Adrenocortical carcinoma (ACC) is a rare cancer for which few treatment options have been available. Currently, the best available treatment involves combination chemotherapy with the adrenolytic drug mitotane, although the response rate remains modest. Over the past 10 years there has been renewed interest in the field owing to the recognition that targeted therapies may provide new avenues for effective treatment of this deadly disease. Molecular analyses have revealed specific signaling alterations in ACC, and advances in drug development have generated the tools to block these pathways. Although convincing evidence for the effectiveness of targeted therapies is not currently available, these studies are in progress and should shift the prognosis of this disease in the years to come.

https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(12)00053-7.pdf

The next generation of therapies for adrenocortical cancers.

Standard chemotherapy for adrenocortical cancer currently is under evaluation in the context of the recently completed FIRM-ACT evaluating the combination of mitotane with either streptozocin or etoposide, cisplatin, and doxorubicin. New agents are eagerly sought by the ACC community that hopes to make progress against this deadly disease. Investigators have begun to dissect the molecular and genomic context of ACC with a goal of identifying potential novel therapeutic agents. One gene consistently overexpressed in ACC is insulin growth factor type 2. Targeting its receptor IGF1R has shown encouraging results in ACC cell lines and against murine xenografts. As a result, clinical trials to evaluate agents targeting the IGF1R have been done including mitotane and IMC-A12 (a monoclonal antibody) and the GALACCTIC trial that has just completed accrual to evaluate OSI-906, a small molecule IGF1R antagonist. On the horizon are other agents targeting other tyrosine kinases, including EGF and FGF, and novel strategies such as individualized tumor analysis to select treatment.

/pdf/targeted-therapies-for-adrenocortical-carcinoma-igf-and-2cmpgv91ey.pdf

Targeted therapies for adrenocortical carcinoma: IGF and beyond.

Several studies reported sexual dimorphism in the signaling mechanisms of renal ischemia/reperfusion (I/R). The anti-apoptotic serum and glucocorticoid-regulated kinase-1 (SGK-1) is up-regulated and has a significant protective role in renal I/R. SGK-1 has several target molecules, and inhibition of the inducible nitric oxide synthase (iNOS) transcription is one of its effector mechanisms. The objective of the present study was to examine if there is a gender-specific expression and activation of SGK-1 during renal I/R injury. In vitro, treatment of HK-2 kidney proximal tubular cells with different concentrations of 17-beta estradiol had no effect, whereas testosterone increased SGK-1 abundance in a dose-dependent manner. In vivo, in a rat model of unilateral renal I/R injury, there was a higher SGK-1 expression and phosphorylation in males 2 and 24 h after ischemia paralleled by reduction in the mRNA expression of iNOS compared to females. Deprivation of testosterone by castration of males resulted in decreased SGK-1 protein level at all time-points and reduced phosphorylation 2 and 24 h after reperfusion. Our results suggest that testosterone up-regulates SGK-1 in the kidney contributing to sexual dimorphisms in the cell signalling machinery. The significance of the testosterone-regulated SGK-1 level and activity in the kidney needs further investigations.

/pdf/gender-differences-in-serum-and-glucocorticoid-regulated-1pf0bso476.pdf

Gender Differences in Serum and Glucocorticoid Regulated Kinase-1 (SGK-1) Expression during Renal Ischemia/Reperfusion Injury

Resume Les carcinomes cortico-surrenaliens (CCS) sont des tumeurs rares connues pour leur comportement agressif, leur potentiel metastatique et leur faible survie a 5 ans (45 %). Leur prise en charge requiert une equipe multidisciplinaire et experte. Le seul traitement curatif est une exerese complete par un chirurgien experimente. Les traitements adjuvants sont peu nombreux et leur efficacite incertaine. Un traitement adjuvant par mitotane en post-operatoire augmente la survie sans recidive chez la majorite des patients mais des etudes complementaires sont necessaires pour determiner les patients chez qui ce traitement sera le plus benefique. Pour optimiser les resultats de ce traitement, il est necessaire de maintenir une mitotanemie entre 14 et 20 mg/l souvent au prix d’effets secondaires difficiles a controler. Une radiotherapie complementaire est proposee en presence de facteurs d’agressivite. En cas de maladie residuelle, progressive ou inextirpable le traitement repose classiquement sur l’association chimiotherapie et mitotane. L’etude FIRM-ACT permet d’etablir que la chimiotherapie la plus efficace est l’EDP (etoposide, doxorubicine et cisplatine). Les premiers resultats des inhibiteurs des tyrosines kinases, chez les patients progressifs malgre une ou deux lignes de chimiotherapie, sont decevants mais cela peut etre en partie explique par l’interaction avec le mitotane qui en diminue les concentrations plasmatiques, en particulier du sunitinib. Des essais cliniques sont en cours pour juger de l’efficacite des autres therapies ciblees, notamment les traitements agissant sur les recepteurs de l’IGF-1.

Corticosurrénalomes: actualités thérapeutiques

Testosterone has been reported to cause blood pressure to increase. However mechanisms that underlie the effect of this hormone on this physiological parameter are currently not well understood. The aims of this study were to investigate effects of testosterone on expression of α, β and γ-epithelial sodium channel (ENaC) proteins and messenger RNAs (mRNAs) in kidneys, the channel known to be involved in Na(+) reabsorption, which subsequently can affect the blood pressure. Methods. Adult male Sprague-Dawley (SD) rats were orchidectomized fourteen days prior to receiving seven days treatment with testosterone propionate (125 µg/kg/day or 250 µg/kg/day) with or without flutamide (androgen receptor blocker) or finasteride (5α-reductase inhibitor). Following sacrifice, the kidneys were removed and were subjected for α, β and γ-ENaC protein and mRNA expression analyses by Western blotting and Real-time PCR (qPCR) respectively. The distribution of α, β and γ-ENaC proteins in kidneys were observed by immunofluorescence. Results. The α, β and γ-ENaC proteins and mRNA levels in kidneys were enhanced in rats which received testosterone-only treatment. In these rats, α, β and γ-ENaC proteins were distributed in the distal tubules and collecting ducts of the nephrons. Co-treatment with flutamide or finasteride resulted in the levels of α, β and γ-ENaC proteins and mRNAs in kidneys to decrease. In conclusions, increases in α, β and γ-ENaC protein and mRNA levels in kidneys mainly in the distal tubules and collecting ducts under testosterone influence might lead to enhance Na(+) reabsorption which subsequently might cause an increase in blood pressure.

Sub-chronic testosterone treatment increases the levels of epithelial sodium channel (ENaC)-α, β and γ in the kidney of orchidectomized adult male Sprague-Dawley rats.

Sunitinib in refractory adrenocortical carcinoma: results of a phase II trial

Renal expression of alpha-ENaC is increased in testosterone treated rats

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Sunitinib in refractory adrenocortical carcinoma: results of a phase II trial

Renal expression of alpha-ENaC is increased in testosterone treated rats