Neuro
`endocrinology
`
`Neuroendocrinology 2004;80(supp| 1):94—98
`DOI: 10.1159/000080749
`
`From Basic to Clinical Research in
`
`Gastroenteropancreatic Neuroendocrine Tumor
`Disease — The Clinician-Scientist Perspective
`
`Bertram Wiedenmann Ulrich-Frank Pape
`
`Department of Internal Medicine, Division of Hepatology and Gastroenterology, Interdisciplinary Center of
`Metabolism and Endocrinology, Charité, Campus Virchow Hospital, University Medicine Berlin, Berlin, Germany
`
`Key Words
`Basic and clinical research - New drugs-
`Neuroendocrine tumor - Unresolved clinical issues
`
`Abstract
`
`Patients with rare tumors represent a diagnostic and
`therapeutic challenge for non-specialized physicians,
`surgeons and other medical doctors. Whereas several
`specialized centers have gathered data for an improved
`diagnosis and therapy of neuroendocrine tumor disease,
`numerous clinical issues have not been resolved on an
`
`evidence—based medicine level. Furthermore, the evalua-
`
`tion of new treatment options has been overshadowed
`by the low incidence of the disease.
`In this article, a
`major medical challenge forthe diagnosis and therapy of
`neuroendocrine tumor disease is addressed. As well,
`new therapeutic treatment options translated from cur-
`rent findings in the fields of molecular and tumor biology
`are discussed.
`
`Copyright O 2004 S. KargerAG, Basel
`
`Neuroendocrine tumors (NETS) originate in different
`organs and sites [1, 2]. Based on their diverse primary
`tumor localizations, NETS of the gastroenteropancreatic
`(GEP) system encompass a family of distinct or even indi-
`vidual tumors, which have to be considered as distinct as
`adenocarcinomas of the stomach, rectum and pancreas
`[3]. NET cells also exhibit, in relation to their primary
`origin, distinct cell biological features, such as distinct
`secretory as well as growth and differentiation properties
`[4].
`For example, NETS located in the rectum (also called
`rectal carcinoids) practically never secrete hormones or
`biogenic amines to cause hypersecretion-related symp-
`toms and syndromes. They usually grow slowly and me-
`tastasize late, i.e. only once a tumor exceeds a diameter of
`1-2 cm [5, 6].
`By contrast, NETS of the colon are usually dedifferen-
`tiated and metastasize early [7]. On the other hand, they
`are similar to NETS of the rectum in that they are non-
`functional, i.e. no secretion of hormones and biogenic
`amines is observed which can cause hypersecretion-relat-
`ed syndromes and symptoms. Despite this, however,
`functionally inactive polypeptides such as chromogranin
`A can be detected in patients with metastatic disease in
`the bloodstream [8].
`By contrast, NETS of the pancreas often secrete hor-
`mones (e.g. insulin, gastrin, glucagon and VIP) but very
`
`E R
`Fax +4161 306 12 34
`E-Mail karger@ka.rger.ch
`www.karger.com
`
`© 2004 S. Karger AG, Basel
`0028-3835/04/0807—0094$21.00/0
`
`Accessible online at:
`www.ka.rger.com/nen
`
`Bertram Wiedenmann, Department of Internal Medicine, Division ofHepatology and
`Gastroenterology, Interdisciplinary Center ofMetabolism and Endocrinology
`Charité, Campus Virchow Hospital, University Medicine Berlin
`Augustenburger Platz 1, DE—13353 Berlin (Germany), Tel. +49 30 450 553 022
`Fax +49 30 450 553 902, E-Mail bertram.wiedenmann@charite.de
`
`
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 001
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`rarely biogenic amines (e.g. serotonin and catechol-
`amines) [5, 9].
`This clinical and tumor biological phenomenon is con-
`trasted by NETS of the ileum, which often secrete biogenic
`amines but rarely hormones (the only exception being
`tachykinins). Similar for both NETs of the pancreas and
`the ileum is their usually low proliferation index as deter-
`mined by Ki67 (< 10%) [2, 5].
`Based on these tumor biological and clinical facts,
`NETs have been diagnosed and treated as separate dis-
`eases, i.e. according to their primary location, state of dif-
`ferentiation and stage [10, l 1].
`NET patients often represent a difficult diagnostic
`challenge at their first doctor’s visit. This holds especially
`true for patients who only exhibit discrete functionality
`such as mild phases of impaired consciousness (e.g. insuli-
`noma), epigastric pain (e.g. gastrinoma) or intermittent,
`nocturnal diarrhea (e.g. carcinoid syndrome).
`This also holds true for patients with MEN-1, which
`are known to be genetically affected by a menin mutation
`[12, 13]; however, in the early tumor stage, only provoca-
`tion tests can detect small or even minimal disease. Clear-
`
`ly, laboratory diagnosis without provocation tests will
`practically always be negative in these very early tumor
`stages. Aside from provocation tests, the bona fide tumor
`markers, chromogranin A and 5-HIAA, will only be raised
`once metastases have formed. Furthermore, these mark-
`ers have to be considered with care, since synthesis of
`these marker molecules depends on the primary tumor
`location as well as the state of tumor differentiation [14].
`Histological diagnosis, in a preoperative setting, re-
`quires the imaging of NET lesions, be they liver metas-
`tases, gastric or rectal polyps or pancreatic lesions. In
`some cases, functionality as well as a positive laboratory
`test may be present but no lesion can be detected [4, 15].
`Only during the course of the disease can the tumor lesion
`be detected. Therefore, more sensitive diagnostic proce-
`dures are required allowing the consistent earlier detec-
`tion of tumor lesions smaller than 5 or even 2 mm. This
`
`would also imply the hope that tumors consisting of less
`than, for example, 1 million tumor cells (corresponding to
`a diameter of approximately 3 mm) should be detectable
`in living tissue. Clearly, in contrast to the given limited in
`vivo conditions, immunohistology can allow the detection
`of a single tumor cell, for example in lymph nodes or in
`bone marrow. Thus, improvement of our current in vivo
`imaging standards is required to come close to the well-
`established in vitro imaging conditions.
`Similarly, endoscopic ultrasound, the continuously im-
`proving MRI technology as well as somatostatin receptor
`
`scintigraphy represent moves in the right direction in
`order to come closer to the ideal in the possible detection
`of the first and only tumor cell [16, 17].
`As far as new therapeutic options in NET disease are
`concerned, surgical methods have been improved by new
`minimally invasive procedures, for example in laparo-
`scopic ileocecal resection. However, it remains to be deter-
`mined if this approach will substitute for the conventional
`‘open’ approach. Considering, for example, that we can
`evaluate the lymph node status in ileal NET just as well by
`laparoscopy as by ‘open surgery’ is very promising.
`Furthermore, local ablative procedures have increas-
`ingly been used by now in NET disease. Although promis-
`ing in terms of control of symptoms, no data have been
`obtained so far in a prospective, randomized, multicen-
`tric setting demonstrating a prolonged survival in NET
`patients.
`Similarly, peptide-guided radioreceptor therapy has
`been used in several trials and shown to be quite promis-
`ing for both control of hypersecretion-related symptoms
`as well as control of tumor growth [l7—19]. So far, how-
`ever, only one prospective multicenter trial with radiola-
`beled octreotate coupled to yttrium 90 via a chemical
`DOTATOC bridge (Octreother) has been performed. Fi-
`nal results of this trial are not yet ready.
`Furthermore, chemotherapy has only partially been
`effective in two NET groups: in pancreatic as well as in
`undifferentiated NETs. In the first group, streptozotocin-
`based regimens combined with 5-FU or doxorubicin are
`of some value [20]. For undifferentiated, anaplastic
`NETs, cis-platinum plus VP16/etoposide can lead to
`some responses [21]. However, these responses last only a
`few months. Based on these limited effects of presently
`used chemotherapeutic agents, new chemotherapeutics
`may be worth testing such as oxalip1atin- or taxol-based
`regimens in anaplastic NETs [22].
`Clearly, based on the above-given limited clinical
`knowledge in the field of diagnostics, as well as therapeu-
`tics in NET disease, a substantial number of clinical ques-
`tions have to be answered in prospective pan-European or
`even global trials.
`The major issues and questions to be answered are:
`(1) development of a staging, grading and subsequent
`TNM classification as an objective measure for prognosis
`in NET patients; (2) evaluation of conventional entero-
`clysma as compared to the newly developed MR-Sellink
`procedure; (3) determination of the cost-effectiveness of
`somatostatin receptor scintigraphy in comparison to oth-
`er imaging procedures in a prospective multicentric set-
`ting; (4) performance of a randomized prospective study
`
`Basic and Clinical Research of GEP NETs
`in an International Context
`
`Neuroendocrinology 2004;80(suppl l):94—98
`
`9 5
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`West-Ward Pharm.
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`Table 1 . Overexpression of growth factors and their cognate recep-
`tors in GEP NETs
`
`PDGF
`bFGF
`TGF-a
`TGF-B
`HGF
`IGF
`VEGF
`
`PDGF-a-R
`FGF-RI, FGF-RII
`EGF-R
`TGF-[3-RI, TGF-B-RII
`HGF-R
`IGF-R
`KDR, Flt-1
`
`25
`26
`27, 28, 29
`24
`29
`30, 31
`23
`
`on surgical debulking vs. medical therapy in patients with
`noncuratively resectable cancer; (5) evaluation of local
`ablative procedures (radiofrequency thermal ablation, la-
`ser-induced thermotherapy and others) in comparison
`with medical therapy under the aspects of both, control of
`symptoms as well as tumor growth; (6) evaluation of
`embolization vs. chemoembolization in a prospective set-
`ting; (7) determination of the antiproliferative effect of
`biotherapeutics in relation to primary localization, tumor
`differentiation and drug bioavailability; (8) evaluation of
`the antiproliferative effect of ‘cold’ vs. ‘hot’ somatostatin
`analogues; (9) evaluation of newly developed biothera-
`peutics (see below); (10) evaluation of the effect of perito-
`neal carcinosis on gastrointestinal motility; (11) evalua-
`tion of the prognostic value of micrometastasis in lymph
`nodes, liver and blood, and (12) evaluation of certain
`tumor biological phenomena such as anoikis, angiogene-
`sis and cell cycle activity in differentiated and undifferen-
`tiated NET cells in vitro. In addition to new chemothera-
`
`peutic agents, biotherapy or targeted therapy should be
`helpful in the expansion of our current therapeutic arma-
`mentarium (see below).
`Clearly, on a cellular level, we will have to learn more
`about the key molecular players involved in the tumor
`biology of NET disease. Furthermore, as far as NET cell
`crosstalk is concerned, aside from NET cells, we have very
`little knowledge concerning the interaction of immuno-
`cytes, endothelial cells, non-NET epithelial cells and neu-
`rons with NET cells. Furthermore, we do not know if
`clonal development of NET cells varies in relation to a
`given specific cellular compartment.
`Despite this, however, new agents developed in the
`field of targeted therapy will, we hope, allow us to study
`possible interference/inhibition of various growth factor
`signalling pathways. Similarly, signalling pathways linked
`
`with G-protein-coupled receptors as well as calcium chan-
`nels represent promising therapeutic targets.
`Interference with these pathways will also include
`interference with angiogenesis and cellular crosstalk (e.g.
`via integrins). It might also allow an improved therapeutic
`control of nuclear replication and membrane transport/
`secretion. This may not only hold true for NET cells but
`may also include immunocytes and other non-NET cells.
`Among the most promising new therapeutic ap-
`proaches in targeted therapy may be the inhibition of syn-
`thesis and/or secretion, as well as receptor binding of
`growth factors such as vascular endothelial growth factors
`[23, 24]. Based on their action on endothelial cell activa-
`tion, followed by a consecutive vascular hyperperrneabili-
`ty and matrix permeation, followed in turn by the induc-
`tion of endothelial proliferation, migration, lumen forma-
`tion and stabilization of pericytes, this growth factor fami-
`ly warrants further detailed studies in NETs. This ap-
`proach is further supported by the fact that NET disease is
`characterized by hypervascularization within the tumor
`tissue [25].
`Growth factor signalling in GEP NETs has so far been
`quite extensively studied [23, 24, 26-32]. Biological pa-
`rameters such as growth, glucose metabolism, survival
`and mitogenesis have mainly been studied in vitro by the
`overexpression of growth factors and their cognate recep-
`tors in GEP NET cell lines. Details and references on the
`
`signalling pathways of PDGF, bFGF, EGF, HGF, IGF
`and VEGF in GEP NET are shown in table 1. Aside from
`
`the biological functions of the various growth factors, the
`function of somatostatin including its analogues has been
`extensively studied in NET [33].
`As comprehensively discussed by Schmid et al. [34],
`somatostatin as well its analogues play an important role
`in the treatment of hypersecretion-related symptoms in
`NETs. However, in order to improve the potency of these
`pharmacological agents, more detailed studies are re-
`quired analyzing the crosstalk of somatostatin analogues
`with phosphatases and calcium channels. In addition, a
`variety of mechanisms of interferon-a action on NET cells
`has been elucidated [35, 36] and justifies this substance as
`both an antisecretory as well as an antiproliferative agent,
`although its side effects have to be considered [37, 38].
`In this context, it is of note that a recent study by
`Mergler et al. [39, 40] suggested for the first time that R-
`type Ca2+ channels are expressed in NETs, which in turn
`can be used as therapeutic targets by interfering with their
`function such as with SNX-482.
`
`Aside from new drug targets, a number of medical
`agents are available on the market for other indications.
`
`96
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`Neuroendocrinology 2004;80(suppl l):94—98
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`Wiedenmann/Pape
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`West-Ward Pharm.
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`The antiproliferative action of COX-2/NSAIDs in NET
`cells has recently been demonstrated in vitro for the first
`time [41]. Clearly, COX-2 inhibitors represent an inter-
`esting new therapeutic approach for NETS based on their
`low side effects and their possible combination with other
`orally available agents (e.g. capecitabine).
`Similarly, other pharmaceutical agents, characterized
`by their signalling via growth factor receptors, G-protein-
`coupled receptors, calcium channels, integrins and nu-
`clear proteins are currently evaluated in numerous clini-
`cal, oncological trials for non-NET indications. These
`include targeted therapeutics such as gefinitib (Iressa®)
`interfering with EGF receptor signalling; imatinib inter-
`fering with PDGF c-kit signalling; SOM 230 interfering
`with somatostatin signalling; bevacizumab (Avastin®) in-
`terfering with VEGF-A signalling; PTK/ZK interfering
`with VEGFR 1-3, PDGFR c-kit and c-Fms signalling;
`Medi-522 and cilengitide interfering with integrin-OLVB3
`signalling; flavopyridol and rapamycin interfering with
`nuclear replication and membrane transport/secretion.
`
`In summary, numerous questions remain to be an-
`swered, both at the level of diagnostics and therapeutics.
`To answer these primary questions, multicentric, pro-
`spective, randomized studies are required in order to gen-
`erate better evidence-based medicine levels than those
`
`that have been obtained so far. Clearly, this also implies
`the performance of studies evaluating the cost-benefit of
`currently applied diagnostics and therapeutics. In addi-
`tion, new therapeutic strategies are required in order to
`improve current, rather limited treatment options espe-
`cially in metastatic NET disease. Here, new targeted ther-
`apies offer new hope especially in the fields of angiogene-
`sis, nuclear replication, cellular adhesion and signal trans-
`duction.
`
`Acknowledgments
`
`The authors are indebted to M. Szott-Emus and E. Zach, Berlin,
`Germany, for their excellent editorial support.
`
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`Faiss S, Pape UF, Bohmig M, Dorlfel Y, Mans-
`rnaun U, Golder W, Riecken E0, Wiedenmann
`B; International Lanreotide and Interferon Alfa
`Study Group: Prospective, randomized, multi-
`center trial on the antiproliferative effect of
`lanreotide, interferon-alfa, and their combina-
`tion for therapy of metastatic neuroendocrine
`gastroenteropancreatic tumors. J Clin Oncol
`2003;21:2689—2696.
`Pape UF, Wiedenmann B: Adding interferon-
`alpha to octreotide slows tumour progression
`compared with octreotide alone but evidence is
`lacking for improved survival in people with
`disseminated midgut carcinoid tumours. Can-
`cer Treat Rev 2003;29:565-569.
`Mergler S, Wiedenmann B, Prada J: R-type
`Ca“ charmel activity is associated with chro-
`mogranin A secretion in human neuroendo-
`crine tumor BON cells. J Membr Biol 2003;
`194:177-186.
`Mergler S, Drost A, Bechstein W0, Neuhaus P,
`Wiedenmann B: Ca2+ channel properties in
`neuroendocrine tumor cell cultures investi-
`gated by whole-cell patch-clamp technique.
`Ann N Y Acad Sci 2004;1014:137-139.
`Detjen KM, Welzel M, Wiedenmann B, Rose-
`wicz S: Nonsteroidal anti-inflammatory drugs
`inhibit growth of human neuroendocrine tu-
`mor cells via G1 cell-cycle arrest. Int J Cancer
`2003;107:844-853.
`
`98
`
`Neuroendocrinology 2004;80(suppl 1):94—98
`
`Wiedenmann/Pape
`
`
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 005
`
`