Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there ...is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.
Next-generation therapies for adrenocortical carcinoma Altieri, Barbara; Ronchi, Cristina L.; Kroiss, Matthias ...
Best Practice & Research Clinical Endocrinology & Metabolism,
20/May , Letnik:
34, Številka:
3
Journal Article
Recenzirano
Almost one decade ago, etoposide, doxorubicin, cisplatin and mitotane (EDP-M) has been established as first-line systemic therapy of metastatic adrenocortical carcinoma (ACC). Although heterogeneous, ...the prognosis of advanced stage ACC is still poor and novel treatments are urgently needed. This article provides a short summary of current systemic ACC treatment and provides a comprehensive overview of new therapeutic approaches that have been investigated in the past years, including drugs targeting the IGF pathway, tyrosine kinase inhibitors, radionuclide treatment, and immunotherapy. The results of most of these trials were disappointing and we will discuss possible reasons why these drugs failed (e.g. drug interactions with mitotane, disease heterogeneity with exceptional responses in very few patients, and resistance mechanisms to immunotherapy). We then will present potential new drug targets that have emerged from many molecular studies (e.g. wnt/β-catenin, cyclin-dependent kinases, PARP1) that may be the foundation of next-generation therapies of ACC.
Corticotropin-independent Cushing's syndrome occurs with adrenocortical tumors or hyperplasia. The authors report that germline duplications of
PRKACA
lead to bilateral adrenal hyperplasia, whereas ...somatic mutations lead to unilateral cortisol-producing adrenal adenomas.
Endogenous hypercortisolism, referred to as Cushing's syndrome, is associated with substantial morbidity and mortality.
1
When Cushing's syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae.
2
Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production. Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age.
3
Whereas only a subset of these tumors is associated with overt Cushing's syndrome, some degree of cortisol excess is present, . . .
Abstract
Context
Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce.
Objective
To assess the ...efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors.
Design and Setting
Multicenter cohort study of three German referral centers.
Patients
One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy.
Outcome Measures
Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression.
Results
Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels >14 mg/L had significantly longer OS (HR 0.42; P = 0.003).
Conclusions
At 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs.
We evaluated the efficacy of mitotane monotherapy in 127 patients with advanced ACC in a contemporary setting and identified factors that predict response to mitotane.
Summary Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R ...and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00924989. Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days 95% CI 256–507 vs 356 days 249–556; hazard ratio 0·94 95% CI 0·61–1·44; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three 3% patients vs no patients in the placebo group), nausea (two 2% vs none), and hyperglycaemia (two 2% vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. Funding Astellas.
Background:
Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently.
Objective:
The aim of this study was to identify markers with prognostic value for ...patients in this clinical setting.
Design, Setting, and Participants:
From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I–III were identified. As an independent validation cohort, 250 patients from three European countries were included.
Outcome Measurements and Statistical Analysis:
Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS).
Results:
Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio HR for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10–19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone.
Conclusion:
This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.
Approach to the Patient With Adrenal Hemorrhage Elhassan, Yasir S; Ronchi, Cristina L; Wijewickrama, Piyumi ...
The journal of clinical endocrinology and metabolism,
04/2023, Letnik:
108, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract
Adrenal hemorrhage is an uncommon, underrecognized condition that can be encountered in several clinical contexts. Diagnosing adrenal hemorrhage is challenging due to its nonspecific ...clinical features. Therefore, it remains a diagnosis that is made serendipitously on imaging of acutely unwell patients rather than with prospective clinical suspicion. Adrenal hemorrhage can follow abdominal trauma or appear on a background of predisposing conditions such as adrenal tumors, sepsis, or coagulopathy. Adrenal hemorrhage is also increasingly reported in patients with COVID-19 infection and in the context of vaccine-induced immune thrombocytopenia and thrombosis. Unexplained abdominal pain with hemodynamic instability in a patient with a predisposing condition should alert the physician to the possibility of adrenal hemorrhage. Bilateral adrenal hemorrhage can lead to adrenal insufficiency and potentially fatal adrenal crisis without timely recognition and treatment. In this article, we highlight the clinical circumstances that are associated with higher risk of adrenal hemorrhage, encouraging clinicians to prospectively consider the diagnosis, and we share a diagnostic and management strategy.
Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph ...adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and ...steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.
Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) ...were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in benign were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted "IGF2" locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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