Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. FINDINGS: Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. INTERPRETATION: Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. FUNDING: Exelixis.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma.

PURPOSE OF REVIEW: To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. RECENT FINDINGS: Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.

FSCN1 as a new druggable target in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for ß-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor-1 (SF-1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC.

Two-dimensional chromatography for enantiomeric analysis of mitotane and its metabolite o,p'-DDA in patients with adrenocortical carcinoma indicates enantioselective metabolism.

Mitotane is a chiral drug used to treat adrenocortical carcinoma, being metabolized to the o,p'-dichlorodiphenyl acetic acid (o,p'-DDA), also a chiral compound. Despite of its therapeutic significance, the overall ratios and enantiomers have not been known. In this study, we analyzed the enantiomers of mitotane and o,p'-DDA in the plasma of patients by a newly developed chiral-phase method employed in two-dimensional chromatography. Important differences were observed in the ratio of (S)/(R)-mitotane, which varied substantially from 1:1.2 to 1:10 whereas the (S)/(R)-o,p'-DDA ratio was relatively conserved, at approximately 2:1. These findings provide evidence for the enantioselective metabolism and provide a method for further analyses of mitotane and metabolites, which can explain the variation in the therapeutic response.

Molecular genotyping of adrenocortical carcinoma: a systematic analysis of published literature 2019-2021.

PURPOSE OF REVIEW: comprehensive molecular characterization of adrenocortical carcinoma (ACC) through next-generation sequencing and bioinformatics analyses is expanding the number of targets with potential prognostic and therapeutic value. We performed a critical review of recent published literature on genotyping of ACC. RECENT FINDINGS: 423 studies were published between 2019 and 2021. After manual curation we summarized selected evidence in two thematic areas: germline deoxyribonucleic acid (DNA) variations, genomic alterations and prognosis. SUMMARY: the evolving genomic landscape of ACC requires target validation in terms of prognostic and predictive value within scientific consortia. Although the existing multiple driver genes are difficult targets in the perspective of precision oncology, alterations in DNA damage repair genes or in promoter hypermethylation could open new venues for repurposing of existing drugs in ACC.

CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial-mesenchymal transition, G2/M phase transition, and PANoptosis.

BACKGROUND: Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. METHODS: By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. RESULTS: Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. CONCLUSIONS: CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.

The role of molecular profiling in adrenocortical carcinoma.

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.

Long Non-Coding RNA H19 Expression Correlates with Autophagy Process in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is characterized by poor prognosis and high mortality. The suppression of the long-non-coding RNA H19, counterbalanced by IGF2 over-expression, leads to down-regulation of the autophagy markers, high proliferation rate and metastatic potential in patients affected by ACC. The administration of the deacetylase inhibitors (DACi) panobinostat, trichostatin A (TSA) and SAHA affected the cell viability of H295R monolayer and spheroids and induced the over-expression of H19 and autophagy transcripts. H19 knock down in H295R cells was not able to modulate the expression level of autophagy transcripts. Instead, H19 knock down was able to impede the ability of DACi to modulate the protein level of the autophagy markers. Furthermore, the administration of higher concentration of DACi was able to down-regulate the protein level of Beclin1 and p62 and to induce the conversion of LC3B-I into the active LC3B-II form, thus confirming an active autophagic process. Neither the active protein level nor the activity of caspases 8 and 3 was prompted by the DACi, thus excluding the involvement of the executioners of apoptosis in H295R decay. The DACi restore H19, the autophagy markers and trigger cell death in ACC cells. The re-activation of autophagy would represent a novel strategy for the treatment of patients affected by this severe malignancy.

Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated. METHODS: Using somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the 'maftools' package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB. RESULTS: TMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB. CONCLUSIONS: TMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients.

Successful administration of mitotane (O, p'-DDD) in pediatric oncology.

INTRODUCTION: Mitotane (o, p'-DDD) is a molecule that was developed many years ago for adrenal cortical carcinoma, but no suitable pediatric dosage form is available for administration to young children. Mitotane requires therapeutic drug monitoring because of its long half-life and difficulty in stabilizing plasma concentrations. Furthermore, Mitotane is a highly lipophilic drug that requires concurrent lipid administration. CASE REPORT: We present the case of a 3-year-old girl who was diagnosed with metastatic adrenal cortical carcinoma. Due to the difficulty in administering the tablets and the non-stabilized mitotane dosages, a nasogastric tube was inserted. An administration protocol based on dispersing the tablets in whole milk was established by the pharmacy team. This led to the stabilization of the disease for at least 1.5 years. MANAGEMENT AND OUTCOME: Mitotanemia is difficult to stabilize even when treatment is administered orally. To maintain biological efficacy, we propose an easily reproducible protocol. The efficacy was stabilized at a dosage of 1500 mg per day. Mitotanemia fluctuated between 14 mg/mL, and 20 mg/mL. The implementation of this protocol prevented treatment discontinuation. DISCUSSION: The administration of narrow therapeutic range drugs via a nasogastric tube is a challenge for healthcare teams, particularly in pediatric patients. Based on the findings of this clinical case, clinicians should consider future use of this protocol. The use of whole milk as a vehicle for mitotane is a simple, effective, and reproducible method to administer the drug to pediatric patients and can be used for other similar cases.

[A Case Report of a Patient with Metastatic Adrenocortical Carcinoma who Received the Combination Etoposide, Doxorubicin, Cisplatin, and Mitotane Therapy and Achieved Remission].

A 40-year-old Japanese female was referred to our institution with a high serum lactate dehydrogenase level. Computed tomography (CT) showed a large right adrenal tumor, 14 cm in size without distant metastases. The patient was clinically diagnosed with T2N0M0 adrenocortical carcinoma and underwent right adrenalectomy. The pathological diagnosis was adrenocortical carcinoma with negative surgical margin. The patient was administered mitotane for 2 years as adjuvant therapy. Subsequently, CT revealed asynchronous multiple metastases, including liver, lung, left kidney, and right acetabulum. The patient received 15 courses of EDP (a combination of etoposide, doxorubicin, and cisplatin) plus mitotane therapy, and had stable disease without new lesions.

Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study.

BACKGROUND: After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. METHODS: In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. RESULTS: Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). CONCLUSIONS: Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

HOX genes promote cell proliferation and are potential therapeutic targets in adrenocortical tumours.

BACKGROUND: Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment. METHODS: We used transgenic mouse models to determine the role of Hoxb9 in adrenal tumour development. Patient transcriptomic data was analysed for the expression of HOX genes and their association with disease. Drug response studies on various adrenocortical models were done to establish novel therapeutic options. RESULTS: Our human ACC dataset analyses showed high expression of HOXB9, and other HOX factors, are associated with poorer prognosis. Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours. This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne1. Adrenal tumour cells were found to be dependent on HOX function for survival and were sensitive to a specific peptide inhibitor. CONCLUSIONS: These studies show Hoxb9 can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC.

Adrenocortical carcinoma: current treatment options.

PURPOSE OF REVIEW: In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). RECENT FINDINGS: Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide, doxorubicin, cisplatin with mitotane (EDP-M), gemcitabine and metronomic capecitabine, or the less used streptozotocin, represent a second-line chemotherapy option. Temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. SUMMARY: ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.

Metabolic and hormonal side effects of mitotane treatment for adrenocortical carcinoma: A retrospective study in 50 Danish patients.

OBJECTIVE: Mitotane is used in the treatment of adrenocortical carcinoma (ACC). Metabolic and hormonal side effects of mitotane, the effect of subsequent treatment with statins and hormones and the effects of discontinuation of mitotane were assessed. PATIENTS AND METHODS: Fifty patients were included. Lipid profiles, thyroid hormones, sex hormones and adrenal function from first year of mitotane treatment and after cessation were evaluated. RESULTS: After 6 months of mitotane treatment total cholesterol increased from (median) 5.1 (IQR 4.3 to 5.8) to 7.4 (6.2-9.0) mmol/L, p < .001. LDL, HDL and triglyceride also increased, all p ≤ .03. Three months of treatment with statins decreased total and LDL-cholesterol, and cessation of mitotane led to further reduction in lipids. Plasma thyroxine decreased from 90 (78-111) to 57 (47-63) nmol/L and free thyroxine from 16.0 (13.0-18.3) to 11.7 (10.5-12.6) pmol/L on mitotane, both p < .001, while TSH remained unchanged. Treatment with thyroxin significantly increased plasma thyroxine and free thyroxine and decreased TSH. Cessation of mitotane increased total T4 (p < .001). Mitotane increased plasma SHBG from 36 (22-51) to 189 (85-259) nmol/L and LH from 4.6 (1.6-8.1) to 20.0 (10.0-34.9) IU/L, both p < .001. In males the changes were accompanied by an increase in testosterone from 9.8 (7.2-14.5) to 27.0 (15.3-34.8) nmol/L, p < .03. Fifteen of 24 tested patients regained normal adrenal function 6 (3-16) months after cessation of mitotane. CONCLUSIONS: Mitotane treatment exerts multiple severe side effects involving both the metabolic and endocrine systems that may require treatment, but the effect appears to be partially reversible.

Novel CYP11B-ligand [123/131I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience.

PURPOSE: Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [123/131I]iodometomidate ([123/131I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. METHODS: Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [123I]IMTO and the most promising compound (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([123I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [131I]IMAZA in one of these patients was performed. RESULTS: We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [131I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. CONCLUSION: We developed the new radiopharmaceutical [123/131I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.

Advanced Adrenocortical Carcinoma: Current Perspectives on Medical Treatment.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I and II tumors, surgery is a curative option, but even in these cases recurrence is frequent. Practical guidelines advocate a combination of mitotane with etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic adrenocortical carcinoma. However, this scheme presents limited efficacy and high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The expectation of their applicability on advanced adrenocortical carcinoma is high but the role of these new therapies persists unclear. This article provides a short summary of last years' findings targeting outcomes, limitations, and adverse effects of these new therapeutic approaches. The results of recent trials and case series pointed pembrolizumab as the most promising drug among these new therapies. It is the most often used ICI and the one presenting the best results with less related adverse effects when in comparison to the standard treatment with mitotane. Hereafter, the identification of specific molecular biomarkers or immune profiles associated with ICI or mTKI good response will facilitate the selection of candidates for these therapies. So far, microsatellite instability and Lynch Syndrome related germline mutations are suggested as predictive biomarkers of good response. Contrarywise, cortisol secretion has been associated with more aggressive ACC tumors and potentially poor responses to immunotherapy.

Predicitve Value of FDG Uptake in the Remaining Adrenal Gland Following Adrenalectomy for Adrenocortical Cancer.

Following initial surgery, patients with adrenocortical carcinoma (ACC) are commonly treated with the adrenolytic substance mitotane in an adjuvant or therapeutic setting. Treatment responses, however, are variable. The objective of the study was to investigate a possible correlation between FDG-PET activity of the remaining adrenal gland and therapeutic response of mitotane treatment. This is a retrospective study enrolling patients from two German centers with operated ACC and minimal information on PET-CT scanning. Eighty-two ACC patients after adrenalectomy were included (66 treated with mitotane and 16 without medical therapy). FDG uptake of the contralateral adrenal gland, liver and mediastinum was analyzed from a total of 291 PET/CT scans (median 4 scans per patient) and correlated with clinical annotations including overall and recurrence free survival. The majority of patients (81%) displayed a temporary increase in adrenal FDG uptake within the first 18 months following surgery, which was not associated with a morphological correlate for potential malignancy. This increase was mainly present in patients treated with mitotane (51/61, 84%) but less frequent in the control group (4/7, 57%). No direct correlation with mitotane plasma levels were evident. Patients following R0 resection with high adrenal uptake showed a tendency towards better clinical outcome without reaching a significance value (HR 1.41; CI 0.42-4.75; p=0.059). FDG update of the contralateral adrenal gland may not be misinterpreted as sign of malignancy but might be rather associated with a trend towards better clinical outcome.

Emerging drugs for the treatment of adrenocortical carcinoma.

Introduction: Adrenocortical cancer (ACC) is a rare and aggressive disease with a median survival of 14-17 months and 5-year survival of around 20% for advanced disease. Emerging evidence of sub-groups of ACC with specific molecular drivers indicate ACC may be amenable to inhibition of receptor tyrosine kinases involved in growth and angiogenic signaling. A significant subset of patients may also be responsive to immune strategies.Areas covered: This review outlines approaches of targeting upregulated growth pathways including Insulin-like Growth Factor, Vascular Endothelial Growth Factor, Fibroblast Growth Factor and Epidermal Growth Factor Receptor in ACC. Data of immune checkpoint blockade with nivolumab, ipilimumab, pembrolizumab and avelumab is explored in detail. Genomic studies indicate that up to 40% of ACC are driven by dysregulated WNT and glucocorticoid signaling, special focus is placed on emerging drugs in these pathways.Expert opinion: Progress in the treatment of ACC has faced challenges stemming from the rarity of the disease. Given recent advances in the understanding of the molecular pathogenesis of ACC, a window of opportunity has now opened to make significant progress in developing therapeutic options that target key pathways such as excessive glucocorticoid signaling, WNT signaling, cell cycle and immune checkpoints.