Annals of Oncology Advance Access originally published online on February 13, 2007
Annals of Oncology 2007 18(8):1307-1313; doi:10.1093/annonc/mdm009
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© 2007 European Society for Medical Oncology
reviews |
New drug development in digestive neuroendocrine tumors
1 Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Canada
2 Department of Medical Oncology
3 Translational Research Laboratory, Institut Català d'Oncologia
4 Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
5 Gastro-Intestinal Unit, MD Anderson Cancer Center, University of Texas, Texas, USA
* Correspondence to: Dr R. Salazar, Department of Medical Oncology, Institut Català d'Oncologia, Avenue Gran Via s/n, 08907, Barcelona, Spain. Tel: +34 93 2607500; Fax: +34 93 2607741; E-mail: ramonsalazar{at}iconcologia.net
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Abstract |
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 Top Abstract introductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The traditional cytotoxic agents are of limited efficacy in the treatment of neuroendocrine tumors of the gastrointestinal tract (NETs). Recent investigations have brought up a number of biological features in this family of neoplasms that could represent targets for anticancer treatment. NETs seem to have an extraordinary tumor vascularization with high expression of proangiogenic molecules such as the vascular endothelial growth factor along with overexpression of certain tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR), the insulin growth factor receptor (IGFR) and their downstream signaling pathway components (PI3K-AKT-mTOR). The rationale of an antiangiogenic approach in the treatment of NETs and the use of other pharmacological strategies such as EGFR, IGFR and mammalian target of rapamycin inhibitors are discussed. Additionally, the emerging results of recent clinical trials with these targeted drugs are presented.
Key words: antiangiogenic therapies, carcinoid tumors, EGFR inhibitors, mTOR inhibitors, neuroendocrine tumors, targeted drug therapy
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introduction |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The traditional DNA-damaging cytotoxic agents are of limited efficacy in the treatment of neuroendocrine tumors of the gastrointestinal tract (NETs). Characterization of specific molecular features of the different types of cancer has prompted a new era of molecular therapeutics with the development of more selective targeted agents. Within this new setting, there is a great, yet unexploited, therapeutic potential in the field of NETs. These neoplasms have a number of biological features, such as an extraordinary tumor vascularization with high expression of several proangiogenic molecules including vascular endothelial growth factor (VEGF) [1, 2] along with overexpression of other druggable oncogenic receptors such as epidermal growth factor receptor (EGFR) [3, 4], insulin growth factor receptor [5, 6] and their downstream signaling pathway components PI3K-AKT-mTOR [7, 8]. In addition, there are a number of other genes involved in the oncogenesis of NETs that could become new therapeutic targets, although most remain to be better defined and their implications in neuroendocrine tumor growth or progression clarified [9–11]. In order to better understand the oncogenic mechanisms (mutations/amplification/methylation) and their biological consequences, functional studies with fresh frozen human tumors to evaluate the prevalence and dependence of up (down)-regulated pathways, both with high-throughput technologies as microarrays and more traditional technology, should be pursued. This will have to match with large clinical databases for predictive biomarker development (clinical–biological correlative studies). These efforts must be collaborative due to the low incidence of the disease.
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preclinical research |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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In preclinical research, one of the major deficiencies in the study of gastroenteropancreatic NETs is the paucity of cultured cell lines derived from human tumors. We need to develop more adequate models for functional validation of new targets and biomarkers discovered through translational research and for new drug experimental pharmacology. There are technical limitations for the establishment of cell lines and orthotopic or s.c. implantation because NETs are low proliferative tumors that are difficult to grow, particularly carcinoid tumors. The BON1 line is derived from a human pancreatic carcinoid and grows indefinitely in culture [12]. The GOT1 line is derived from a liver metastasis of a human midgut carcinoid and is maintained primarily as a xenograft in mice [13]. Recently, the KRJ1 line derived from a human carcinoid tumor has been described [14]. Transgenic models only exist for pancreatic NETs but not for carcinoids, and they are far from resembling the human tumors. The ability to create animal models that closely mimic the disease in humans would greatly accelerate our knowledge in the biology of these tumors.
Regardless of these limitations, new targeted therapeutic approaches have been postulated for NETs. Some have already been evaluated in the clinical setting with promising results while others remain unexplored or in early stages of development.
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antiangiogenic approach |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The implication of angiogenesis in tumor progression has been extensively described in the literature [15, 16]. The concept of angiogenesis has thrived in a broad application on successful clinical trials with antiangiogenic therapies against a variety of tumor types [17]. Experimental evidence of the importance of angiogenesis in tumor progression is on the basis of the analysis of molecular mechanisms in tumors from animal models, as well as on promising results in the application of experimental antiangiogenic therapies in these models ranging from tumor stabilization to tumor regression depending on the model used [18–20]. Clinical evidence comes from several successful clinical trials with antiangiogenic molecules such as the use of a VEGF-blocking humanized monoclonal antibody bevacizumab in combination with chemotherapy in metastatic colorectal cancer [21], breast cancer [22] and other tumor types [17].
Regarding NETs, several antiangiogenic drugs have been evaluated in a transgenic mouse model of insulinoma, RIP-Tag2, developed by Hanahan and collaborators [23]. Early studies with the aminopeptidase inhibitor TNP-470, minocycline and interferon 
/ß demonstrated an antiangiogenic effect together with an effective tumor growth impairment [9]. Further studies utilized the naturally occurring antiangiogenic molecules angiostatin and endostatin which demonstrated both antiangiogenic [18] and antitumoral effects in different stages of islet cell tumor progression (Casanovas O. and Hanahan D., unpublished data). Several other antiangiogenic therapies targeting the VEGF-VEGFR2/KDR signaling axis have shown to be effective in mouse models of NETs. In particular, several chemical small molecule compounds that inhibit the VEGFR2/KDR tyrosine kinase (TK) catalytic domain (SU5416, SU10944 and SU11248) and a monoclonal antibody that blocks VEGFR2 activation (DC101) have been tested in the RIP-Tag2 mouse model of insulinoma with consistent antiangiogenic effects in microvessel density, endothelial cell proliferation and antitumor activity with increased apoptosis [2, 24, 25].
Another critical cellular component of the blood vessels, the pericytes, has shown to be relevant as target for angiogenesis. A model describing dual VEGF/PDGFR pericyte/endothelial dependency for neovascularization has been postulated, and this could lead to better antiangiogenic therapies [18, 26]. Experimental studies with the RIP1-tag2 transgenic mouse model, essentially indicate a potential synergy when both pericyte VEGF and endothelial cell PDGF receptors and pathways are inhibited by kinase inhibitors [25, 26].
Currently, there are a number of antiangiogenic compounds undergoing evaluation in the clinic. These could be divided into three groups as follows: (i) drugs targeting VEGF, such as the VEGF monoclonal antibody bevacizumab and a more recent related compound, VEGF-trap; (ii) small molecules that inhibit the receptor TK domains of VEGFR and PDGFR, such as SU11248 or sunitinib, sorafenib and valatanib and (iii) other compounds with different antiangiogenic mechanisms, such as thalidomide or endostatin (Table 1).
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bevacizumab
The VEGF monoclonal antibody bevacizumab (AvastinTM, Roche, Basilea, Switzerland) has already reached the clinical practice in the treatment of advanced colorectal cancer, where it is used in combination with chemotherapy in the first-line setting. The first reported clinical trial of bevacizumab in NETs was performed in 44 patients with advanced carcinoid tumors who were on stable doses of octreotide. They were randomized to receive either bevacizumab 15 mg/kg on an every 3 weeks basis or weekly pegylated interferon
-2b (PIF) (0.5 mcg/kg) during 18 weeks [27]. Bevacizumab was superior to PIF both in terms of time to progression (TtP) and reduction in blood tumor perfusion measured by functional computed tomography scan. These data have provided the concept for the design of a Southwest Oncology Group phase III trial (study S0518) in which patients with advanced poor-prognosis carcinoid tumor under stable doses of depot octreotide will be randomized to receive either s.c. interferon -2b or bevacizumab. The treatment with bevacizumab is generally well tolerated although with an increased risk for hypertension and thromboembolic arterial and bleeding events in larger series of patients with ovarian and colorectal cancer [21, 28]. In these series, there was also an increased risk of gastrointestinal perforations, although the absolute number of this potentially fatal event was low. The experience with bevacizumab in other solid tumors such as colorectal cancer has shown that its addition to chemotherapy can significantly improve outcome, whereas it has very little clinical activity as a single agent. This synergy could be explained by a reduction of the interstitial pressure within tumors and higher bioavailability of the cytotoxic agents within the tumor, along with other potential complex and poorly understood pharmacodynamic interactions [29]. The combination of temozolomide with bevacizumab has recently been reported in a small phase II trial with promising activity in pancreatic islet cell carcinomas. The objective response rate (RR) was 24% by Response Evaluation Criteria in Solid Tumors (RECIST), but 0% in carcinoid tumors [30]. Currently, an National Cancer Institute (NCI)-sponsored phase I–II trial of the oxaliplatin-based chemotherapy schedule FOLFOX plus bevacizumab in refractory carcinoid and pancreatic endocrine tumors is ongoing at University of California, San Francisco (San Francisco, CA, USA, http://clinicaltrials.gov/ct/show/NCT00227617). Other exploratory combinations with streptozocin-based regimens in pancreatic islet cell carcinomas are planned.
In addition, bevacizumab is being tested in combination with 2-methoxyestradiol (Panzem) in patients with locally advanced or metastatic carcinoid tumors (http://clinicaltrial.gov/ct/show/NCT00328497). Panzem is a metabolite of estradiol that inhibits hypoxia-inducible factor (HIF)-1 and has other antiangiogenic and cytotoxic properties [31].
small multi-TK inhibitors
sunitinib.
Sunitinib malate (SU-11248, SutentTM; Pfizer, New York, NY) is a highly potent, selective inhibitor of certain protein TKs such as VEGFR-1 to 3, PDGFR, FLT-3, c-Kit and RET [32]. Its antitumor activity results from both inhibition of angiogenesis and direct antiproliferative effects on tumor cells. Sunitinib has been recently approved by the Food and Drug Administration (FDA) for its use in advanced renal cell carcinoma (RCC) (http://www.fda.gov/bbs/topics/news/2006/NEW01302.html). In NETs, a large phase II trial with >100 patients reported a 15% RR in pancreatic islet cell carcinomas and 2% RR in carcinoid tumors, along with high rates of disease stabilization (75% for islet cell carcinomas and 93% for carcinoids). Its safety profile is acceptable with low rates of grade 3 and 4 diarrhea, fatigue, glossodynia, nausea, granulocytopenia, thrombocytopenia and hypertension [33]. This trial has been complemented with a pharmacodynamic evaluation of a number of potential soluble surrogate biomarkers. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), interleukin-8 (IL-8) and a novel biomarker, sVEGFR-3, were measured via enzyme-linked immunosorbent assay analysis at three different time points. The authors concluded that sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib in NETs, and IL-8 may be of particular interest as a potential predictor of response [34].
Currently, a company-sponsored international phase III randomized, double-blind study of sunitinib given daily as a continuous dose versus placebo in patients with advanced carcinoids and islet cell tumors has already started recruitment in a number of countries.
sorafenib.
Sorafenib (BAY 43-9006, NexavarTM; Bayer Pharmaceuticals Corporation, West Haven, CT) is a novel, oral and multitargeted agent with potent activities against Raf kinase and VEGFR-2, resulting in tumor growth inhibition via interference with cellular proliferation and angiogenesis. Besides Raf kinase and VEGFR-2, sorafenib exhibits median inhibitory concentrations (IC50) in nanomolar ranges for other receptor TKs such as VEFGR-3, PDGFR-ß, Flt-3, c-Kit and fibroblast growth factor receptor-1. Sorafenib has also recently been approved by the FDA for the treatment of advanced RCC (http://www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html).
An international multicenter phase II study led by the Mayo Clinic is evaluating the efficacy of sorafenib in metastatic NETs. No results are available yet (http://clinicaltrials.gov/ct/show/NCT00131911).
vatalanib.
Vatalanib (PTK787/ZK222584; Schering AG, Novartis, Basel, Switzerland) is a synthetic, low molecular weight, orally bioavailable drug that inhibits all VEGFR TKs, showing in vitro activity in the submicromolar range. It also inhibits other kinases such as PDGFR-ß and c-Kit TKs but at higher concentrations [19]. Both the Eastern Cooperative Oncology Group and the European Neuroendocrine Tumors Society have designed a trial to explore this compound as single agent or in combination with somatostatin analogues in NETs (http://clinicaltrials.gov/ct/show/NCT00303732) (http://www.neuroendocrine.net/rel/content.php4?rubrik_id=2&headline=Study%20Protocols%20of%20Clinical%20Trials).
imatinib.
Imatinib mesylate (GleevecTM; Novartis) is a small molecule that selectively inhibits ABL, PDGFR and c-Kit TKs. A small Israeli study where 15 patients with NETs received imatinib at doses ranging from 400 to 800 mg showed no activity and remarkable toxicity [35]. Similarly, imatinib at a dose of 800 mg daily was evaluated in a phase II study involving 27 patients. Only one of 27 patients achieved objective response. A significant number of patients with progressive disease, however, achieved stabilization. Patients with early reductions in biochemical output also had significantly longer progression-free survival duration [36]. The reason for this low tumor RR could be related to the absence of dual VEGFR/PDGFR inhibition with imatinib, along with a low level of PDGFR inhibition (10 times lower than sunitinib).
thalidomide
Thalidomide (ThalidomidTM) is an orally bioavailable drug that is postulated to have antiangiogenic activity through its capacity to interfere with the basic fibroblast growth factor and VEGF pathways [37]. In a small phase II study from the Ohio University, 18 patients were treated with single agent thalidomide. No responses were observed but a small percentage of patients who presented with progressive disease at the time of study entry achieved disease stabilization [37, 38]. Subsequent combination studies have been performed with encouraging results. Kulke et al. conducted a phase II study evaluating the efficacy of the combination of temozolomide and thalidomide in patients with metastatic carcinoid tumors, pheochromocytoma or pancreatic NETs. Twenty-nine patients (15 carcinoids, 11 pancreatic NETs and 3 pheocromocytomas) received temozolomide at a dose of 150 mg/m2 for 7 days every other week and thalidomide at doses of 50 to 400 mg daily. A biochemical RR (decrease in chromogranin A) of 40% and a radiological RR of 25% were reported. The antitumor activity appeared more significant in pancreatic NETs compared with carcinoids (45% partial radiological response versus 7%). This combination was, however, associated with remarkable cumulative toxicity resulting in the majority of the patients discontinuing therapy before disease progression mostly due to sensitive neuropathy, opportunistic infections or/and thrombocytopenia [39].
endostatin
Endostatin is a 20-kDa proteolytic fragment of collagen XVIII with antiangiogenic and antitumor activity in preclinical studies. Both preclinical and human phase I studies of recombinant human endostatin (rhEndostatin) indicated activity in NETs. A phase II study of endostatin in patients with advanced NETs, however, did not result in significant tumor regression, although 80% of patients experienced stable disease [40].
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EGFR inhibitors |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The type I receptor TK family comprises four structurally related transmembrane receptors: EGFR (or erbB-1), HER2neu (or erbB-2), HER3 and HER4 [41]. Upon ligand binding, receptor dimerization occurs leading to autophosphorylation of specific tyrosine residues that will then serve as binding sites for signal transducers and adapter molecules. This cascade then initiates critical pathways resulting in cell proliferation, differentiation, migration, adhesion, survival and transformation. The expression or overexpression of EGFR and HER2neu receptors have been associated with tumor progression and resistance to therapy in multiple malignancies and its expression has been reported in NETs [3]. Several potential strategies to target the EGFR have been developed. Among these, the monoclonal antibodies against the extracellular domain of the EGFR (such as cetuximab or panitunumab) and the low molecular weight TK inhibitors (i.e. gefitinib and erlotinib) are the ones that have consistently reached the clinical setting. Some preclinical and clinical studies in neuroendocrine cell lines indicated a role of EGFR as a possible target and showed some efficacy of certain EGFR inhibitors in this tumor type [4, 42].
gefitinib
A recently reported phase II study of gefitinib in 37 patients with progressive NETs (22 with carcinoid tumor and 15 with islet cell carcinoma) revealed a 6-month PFS of 30% for the former and 10% for the latter. However, no objective responses have been observed [43].
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mammalian target of rapamycin inhibitors |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The mammalian target of rapamycin (mTOR) is a serine–threonine kinase that participates in the regulation of apoptosis, proliferation and cell growth through modulation of cell cycle progression [8]. mTOR modulates translation of key mRNAs of proteins required for cell cycle progression from G1 to S phase, such as 4E-binding protein (4E-BP1) and p70S6 kinase [44]. Signaling through the PI3K/AKT/mTOR pathway leads to an increase in translation, particularly of proteins regulating cell cycle progression and metabolism. In cancer cells, aberrant activation of this pathway may occur through increased signaling via growth factor receptors, activating mutations/amplification of the pathway kinases, or by loss of the tumor suppressor protein PTEN. Both have been described in NETs [5, 7]. There are also clues from clinical observations that mTOR complex may play an important role in NETs. First, TSC1 and TSC2 complex inhibit mTOR when normally expressed and tuberous sclerosis is a hereditary disease with germline mutations in TSC2 which is associated with malignant pancreatic islet cell carcinomas. Secondly, in neurofibromatosis, NF1 loss is associated with constitutive mTOR activation because NF1 regulates mTOR through TSC2. Neurofibromatosis is associated with carcinoid of ampulla of Vater, duodenum and mediastinum [45]. Finally, islet cell carcinomas also occur in
12% of patients with von Hippel-Lindau (vHL) disease [46, 47]. The vHL gene is located on chromosome 3p26-p25. Allelic deletion at chromosome 3p, the site of vHL gene, has also been described to occur frequently in sporadic carcinoid and islet cell tumors [48, 49]. Tumors arising in the setting of Hippel-Lindau disease are often angiogenic and vascular. This is likely because the vHL protein together with mTOR regulates the HIF-1 expression. Activation of mTOR leads to HIF-1 production while vHL protein targets it for degradation. Recent research has revealed a significant complexity of the mTOR complex that seems to interconnect with other well-described pathways representing interesting targets for combined therapy. Rapamycin-insensitive companion of mTOR (RICTOR) and regulatory associated protein of mTOR (RAPTOR) are key partnering proteins which complex with mTOR and modulate its functions. When mTOR is blocked through the use of an mTOR inhibitor, AKT may be up-regulated through an alternative activation by the mTOR–RICTOR complex [50, 51]. In addition, O'Reilly et al. [52] have recently described AKT phosphorylation through a feedback loop of the PI3K/AKT/mTOR pathway from the insulin-like growth factor I receptor (IGF-IR). The results from this finding are of special interest in NETs given the known effect of octreotide in decreasing IGF-I [53].
Sirolimus (rapamycin) and its derivatives are immunosuppressive macrolides that block mTOR and yield potential antiproliferative activity in a variety of malignancies. Two rapamycin derivatives have recently been evaluated in NETs: temsirolimus and everolimus.
temsirolimus
Temsirolimus (CCI-779; Wyeth, Philadelphia, PA) binds intracellularly to the immunophilin FKBP-12 (FK 506-binding protein-12) and creates a complex that inhibits the protein kinase activity of mTOR. Inhibition of mTOR prevents phosphorylation of p70S6 kinase, 4E-BP1 and, indirectly, other proteins involved in transcription and cell cycle control, leading to G1 growth arrest.
Results from a multicenter study, sponsored by the NCI (USA) and led by the Princess Margaret Phase II Consortium in Canada have recently been communicated [54]. Thirty-seven patients with advanced progressive NETs were treated with i.v. weekly doses of 25 mg of temsirolimus. Along with the evaluation of clinical activity, pharmacodynamic studies were performed in paired tumor biopsies. Overall, treatment with temsirolimus was well tolerated, with fatigue, hyperglycemia and rash/desquamation as the most frequent adverse events. Single-agent temsirolimus has demonstrated clinical activity in this population of patients with advanced NETs. Two patients achieved a confirmed PR and a third patient had an unconfirmed PR at the end of cycle 8 and discontinued therapy not due to toxicity. Twenty additional patients had stable disease (SD) of at least 2-month duration and among these, 10 patients continued treatment beyond six cycles. Response outcomes were similar between the carcinoid and islet cell carcinoma histologies, with PR rates of 4.8% and 6.7%, respectively. The intent-to-treat RR for the entire cohort was 5.6% (95% confidence interval 0.6%–18.7%), median TtP was 6 months and 1-year overall survival rate was 71.5%. Biochemical responses (decrease in chromogranin A and/or 5-HIAA) were not assessed in this study.
Paired baseline and post-treatment biopsies were obtained from 23 patients, and 13 paired samples were evaluable. Baseline expression levels of pAKT, pS6, pmTOR and peIF4G were determined and compared with expression levels following 2 weeks of temsirolimus treatment. Pharmacodynamic evaluations in paired biopsies, confirmed, for the first time in this patient population, that temsirolimus effectively down-regulates the phosphorylation of S6, and that higher baseline levels of pS6 and pmTOR seem to predict for a better response. Additionally, increases in the expression of pAKT were noted after treatment with temsirolimus and this was associated with a more prolonged TtP.
everolimus
The results of a phase II study combining everolimus (RAD001; Novartis) at 5 mg orally daily and depot octreotide (30 mg i.m. every 28 days) in low-grade NETs have been recently communicated [55]. Four out of twenty-seven evaluable patients (14.8%) achieved a partial response, 19 patients presented SD and 3 progressed. Additionally, one-third of the patients had a >50% reduction in chromogranin A. Toxicities were mild to moderate, including those expected from everolimus such as stomatitis and myelosupression. An additional cohort of patients treated with everolimus 10 mg daily and the same dose of octreotide has completed accrual. The preliminary results of this cohort are expected in 2007.
On the basis of these encouraging results, the RAD001 In Advanced Neuroendocrine Tumors (RADIANT) trials are under development. RADIANT-1, an open label, stratified, single-arm phase II study of everolimus in patients with advanced pancreatic NETs having failed previous cytotoxic chemotherapy, is now opening for accrual (http://clinicaltrial.gov/ct/show/NCT00363051). This trial contains two separate cohorts for patients using or not using concurrent depot octreotide. In addition, two phase III placebo-controlled randomized trials in patients receiving depot octreotide are planned: RADIANT-2 in patients with advanced carcinoid tumors and RADIANT-3 in patients with advanced pancreatic islet cell tumors.
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other targets |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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BB-10901 is an immune conjugate of huN-901 (a humanized monoclonal antibody) and DMI (a semisynthetic derivative of the plant-derived ansa macrolide maytansine). The antibody selectively attaches to the CD56 antigen, a neural cell adhesion molecule expressed on the cellular surface of NETs, where it is designed to deliver the cytotoxic. A phase I study of BB-10901 in patients with metastatic carcinoid tumors and other solid tumors is currently ongoing (http://clinicaltrials.gov/ct/show/NCT00346385).
Depsipeptide (FR901228; Fujisawa, Osaka, Japan) is a histone deacetylase inhibitor that exerts its anticancer effects by modulating the transcription of target genes. Depsipeptide has been reported to show antiproliferative and apoptotic effects probably through the regulation of caspases. A phase II study of depsipeptide in patients with locally advanced or metastatic NETs was terminated prematurely due to an unexpected high number of serious cardiac adverse events. Therefore, the objective RR could not be determined [56].
IGF-I is an autocrine regulator of carcinoid tumors. Blockade of IGF-I signaling has been proposed as a therapeutic target in the treatment of patients with carcinoid syndrome and is thought to be one of the effects of somatostatin analogues. Rapamycin inhibits IGF-I induced proliferation in the BON carcinoid cell line [5] but the IGF-I receptor activation could feedback a resistance loop after mTOR inhibition as indicated by a study reported in the 2005 American Society of Clinical Oncology Annual Meeting that showed that IGF-I receptor is involved in the activation of AKT when everolimus is administered to cancer cells in culture [57]. These experimental results support dual targeting with mTOR inhibitors and IGF-IR antagonists and it appears to be a promising antitumor strategy in NETs.
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conclusions |
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TopAbstractintroductionpreclinical researchantiangiogenic approachEGFR inhibitorsmammalian target of rapamycin...other targetsconclusionsReferences |
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The emerging knowledge of NETs molecular biology has facilitated the development of clinical trials with new targeted therapies of several pharmacological groups; a number of antiangiogenic and mTOR inhibitors seem promising options with interesting early phase II of clinical activity. Although caution must be exercised when interpreting high percentages of disease stabilization, because many of the reported trials did not require patients to have progressive disease, or provide precise extent of disease progression, as an inclusion criterion. Confirmatory studies about the efficacy and tolerability of these drugs are needed and the future may be sought by combining targeted therapies with each other or with the more classical cytotoxic chemotherapy agents, or alternatively with different approaches such as gene transfers or immunotherapy. The clinical development of new molecules and combinations would benefit from a parallel biomarker development program. The presence or absence of certain biomarkers could improve patient selection and could also aid in determining efficacy early in the program. Initial biomarker studies in tumor and surrogated tissues have already been reported by some groups (i.e. sunitinib and temsirolimus).
When facing these challenges, there are clear financial constraints for expensive technology and networking, which can be dealt with by setting up international foundations or consortiums with multigovernmental funding, i.e. European Union/US-NCI/UK-MRC. Searching for funding from public and private sources is not an easy task when dealing with rare tumors, and support from patient advocate groups should be sought. It is also essential to stimulate the pharmaceutical companies' interest in the area of NETs. NETs fall under an orphan drug indication and should be viewed as an opportunity to pursue accelerated registration programs. Health authorities could consider the promotion of more indulgent and specific fast track programs to attract industry and facilitate clinical research projects in such population of patients.
Finally, investigators must stimulate collaborative phase II trials with drugs against relevant targets registered for other indications, and must actively search for consensus to design and perform collaborative phase II–III intergroup trials, including retrospective and, when possible, prospective translational end points with tissue collection in clinical trials.
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Footnotes |
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Chairman of the Spanish Task Force Gastrointestinal NETs group. 
Received for publication November 18, 2006. Accepted for publication November 27, 2006.
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References |
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