Searchable abstracts of presentations at key conferences in endocrinology

ea0090p113 | Endocrine-related Cancer | ECE2023

In silico neoantigen prediction - a forceful avenue to improve immunotherapy in human adrenocortical carcinoma

Landwehr Laura-Sophie , Appenzeller Silke , Olsner Laura , Weigand Isabel , Sbiera Silviu , Fassnacht Martin , Kroiss Matthias

Introduction: Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine malignancies and confers a poor prognosis in advanced stages. Effective treatments are lacking. The results of immune checkpoint inhibition were disappointing with few responders only deriving clinical benefit. For the development of novel immunotherapies such as tumor vaccines and T cell-based treatments, target identification is essential. Tumor-specific mutant neoantigens that may be recogn...

ea0070oc1.4 | Adrenal and Cardiovascular Endocrinology | ECE2020

Immune infiltrate and PD-1 / PD-L1 expression in adrenocortical carcinoma: who can predict patients´ outcome?

Landwehr Laura-Sophie , Sbiera Iuliu , Schreiner Jochen , Weigand Isabel , Kroiss Matthias , Fassnacht Martin , Sbiera Silviu

Context: Adrenocortical carcinoma (ACC) are endocrine malignant neoplasms associated with severe aggressiveness. Tumour-related glucocorticoid excess occurs in 60% of patients and is associated with poor prognosis. First clinical trials using immune checkpoint inhibitors are quite unsatisfactory and treatment advancements are urgently needed.Recently, we characterized tumour-infiltrating lymphocytes (TILs) in ACC and identified the detrimental dependency...

ea0070aep83 | Adrenal and Cardiovascular Endocrinology | ECE2020

JIL-O: Establishment of a new steroidogenic human adrenocortical carcinoma cell line

Landwehr Laura-Sophie , Jochen Schreiner , Herterich Sabine , Appenzeller Silke , Fassnacht Martin , Kroiss Matthias , Weigand Isabel

Adrenocortical carcinoma (ACC) is a rare malignancy with heterogeneous but dismal prognosis and despite numerous efforts to improve patient care, effective treatment options are still lacking. ACC in vitro research faces for decades one major obstacle - the unavailability of different ACC cell line models. Here, we present a newly established human ACC cell line that was directly transferred to and now proliferates in cell culture. JIL-O cell line was derived from a p...

ea0093oc15 | Oral communication 3: Adrenal Tumors and Neuroendocrine Tumors | EYES2023

Targeting the ferroptosis-macrophage crosstalk in adrenocortical carcinoma

Triebig Alexandra , Weigand Isabel , Atici Sena , Angeli Jose Pedro Friedmann , Kroisz Matthias

Background: Ferroptosis is an emerging form of regulated necrotic cell death characterized by excessive lipid peroxidation. Adrenocortical carcinoma (ACC) cells have been shown to be highly susceptible to ferroptosis caused by active steroid hormone synthesis. While therapeutic activation of ferroptosis has been proposed as a novel treatment strategy, its impact on the tumor immune microenvironment (TIME) remains elusive. Macrophages are an important TIME component and modulat...

ea0063gp100 | Adrenal and Neuroendocrine - Basic | ECE2019

Characterization of cell death induced by mitotane in adrenocortical carcinoma cells

Weigand Isabel , Schreiner Jochen , Rohrig Florian , Kiseljak-Vassiliades Katja , Hofner Kerstin , Kendl Sabine , Fassnacht Martin , Sbiera Silviu , Kroiss Matthias

Background: Mitotane is the only drug approved for treatment of adrenocortical carcinoma (ACC). We have found that mitotane leads to endoplasmic reticulum stress and decreased viability in ACC cells. It is not known by which downstream mechanisms cell death is induced by mitotane.Aim: To characterize the mechanisms underlying cell death resulting from mitotane treatment in ACC cells.Methods: Lipid peroxidation in the ACC cell line ...

ea0041oc2.3 | Receptors & Signalling | ECE2016

PRKACA mutations in adrenal Cushing impair association with the PKA regulatory subunit

Bathon Kerstin , Weigand Isabel , Ronchi Cristina L. , Di Dalmazi Guido , Beuschlein Felix , Sbiera Silviu , Fassnacht Martin , Calebiro Davide

In a previous study we found mutations in the main catalytic subunit of protein kinase A (PKA Cα) to be responsible for cortisol-secreting adrenocortical adenomas (ACAs). These mutations interfere with the formation of a stable holoenzyme, thus causing constitutive PKA activation. More recently, we identified additional mutations affecting PKA Cα in ACAs associated with overt Cushing syndrome: Ser213Arg_Leu212_Lys214insIle-Ile-Leu-Arg, Cys200_Gly201insVal, Trp197Arg,...

ea0037gp.02.03 | Adrenal (1) | ECE2015

Differential expression of the PKA subunits in adrenocortical adenomas

Weigand Isabel , Ronchi Cristina , Calebiro Davide , Rank Petra , Steinhauer Sonja , Beuschlein Felix , Allolio Bruno , Fassnacht Martin , Sbiera Silviu

Recently, mutations in the PRKACA (catalytic subunit α of the PKA) gene have been identified as causative in 35% of adrenocortical adenomas (ACA) with overt Cushing’s syndrome (Beuschlein et al. 2014). These mutations lead to constitutive activation of PKA signaling and subsequently to an excessive production of cortisol. Protein kinase A is a heterotetramer consisting of two catalytic and two regulatory subunits with several isoforms (Cα, β, &#947...

ea0070oc7.5 | Endocrine-related Cancer | ECE2020

Differential adrenal toxicity of SOAT1-inhibitors

Weigand Isabel , Sbiera Silviu , Kendl Sabine , Hanna Urlaub , Constanze Hantel , Katja Kiseljak-Vassiliades , Margaret E Wierman , Fassnacht Martin , Kroiss Matthias

Background: Mitotane is the only approved treatment for advanced adrenocortical carcinoma and was shown to inhibit Sterol-O-Acyl transferase 1 (SOAT1) which leads to the depletion of cholesterol esters and increase of free cholesterol in the ACC cell line H295R. Downstream activation of the endoplasmic reticulum stress (ER-stress) pathway results in decreased adrenocortical cell viability.Aim: To better characterize the effects of SOAT1 inhibition in ACC...

ea0056oc5.3 | Diving deep into adrenal cortex diseases | ECE2018

PRKACA L206R mutation in adrenal Cushing’s syndrome makes PKA RIIβ susceptible for caspase-mediated cleavage

Weigand Isabel , Ronchi Cristina L. , Hofner Kerstin , Vanselow Jens T. , Herterich Sabine , Bathon Kerstin , Schlosser Andreas , Fassnacht Martin , Calebiro Davide

Protein Kinase A (PKA) consists of two catalytic and two regulatory subunits with several isoforms (Cα, β, γ and RIα, IIα, Iβ, IIβ, respectively). Type II regulatory subunits are phosphorylated by PKA in their inhibitory sites, while type I are not. Somatic activating mutations in the gene encoding the catalytic subunit α (Cα) of PKA (PRKACA) have been found in 30–40% of cortisol-producing adrenocortical adenomas (CPA). We rece...

ea0056gp32 | Adrenal cortex | ECE2018

PRKACA L206R mutation in adrenal Cushing induces histone H1.4 hyper-phosphorylation

Bathon Kerstin , Weigand Isabel , Vanselow Jens T , Ronchi Cristina L , Sbiera Silviu , Schlosser Andreas , Fassnacht Martin , Calebiro Davide

We previously identified mutations in PRKACA, coding for the catalytic a (Ca) subunit of protein kinase A (PKA), as the main genetic alteration in cortisol-producing adrenal adenomas (CPAs) responsible for Cushing’s syndrome. Here, we further investigated the mechanism of action of all PRKACA mutations identified so far by our team (L206R, L199_C200_insW, S213R_L212_K214insIILR, C200_GlyinsV, W197R, del244-248+E249Q and E32V). Five out of seven mutants s...