IGF1-R inhibition and liposomal doxorubicin: Progress in preclinical evaluation for the treatment of adrenocortical carcinoma

Beuschlein, Felix; Jakoby, Judith; Mentz, Susanne; Zambetti, Gerard P.; Jung, Sara; Reincke, Martín; Süss, Regine; Hantel, Constanze

doi:10.1016/j.mce.2016.03.023

Cited by 12 publications

(13 citation statements)

References 28 publications

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“…Following the same line, we were recently able to include MUC-1-xenografts for the first time in a therapeutic study with two different anti-IGF-1R inhibiting approaches. These experiments also indicated sub-group dependent differences in the expression of components of the IGF-system, as well as in therapeutic outcome versus NCI-H295R and SJ-ACC3, thereby also better reflecting clinical observations than with NCI-H295R alone [ 20 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

Hantel¹,

Shapiro²,

Poli

et al. 2016

Oncotarget

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110

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In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.

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Section: Discussionmentioning

confidence: 99%

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

Hantel¹,

Shapiro²,

Poli

et al. 2016

Oncotarget

Self Cite

110

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“…22 another interesting in vivo study investigated the efficacy of liposomal doxorubicin associated with an igF1r antibody (1H7) in cell-derived Nci-H295r and tissue-derived SJ-acc3 and MUc-1 xenografts mouse models. 21 The authors used three different therapeutic approaches: the scheme with liposomal doxorubicin + free anti igF1r antibody 1H7 (l+ab), the scheme with anti igF1r targeted doxorubicin loaded immunoliposomes (il) and injection of sodium chloride as control. They showed that both l+ab and il schemes caused a significant reduction in tumor size and higher rates of complete or partial remission in mouse after long-term treatment.…”

Section: Evidence Synthesismentioning

confidence: 99%

“…They showed that both l+ab and il schemes caused a significant reduction in tumor size and higher rates of complete or partial remission in mouse after long-term treatment. 21 However, only few clinical studies investigated the combination of igF1r/ir inhibitors with other anticancer treatment. a phase i trial in advanced solid tumors, including 10 acc patients, reported a stable disease for more than 8 months in 40% of acc patients (4 out 10) treated with the combination of cixutumumab and temsirolimus, an mTor inhibitor (Table i).…”

Section: Evidence Synthesismentioning

confidence: 99%

“…17 igF1r seems to be involved in acc tumorigenesis 19 and different preclinical studies, which investigated the targeting of this receptor showed promising results. [20][21][22] However, phase i and iii trials evaluating two pharmaceutical agents, figitumumab and linsitinib, targeting the igF1r and both igF1r -insulin receptor (ir), respectively, failed to demonstrate significant clinical benefit, except in a few patients. 23,24 one of the lack of these studies was that predictive biomarkers, such as the evaluation of the igF system members, which were necessary for the identification of the probable responders, were not used.…”

Section: Introductionmentioning

confidence: 99%

“…20,66,86 However, these promising results were not confirmed in clinical trials. 23,24 Better results were observed in preclinical studies investigating the effects of these agents with other types of anticancer therapy; 21,94 • an in-vitro study suggested the potential antitumor activity of metformin in acc cells. 97 clinical studies are necessary to validate that.…”

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confidence: 99%

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The role of insulin-like growth factor system in the adrenocortical tumors

Altieri¹,

Colao²,

Faggiano³

2018

Minerva Endocrinol

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The different presentation of adrenocortical tumors in benign adenoma (aca) or adrenocortical carcinoma (acc) is related to the variability at the molecular level. The insulin-like growth factor (igF) system is one of the most frequently altered pathways in acc. in this review we will critically analyze the evidence regarding the pathogenic role of the igF system in adrenal tumorigenesis, focusing on acc. We will also examine the preclinical and clinical studies which investigated the targeting of the igF system as a therapeutic approach in acc. EVIDENCE ACQUISITION: The IGF system plays a crucial role in the embryogenesis of adrenal glands. No significant alterations of the igF system were observed in aca. in acc, the IGF2 overexpression is one of the most frequent molecular change presented in more than 85% of cases. However, IGF2 seems to be only a tumor progression factor which requires additional hits to trigger adrenal tumorigenesis. also, the igF1 receptor (igF1r) appears to be higher expressed in acc. Many igF1r target-drugs have been developed to inhibit the activation of the igF system. eVideNce SYNTHeSiS: Preclinical studies using antibody or tyrosine kinase which target the igF1r, or the dualtargeting of igF1r and insulin receptor (ir) reduced acc cells proliferation both in vitro and in vivo in mouse xenograft model. However, these promising results were not confirmed in clinical trials. coNclUSioNS: Nowadays, predictive markers for the response of target-igF therapy are missing and further studies which investigate new molecular markers and evaluate the entire igF receptors, including the ir, are urgently needed.

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An update on adrenocortical cell lines of human origin

et al. 2022

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Adrenocortical carcinoma (ACC) is a rare, heterogenous and highly malignant disease. Management of ACC is dependent on disease stage with complete surgical resection as the only potentially curative option. However, advanced, un-resectable, metastatic stages and also recurrences often require systemic treatments, which are unfortunately nowadays still unsatisfactory. The scarcity of preclinical models reflecting patient heterogeneities and furthermore drug-resistant phenotypes, has hampered the progress and development of new therapies in recent years. In this review, we provide an overview on the classical models and substantial progress which has been made over the last years in context of this aggressive disease.

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IGF1-R inhibition and liposomal doxorubicin: Progress in preclinical evaluation for the treatment of adrenocortical carcinoma

Cited by 12 publications

References 28 publications

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

The role of insulin-like growth factor system in the adrenocortical tumors

An update on adrenocortical cell lines of human origin

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