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  • 1
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    Online Resource
    Targeting PI3K and CDKs as effective therapeutic option for PPGLs in vitro and in vivo
    Bioscientifica ; 2021
    In:  Endocrine Abstracts ( 2021-05-15)
    Details
    In: Endocrine Abstracts, Bioscientifica, ( 2021-05-15)
    Type of Medium: Online Resource
    ISSN: 1479-6848
    URL: Article
    DOI: 10.1530/endoabs.73.OC15.3
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2021
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  • 2
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    Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines
    Bioscientifica ; 2012
    In:  Journal of Molecular Endocrinology Vol. 49, No. 2 ( 2012-06-19), p. 79-96
    Details
    In: Journal of Molecular Endocrinology, Bioscientifica, Vol. 49, No. 2 ( 2012-06-19), p. 79-96
    Abstract: Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line – both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses down to 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs.
    Type of Medium: Online Resource
    ISSN: 0952-5041 , 1479-6813
    URL: Article
    DOI: 10.1530/JME-12-0028
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2012
    detail.hit.zdb_id: 1478171-2
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  • 3
    Online Resource
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    The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance
    Bioscientifica ; 2018
    In:  Endocrine-Related Cancer Vol. 25, No. 10 ( 2018-10), p. 893-908
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 25, No. 10 ( 2018-10), p. 893-908
    Abstract: Pancreatic neuroendocrine tumors (panNETs) are often inoperable at diagnosis. The mTORC1 inhibitor everolimus has been approved for the treatment of advanced NETs. However, the regular development of resistance to everolimus limits its clinical efficacy. We established two independent everolimus-resistant panNET (BON1) cell lines (BON1 RR1, BON1 RR2) to find potential mechanisms of resistance. After 24 weeks of permanent exposure to 10 nM everolimus, BON1 RR1 and BON1 RR2 showed stable resistance with cellular survival rates of 96.70% (IC 50  = 5200 nM) and 92.30% (IC 50  = 2500 nM), respectively. The control cell line showed sensitivity to 10 nM everolimus with cellular survival declining to 54.70% (IC 50  = 34 nM). Both resistant cell lines did not regain sensitivity over time and showed persistent stable resistance after a drug holiday of 13 weeks. The mechanisms of resistance in our cell line model included morphological adaptations, G1 cell cycle arrest associated with reduced CDK1(cdc2) expression and decreased autophagy. Cellular migration potential was increased and indirectly linked to c-Met activation. GSK3 was over-activated in association with reduced baseline IRS-1 protein levels. Specific GSK3 inhibition strongly decreased BON1 RR1/RR2 cell survival. The combination of everolimus with the PI3Kα inhibitor BYL719 re-established everolimus sensitivity through GSK3 inhibition and restoration of autophagy. We suggest that GSK3 over-activation combined with decreased baseline IRS-1 protein levels and decreased autophagy may be a crucial feature of everolimus resistance, and hence, a possible therapeutic target.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-18-0159
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2018
    detail.hit.zdb_id: 2010895-3
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  • 4
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    Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies
    Bioscientifica ; 2017
    In:  Endocrine-Related Cancer Vol. 24, No. 6 ( 2017-06), p. R239-R259
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 24, No. 6 ( 2017-06), p. R239-R259
    Abstract: Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-16-0542
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2017
    detail.hit.zdb_id: 2010895-3
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  • 5
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    Antitumoral Activity of the MEK Inhibitor Trametinib (TMT212) Alone and in Combination with the CDK4/6 Inhibitor Ribociclib (LEE011) in Neuroendocrine Tumor Cells In Vitro
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 6 ( 2021-03-23), p. 1485-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 6 ( 2021-03-23), p. 1485-
    Abstract: Objectives: This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. Methods: Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively. Results: Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells. Conclusions: MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13061485
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 6
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    Online Resource
    Sino-European Differences in the Genetic Landscape and Clinical Presentation of Pheochromocytoma and Paraganglioma
    The Endocrine Society ; 2020
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 105, No. 10 ( 2020-10-01), p. 3295-3307
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 105, No. 10 ( 2020-10-01), p. 3295-3307
    Abstract: Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations. Objective To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations. Design Cross-sectional study. Setting 2 tertiary-care centers in China and 9 in Europe. Participants Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans. Main Outcome Measures Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes. Results Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1] ) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3] ), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5] ) and SDHx (10.7% [8.4–13.0] vs 4.2% [2.6–5.7] ). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations. Conclusions This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgaa502
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2026217-6
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  • 7
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    Signaling Pathways in Pheochromocytomas and Paragangliomas: Prospects for Future Therapies
    Springer Science and Business Media LLC ; 2012
    In:  Endocrine Pathology Vol. 23, No. 1 ( 2012-3), p. 21-33
    Details
    In: Endocrine Pathology, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2012-3), p. 21-33
    Type of Medium: Online Resource
    ISSN: 1046-3976 , 1559-0097
    URL: Article
    DOI: 10.1007/s12022-012-9199-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 2091856-2
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  • 8
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    Proneuropeptide Y and neuropeptide Y metabolites in healthy volunteers and patients with a pheochromocytoma or paraganglioma
    Elsevier BV ; 2022
    In:  Clinica Chimica Acta Vol. 534 ( 2022-09), p. 146-155
    Details
    In: Clinica Chimica Acta, Elsevier BV, Vol. 534 ( 2022-09), p. 146-155
    Type of Medium: Online Resource
    ISSN: 0009-8981
    URL: Article
    DOI: 10.1016/j.cca.2022.07.018
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1499920-1
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  • 9
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    Phäochromozytom – Modellerkrankung für die personalisierte Medizin
    Georg Thieme Verlag KG ; 2021
    In:  DMW - Deutsche Medizinische Wochenschrift Vol. 146, No. 23 ( 2021-11), p. 1520-1526
    Details
    In: DMW - Deutsche Medizinische Wochenschrift, Georg Thieme Verlag KG, Vol. 146, No. 23 ( 2021-11), p. 1520-1526
    Abstract: Pathophysiologie und Epidemiologie Phäochromozytome und Paragangliome (PPGL) sind Tumoren des Nebennierenmarks bzw. der Paraganglien mit malignem Potenzial. Sie lassen sich anhand der zugrunde liegenden Mutationen in Cluster unterteilen. Cluster-1-Tumoren basieren auf einer Aktivierung von Pseudohypoxie-Signalwegen, Cluster-2-Tumoren auf einer Aktivierung von Tyrosinkinase-abhängigen Signalwegen. Cluster-3-Tumore sind mit Veränderungen in Wnt-abhängigen Signalwegen assoziiert (auf Cluster 3 wird im Weiteren nicht genauer eingegangen, da vieles hierzu noch unbekannt ist). In 30–35 % der Fälle liegen (autosomal-dominant vererbte) Keimbahnmutationen vor. Weitere 35–40 % der Fälle beruhen auf somatischen Mutationen. Die Penetranz der Erkrankung ist abhängig vom betroffenen Gen, liegt jedoch bei allen Genen unter 50 %. Cluster-1-Tumoren sind häufiger extraadrenal lokalisiert und haben das höchste Metastasierungsrisiko. Cluster-2-Tumoren sind meist adrenal lokalisiert und haben ein geringes Metastasierungsrisiko. Klinik und Diagnostik Patient*innen mit bekannter Keimbahnmutation sowie solche mit klinischen Zeichen und Symptomen eines PPGL, mit einem adrenalen Inzidentalom oder einem PPGL in der Vorgeschichte, sollten auf ein PPGL gescreent werden. Hierfür werden Metanephrin (MN), Normetanephrin (NMN) und 3-Methoxythyramin (3MT) im Plasma (optimalerweise mittels Massenspektrometrie LC/MS-MS) bestimmt. Cluster-1-Tumoren weisen ein noradrenerges, Cluster-2-Tumoren ein adrenerges Sekretionsmuster auf, wobei letztere mit einer ausgeprägteren und häufig intermittierenden Klinik (Palpitationen, Tremor, Hyperhidrosis, Angst, hypertensive Entgleisung) einhergehen. Werden deutlich erhöhte MN- und/oder NMN-Spiegel festgestellt, erfolgt eine bildgebende Tumorsuche mittels CT oder MRT, ggf. wird diese um eine funktionelle Bildgebung ergänzt. Therapie Lokalisierte PPGL werden operativ entfernt. Dies kann meist minimalinvasiv erfolgen und sollte an einem erfahrenen Zentrum durchgeführt werden. Um Komplikationen zu vermeiden, erfolgt präoperativ eine medikamentöse α-Rezeptorblockade. Metastasierte PPGL werden derzeit mit Radionuklidtherapie, Chemotherapie oder Tyrosinkinase-Inhibitoren behandelt, auch wenn es noch keine offiziell zugelassenen Therapien gibt. Weitere neue Therapien befinden sich derzeit in der klinischen Testung. Vor- und Nachsorge Die meisten Patient*innen, insbesondere die mit bestimmten Risikokonstellationen, benötigen aufgrund des Rezidiv- und Metastasenrisikos ein lebenslanges Follow-up, welches abhängig von der zugrunde liegenden Mutation gestaltet wird. Hierzu gehört die regelmäßige (meist jährliche) Bestimmung von MN und NMN im Plasma sowie in bestimmten Fällen auch eine Bildgebung. Da bei SDHx-Mutationen auch hormoninaktive PPGL auftreten können, werden für diese Patient*innen auch regelmäßige bildgebende Kontrollen nach einer kürzlich erschienenen Leitlinie empfohlen.
    Type of Medium: Online Resource
    ISSN: 0012-0472 , 1439-4413
    URL: Article
    DOI: 10.1055/a-1240-9835
    RVK:
    XA 39100
    RVK:
    XA 10000
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2021
    detail.hit.zdb_id: 2035474-5
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  • 10
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    Preanalytical Considerations and Outpatient Versus Inpatient Tests of Plasma Metanephrines to Diagnose Pheochromocytoma
    The Endocrine Society ; 2022
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 107, No. 9 ( 2022-08-18), p. e3689-e3698
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 9 ( 2022-08-18), p. e3689-e3698
    Abstract: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. Objective We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. Methods Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. Results Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. Conclusion Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgac390
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2026217-6
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