. Ongoing clinical trials are evaluating the efficacy of mTOR inhibitors in combination with a broad spectrum of chemotherapeutic agents. With regard to pNETs, streptozotocin as well as temozolomide are interesting alkylating agents to be combined with everolimus.

The rapamycin-induced Akt activation observed in some cancer cell lines and in clinical trials has increased the interest in overcoming this feedback loop activation by using mTOR inhibitors in combination with antagonists of upstream signaling, such as IGF-1 receptor inhibitors [Wan et al. 2007]. IGF-1 is a well known growth factor for pNETs. In preclinical models, IGF-1 receptor inhibition prevents rapamycin-induced Akt activation, thus sensitizing tumor cells to mTOR inhibition. The epidermal growth factor receptor analog erlotinib also induces synergistic growth inhibition with everolimus in in vivo studies of NET cells.

Another interesting combination is peptide receptor radiotherapy (PRRT) combined with mTOR inhibitors [Beuvink et al. 2005]. Preliminary results by combining ¹⁷⁷lutetium-DOTATATE with everolimus have been reported from a group in Australia and there are also single patient reports suggesting that this combination might be effective in enhancing the antitumor effect of PRRT.

The evidence-based medical treatment of advanced pNETS with everolimus is a new therapeutic tool for patients with progressive disease. However, single-drug treatment is mostly cytostatic and rarely induces tumor shrinkage. The combination of everolimus with cytotoxic agents, other targeted agents, and radioactive treatment may show both additive and synergistic antitumor effects. Unfortunately, some combinations may be limited by additive toxicities, such as everolimus with erlotinib, despite strong inhibitory effects in vitro. A better understanding of mTOR signaling, the mechanism of action of rapamycin, and the identification of biomarkers of response will lead to more optimal targeting of this pathway for cancer therapy.

Footnotes

Funding

The article was supported with funding from K12 CA 0906525 during the writing of this paper.

Conflict of interest statement

Eric Liu is on the speaker bureau for Novartis. Paula Marincola has no conflicts of interest. Kjell Oberg is an advisor to Novartis, Pfizer, and IPSEN.

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Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations

Abstract

Keywords

Introduction

Mammalian target of rapamycin pathway

Evidence for mammalian target of rapamycin pathway in pathogenesis of pancreatic neuroendocrine tumors

Mammalian target of rapamycin inhibitors

Results from RADIANT studies

RADIANT-1

RADIANT-2

RADIANT-3

Limitations

Conclusion and next steps

Footnotes

Funding

Conflict of interest statement

References