Die Rolle der Rap-1/B-Raf-Signaltransduktion in der molekularen Pathogenese von gastroenteropankreatischen neuroendokrinen Tumoren

Gastroenteropankreatische neuroendokrine Tumore (GEP-NETs) sind seltene Tumore, die aus Zellen des diffusen neuroendokrinen Systems des Gastrointestinaltraktes oder Pankreas entstehen. Unter den funktionellen GEP-NETs zaehlen zu den haeufigsten Serotonin-produzierende neuroendokrinen Tumore, Insulinome und Gastrinome. Ueber die molekulare Pathogenese von GEP-NETs ist wenig bekannt. Im Gegensatz zu den haeufigeren Tumoren des Verdauungstraktes wie dem kolorektalen Adenokarzinom, dem Magenkarzinom und dem Pankreaskarzinom sind in den sporadischen GEP-NETs weder Veraenderungen in Onkogenen noch in Tumorsuppressorgenen typisch. Auch eine Ueberexpression von Genprodukten der EGF-Rezeptorfamilie sind bei den GEP-NETs nicht bekannt. In endokrinen Zellen stimuliert das kleine G-Protein Rap1 Signaltransduktion ueber die MAP-Kinasen durch Aktivierung von B-Raf. In papillaeren Schilddruesenkarzinomen, die ihren Ursprung von neuroendokrinen Zellen nehmen, wurden B-Raf-Mutationen nachgewiesen. Auch in malignen Melanomen, deren Ursprungszellen aehnliche Eigenschaften aufwiesen wie die Zellen des diffusen neuroendokrinen Systems des Gastrointestinaltraktes, aus denen die GEP-NETs entstehen, wurden aktivierende B-Raf-Mutationen nachgewiesen. Wir untersuchten die Expression von Rap1 und B-Raf immunhistochemisch in 49 GEP-NETs. Diese Experimente zeigten eine hochselektive Expression von B-Raf in gastroenteropankreatischen neuroendokrinen Zellen, aus denen die GEP-NETs entstehen. Im Vergleich zu den festgelegten internen Standards zeigten Rap1 und B-Raf in der Mehrzahl der GEP-NETs eine deutliche Ueberexpression. Mittels Luziferaseassay fanden wir heraus, dass vor allem Wildtyp-Rap1 und die aktivierte Mutante B-Raf BxB eine starke Aktivierung des ERK-abhaengigen Transkriptionsfaktors Elk-1 in einer neuroendokrinen Tumorzellinie (BON-Zellen) induzieren und somit die Signaltransduktion ueber Rap1/B-Raf/MEK/ERK aktivieren. Die Mehrheit der GEP-NETs ist wenig chemosensitiv, was eine Klaerung der Pathogenese mit Identifizierung von moeglichen Angriffspunkten fuer eine konservative Behandlung umso wichtiger werden laesst. Auf der Suche nach therapeutischen Angriffspunkten von GEP-NETs untersuchten wir in MTT-Assays den Effekt des Rafkinase-Inhibitors BAY 43-9006 auf Wachstum und Apoptose von neuroendokrinen Tumorzellinien (In-R1-G9- und BON-Zellen) und in Westernblots den Effekt von BAY 43-9006 auf die Kinasen des MEK-ERK-Moduls. Wir wiesen nach, dass BAY 43-9006 in relativ hohen Konzentrationen die Proliferation der neuroendokrinen Tumorzellen inhibierte. Die Phosphorylierung der Downstreamkinasen wurde aber bereits durch niedrigere Konzentrationen induziert. Rafkinase-Inhibitoren sind also eine vielversprechende Option in der konservativen Behandlung von GEP-NETs

Localization Defines Streptozotocin/5-FU Response in Primary Pancreatic Neuroendocrine Tumours

Introduction: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. Methods: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. Results: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. Conclusion: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration

Patient-Reported Outcomes and Quality of Life with Sunitinib Versus Placebo for Pancreatic Neuroendocrine Tumors: Results From an International Phase III Trial

The objective of this analysis was to compare patient-reported outcomes and health-related quality of life (HRQoL) in a pivotal phase III trial of sunitinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NCT00428597). Patients received sunitinib 37.5 mg (n = 86) or placebo (n = 85) on a continuous daily-dosing schedule until disease progression, unacceptable adverse events (AEs), or death. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 at baseline, Day 1 of every 4-week cycle, and end of treatment or withdrawal. Changes >= 10 points on each scale or item were deemed clinically meaningful. Sunitinib had anti-tumor effects and improved progression-free survival (PFS) compared with placebo. The study was terminated early for this reason and because of more serious AEs and deaths with placebo. Baseline HRQoL scores were well balanced between study arms, and were generally maintained over time in both groups. In the first 10 cycles, there were no significant differences between groups in global HRQoL, cognitive, emotional, physical, role, and social functioning domains, or symptom scales, except for worsening diarrhea with sunitinib (p < 0.0001 vs. placebo). Insomnia also worsened with sunitinib (p = 0.0372 vs. placebo), but the difference was not clinically meaningful. With the exception of diarrhea (a recognized side effect), sunitinib had no impact on global HRQoL, functional domains, or symptom scales during the progression-free period. Hence, in patients with pancreatic neuroendocrine tumors, sunitinib provided a benefit in PFS without adversely affecting HRQoL

Neuroendocrine Neoplasia within the German NET Registry

Neuroendocrine neoplasias (NEN) comprise a rare tumor entity with heterogeneous biology, prognosis and therapeutic options. Together with the recent publication of the first German guidelines on diagnostics and therapy of NEN, an analysis of the German NET-registry cohort of the German Society of Endocrinology (DGE) was performed. For this purpose, 2686 cases were extracted and their patient characteristics (e. g., age, sex, histopathological characterization, grading and staging) were displayed and outcomes were calculated. Additionally, the systemic treatment reality in the two largest subgroups, small intestinal and pancreatic NEN, was analyzed within metastatic patients. Distribution of primary tumor localization, histopathological classification, disease stage and overall survival was comparable with results from international registry studies. In concordance with current guidelines, somatostatin analogues (SSA) and peptide-receptor-radionuclide-therapy (PRRT) were the most common therapeutic modalities in small intestinal NEN. In pancreatic NEN, chemotherapy was used in first line as often as SSA. In second line, chemotherapy was used as often as PRRT. WHO-classification of 2010 and TNM staging proved to be of prognostic relevance. The current analysis of the German NET-registry characterizes a multicentric, interdisciplinary cohort of NEN patients throughout Germany and it describes the applied systemic treatment modalities and overall outcome as well as the prognostic value of the WHO classification of 2010 and TNM staging

Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need

The subject of colorectal neuroendocrine neoplasms (NENs), subdivided into well-differentiated NENs, termed neuroendocrine tumours (NETs; grade (G) 1 and 2), and poorly differentiated NENs, termed neuroendocrine carcinomas (NECs; G3) according to the 2010 World Health Organisation (WHO) classification, has arguably not had as much attention or study as NENs occurring in other sites. Colorectal NETs and NECs are however easier to study than many others since they are usually not difficult to remove and are increasingly detected because of intensified colorectal cancer screening and surveillance programmes. Colorectal NETs and NECs show site-specific heterogeneity with variable behaviour and different therapeutic options; these various aspects provide unique challenges. Because of bowel cancer screening programmes, colorectal NENs, like conventional adenocarcinomas, may be diagnosed at a stage that is associated with improved survival. In this article we intend to describe and define areas of unmet needs relating to the epidemiology, classification, pathology, diagnosis and therapy of colorectal NETs (including NETs G3), colorectal NECs, and finally, mixed adeno-neuroendocrine carcinomas (MANECs) by reviewing and discussing the relevant literature

Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms

Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs