Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors

Martino, Maria Cristina De; Feelders, Richard A; Herder, Wouter W. de; Koetsveld, Peter M. van; Dogan, Fadime; Janssen, Joseph A M J L; Waaijers, A. M.; Pivonello, Claudia; Lamberts, Steven W. J.; Colao, Annamaria; Krijger, Ronald R. de; Pivonello, Rosario; Hofland, Leo J.

doi:10.1530/erc-13-0112

Cited by 27 publications

(29 citation statements)

References 33 publications

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“…Presently, there is no evidence that clearly supports a key role of this pathway in the pathogenesis of ACCs. This is supported by the finding that adrenocortical adenomas have higher mRNA expression of p-mTOR than ACCs [13]. Currently, there is no clear rationale behind the use of mTOR inhibitors as a targeted therapy in ACCs.…”

Section: Discussionmentioning

confidence: 94%

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

et al. 2018

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Objective: Adrenocortical carcinoma (ACC) is a rare disease with a dismal prognosis. We aimed to evaluate if a personalized medicine approach may be useful for matching patients with ACC to targeted therapies. Methods: This is an analysis of 10 molecularly profiled ACCs that were progressing under standard of care treatment. The profile consisted of a 50-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for several proteins or chromosomal aberrations. Results: In 6 (60%) tumor samples, no somatic mutation was detected, while in 3 (30%) tumors 1 mutation was detected and in 1 (10%) tumor 2 mutations were detected. These mutations were CTNNB1 (2 samples), TP53 (1 sample), RB1 (1 sample) and APC (1 sample). Expression of phospho-mTOR and of EGFR was commonly detected by IHC (87.5 and 62.5%). In 4 (50%) samples, IHC revealed a weak expression of progesterone receptor. Less frequent alterations were expression of PDGFR-α, c-KIT, and estrogen receptor, each in 1 case. Conclusions: Based on the molecular profile, no recommendation for targeted therapy was made by the multi-disciplinary team. Currently, ACC might not be suitable for a precision medicine approach according to our tests.

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Section: Discussionmentioning

confidence: 94%

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

et al. 2018

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“…The role of the mammalian target of rapamycin (mTOR), a downstream effector of IGF2, has been investigated in adrenal tumors by several studies, and mTOR appeared to be a potential therapeutic target in a subset of patients with ACC (Table 5; De Martino et al 2014). Doghman et al (2010) reported for the first time involvement of miRNAs in regulation of mTOR signaling in childhood adrenocortical tumors.…”

Section: Future Directions and Pathway Driven Therapiesmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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“…Genetic studies have identified alterations in the FGF-R cascade (Laurell et al 2009), and overexpression of VEGF-R, PDGF-R, EGF-R, and the FGF-R signalling pathways (Xu et al 2011, Wang et al 2012. Preclinical studies support the idea that mTOR inhibitors can upregulate Akt phosphorylation in ACCs (Liu et al 2009, De Martino et al 2014.…”

Section: Molecular Profilementioning

confidence: 82%

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Angelousi¹,

Dimitriadis²,

Zografos³

et al. 2017

Endocrine-Related Cancer

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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.

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Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors

Cited by 27 publications

References 33 publications

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

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