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

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A Shining Light in the Darkness for the Treatment of Pancreatic Neuroendocrine Tumors MINI REVIEW A Shining Light in the Darkness for the Treatment of Pancreatic Neuroendocrine Tumors 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 com- pleted 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 AUGUST 2011CANCER DISCOVERY | 213 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2011 American Association for Cancer Research. MINISECTION REVIEW Capdevila et al. 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
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