RESUMO
Adrenocortical carcinoma (ACC) is an orphan cancer with 35% five-year survival that has been unchanged for last five decades. Patients often present with severe hypercortisolism or with mass effects. The only Food and Drug Administration (FDA)-approved drug for ACC is mitotane, an insecticide derivative, which provides only limited additional months of survival, but with toxicities. Little progress in the field has occurred due to a lack of preclinical models. We recently developed new human ACC in vitro and in vivo research models. We produced the first two new ACC cell lines for the field, CU-ACC1 and CU-ACC2, which we have distributed for global collaborations. In addition, we developed 10 ACC patient-derived xenograft (PDX) and two humanized ACC-PDX models to test new therapeutics and examine the mechanism of mitotane action in combination with immunotherapy. These new preclinical models allow us to identify novel targets and test new therapeutics for our patients with adrenal cancer.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Mitotano , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/terapia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/terapia , Animais , Mitotano/uso terapêutico , Doenças Raras/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos , Antineoplásicos Hormonais/uso terapêuticoRESUMO
INTRODUCTION: Mitotane (o,p'-DDD) is the drug of choice for Adrenocortical Carcinomas (ACC) and its measurement in plasma is essential to control drug administration. OBJECTIVE: To develop and validate a simple, reliable and straightforward method for mitotane determination in plasma samples. METHOD: Drug-free plasma samples were collected in potassium-ethylenediamine tetraacetate (K-EDTA) tubes and spiked with 1.0, 2.5, 10.0, 25.0 and 50.0 µg/mL of mitotane (DDD). The p,p'-DDD was used as an Internal Standard (IS) and was added at 25.0 µg/mL concentration to all samples, standards and controls. Samples were submitted to protein precipitation with acetonitrile and then centrifuged. 50 uL of the supernatant was injected into an HPLC system coupled to a Diode Array Detector (DAD). DDD and IS were detected at 230 nm in a 12 min isocratic mode with a solvent mixture of 60 % acetonitrile and 40 % formic acid in water with 0.1 % pump mixed, at 0.6 mL/min flow rate, in a reversed-phase (C18) chromatographic column kept at 28°C. The sensitivity, selectivity, precision, presence of carry-over, recovery and matrix-effect, linearity, and method accuracy were evaluated. RESULTS: The present study's method resulted in a symmetrical peak shape and good baseline resolution for DDD (mitotane) and 4,4'-DDD (internal standard) with retention times of 6.0 min, 6.4 mim, respectively, with resolutions higher than 1.0. Endogenous plasma compounds did not interfere with the evaluated peaks when blank plasma and spiked plasma with standards were compared. Linearity was assessed over the range of 1.00-50.00 µg/mL for mitotane (R2 > 0.9987 and a 97.80 %â105.50 % of extraction efficiency). Analytical sensitivity was 0.98 µg/mL. Functional sensitivity (LOQ) was 1.00 µg/L, intra-assay and inter-assay coefficient of variations were less than 9.98 %, and carry-over was not observed for this method. Recovery ranged from 98.00 % to 117.00 %, linearity ranged from 95.00 % to 119.00 %, and high accuracy of 89.40 % to 105.90 % with no matrix effects or interference was observed for mitotane measurements. Patients' sample results were compared with previous measurements by the GC-MS method with a high correlation (r = 0.88 and bias = -10.20 %). CONCLUSION: DDD determination in plasma samples by the developed and validated method is simple, robust, efficient, and sensitive for therapeutic drug monitoring and dose management to achieve a therapeutic index of mitotane in patients with adrenocortical cancer.
Assuntos
Antineoplásicos Hormonais , Mitotano , Mitotano/sangue , Humanos , Reprodutibilidade dos Testes , Antineoplásicos Hormonais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/sangue , Limite de Detecção , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Sensibilidade e Especificidade , CalibragemRESUMO
INTRODUCTION: Adrenocortical carcinoma (ACC) is rare and an aggressive tumour. Mitotane is the mainstay adjuvant drug in treating ACC. The study aimed to describe patients diagnosed with precocious puberty (PP) and other endocrinological complications during mitotane therapy. MATERIAL AND METHODS: This retrospective study enrolled 4 patients with ACC treated with mitotane therapy complicated by PP. We analysed clinical manifestations, radiological, histopathological findings, and hormonal results. RESULTS: The median age at the diagnosis of ACC was 1.5 years. All patients were treated with surgery and mitotane, accompanied by chemotherapy regimens in 2 cases. The median time from surgery to the initiation of mitotane therapy was 26 days. During mitotane treatment, PP was confirmed based on symptoms, and hormonal and imaging tests. In one patient, incomplete peripheral PP was followed by central PP. The median time from the therapy initiation to the first manifestations of PP was 4 months. Additionally, due to mitotane-induced adrenal insufficiency, patients required a supraphysiological dose of hydrocortisone (HC), and in one patient, mineralocorticoid (MC) replacement with fludrocortisone was necessary. In 2 patients, hypothyroidism was diagnosed. All patients presented neurological symptoms of varying expression, which were more severe in younger children. CONCLUSIONS: The side effects of using mitotane should be recognized quickly and adequately treated. In prepubertal children, PP could be a complication of therapy. The need to use supraphysiological doses of HC, sometimes with MC, should be highlighted. Some patients require levothyroxine replacement therapy. The neurotoxicity of mitotane is a significant clinical problem.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos Hormonais , Mitotano , Puberdade Precoce , Humanos , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/induzido quimicamente , Mitotano/uso terapêutico , Mitotano/efeitos adversos , Feminino , Carcinoma Adrenocortical/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Estudos Retrospectivos , Masculino , Pré-Escolar , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Lactente , Criança , Doenças do Sistema Endócrino/induzido quimicamenteRESUMO
OPINION STATEMENT: Adrenocortical cancer (ACC) is a rare and aggressive disease. Surgery has traditionally been the primary treatment for locally advanced disease with ongoing controversy around the optimal neoadjuvant and adjuvant treatment options. Unfortunately, local recurrence and the eventual development of metastatic disease is common and five-year survival rates are poor. While many trials have evaluated novel systemic agents to treat advanced adrenocortical cancer, only a few drugs have demonstrated any response at all. To date, only one drug, mitotane, is approved in the US for ACC and no regimen has clearly shown an increase in overall survival. In advanced metastatic or unresectable disease, data supports the first line regimen of EDP chemotherapy + mitotane as the primary treatment modality. In the second line, while data is limited, we would recommend consideration of immunotherapy using a PD(L)1 agent combined with a TKI/VEGF inhibitor or combination immunotherapy with PD1/CTLA-4 drugs. In all cases, we always prefer a clinical trial as available. This article reviews data from multiple studies evaluating novel systemic agents against ACC and discusses current systemic therapy combinations and ongoing clinical trials.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Protocolos de Quimioterapia Combinada Antineoplásica , Gerenciamento Clínico , Estadiamento de Neoplasias , Humanos , Carcinoma Adrenocortical/terapia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/diagnóstico , Neoplasias do Córtex Suprarrenal/terapia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Terapia de Alvo Molecular , Resultado do Tratamento , Ensaios Clínicos como AssuntoRESUMO
OBJECTIVES: Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors. DESIGN/SETTING: A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites. PARTICIPANTS: 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women. INTERVENTIONS: Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request. MAIN OUTCOME MEASURES: The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%. RESULTS: The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events. CONCLUSIONS: Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months. TRIAL REGISTRATION NUMBER: NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).
Assuntos
Carcinoma Adrenocortical , Antígeno CTLA-4 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Idoso , Antígeno CTLA-4/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Ipilimumab/uso terapêutico , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Estudos Prospectivos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosAssuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos Hormonais , Mitotano , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Feminino , Criança , Masculino , Adolescente , Terapia de Reposição HormonalRESUMO
Background: Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective: We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods: In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results: PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion: ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos Hormonais , Mitotano , Testes Farmacogenômicos , Humanos , Mitotano/uso terapêutico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/metabolismo , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Feminino , Masculino , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Pessoa de Meia-Idade , Adulto , Idoso , FarmacogenéticaAssuntos
Neoplasias do Córtex Suprarrenal , Anilidas , Mitotano , Piridinas , Humanos , Piridinas/uso terapêutico , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Anilidas/uso terapêutico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Resultado do TratamentoRESUMO
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.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Anilidas , Piridinas , Humanos , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/farmacocinética , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/mortalidade , Adulto , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/mortalidade , Idoso , Estudos Prospectivos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare yet highly malignant tumor associated with significant morbidity and mortality. This study aims to delineate the clinical features, survival patterns, and treatment modalities of ACC, providing insights into the disease's prognosis. MATERIALS AND METHODS: A retrospective analysis of 157 ACC patients was performed to assess treatment methodologies, demographic patterns, pathological and clinical attributes, and laboratory results. The data were extracted from the hospital's database. Survival analyses were conducted using the Kaplan-Meier method, with univariate and multivariate analyses being performed through the log-rank test and Cox regression analyses. RESULTS: The median age was 45, and 89.4% had symptoms at the time of diagnosis. The median tumor size was 12 cm. A total of 117 (79.6%) patients underwent surgery. A positive surgical border was detected in 26 (24.1%) patients. Adjuvant therapy was administered to 44.4% of patients. The median overall survival for the entire cohort was 44.3 months. Median OS was found to be 87.3 months (95% confidence interval [CI] 74.4-100.2) in stage 2, 25.8 (95% CI 6.5-45.1) months in stage 3, and 13.3 (95% CI 7.0-19.6) months in stage 4 disease. Cox regression analysis identified age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as significant factors associated with survival in patients with nonmetastatic disease. In metastatic disease, only patients who underwent surgery exhibited significantly improved overall survival in univariate analyses. CONCLUSION: ACC is an uncommon tumor with a generally poor prognosis. Understanding the defining prognostic factors in both localized and metastatic diseases is vital. This study underscores age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as key prognostic determinants for localized disease, offering critical insights into the complexities of ACC management and potential avenues for targeted therapeutic interventions.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias do Córtex Suprarrenal/terapia , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/cirurgia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/terapia , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Turquia/epidemiologia , Prognóstico , Adulto Jovem , Análise de Sobrevida , Adolescente , Estimativa de Kaplan-Meier , Resultado do TratamentoRESUMO
Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos , Compostos Bicíclicos Heterocíclicos com Pontes , Pirazóis , Pirimidinas , Sulfetos , Sulfonamidas , Humanos , Animais , Camundongos , Carcinoma Adrenocortical/tratamento farmacológico , Mitotano , Xenoenxertos , Enzimas Ativadoras de Ubiquitina/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Organoides , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Proteínas Nucleares/uso terapêuticoRESUMO
OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50â mg/kg/d (1500â mg/m²/d) which can be increased up to 4000â mg/m2/d. Blood levels should range between 14 and 20â mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Criança , Mitotano/efeitos adversos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/efeitos adversos , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologiaRESUMO
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.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Fator A de Crescimento do Endotélio Vascular , Imunoterapia , Terapia Combinada , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genéticaRESUMO
Adrenocortical carcinoma (ACC) is a malignant carcinoma with an extremely poor prognosis, and its pathogenesis remains to be understood to date, necessitating further investigation. This study aims to discover biomarkers and potential therapeutic agents for ACC through bioinformatics, enhancing clinical diagnosis and treatment strategies. Differentially expressed genes (DEGs) between ACC and normal adrenal cortex were screened out from the GSE19750 and GSE90713 datasets available in the GEO database. An online Venn diagram tool was utilized to identify the common DEGs between the two datasets. The identified DEGs were subjected to functional assessment, pathway enrichment, and identification of hub genes by performing the protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The differences in the expressions of hub genes between ACC and normal adrenal cortex were validated at the GEPIA2 website, and the association of these genes with the overall patient survival was also assessed. Finally, on the QuartataWeb website, drugs related to the identified hub genes were determined. A total of 114 DEGs, 10 hub genes, and 69 known drugs that could interact with these genes were identified. The GO and KEGG analyses revealed a close association of the identified DEGs with cellular signal transduction. The 10 hub genes identified were overexpressed in ACC, in addition to being significantly associated with adverse prognosis in ACC. Three genes and the associated known drugs were identified as potential targets for ACC treatment.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Mapas de Interação de Proteínas , Humanos , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes , Perfilação da Expressão Gênica , Ontologia Genética , Bases de Dados Genéticas , Biomarcadores Tumorais/genética , PrognósticoRESUMO
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/ß-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/ß-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/ß-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/ß-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/ß-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Estados Unidos , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Via de Sinalização Wnt , beta Catenina , Processos Neoplásicos , Neoplasias do Córtex Suprarrenal/tratamento farmacológicoRESUMO
No disponible
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/etiologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , HormôniosRESUMO
OBJECTIVE: The aim of this study was to determine the correlation between human adrenocortical carcinoma and the proteins involved in tumor angiogenesis, and to evaluate the angiogenic status of adrenocortical carcinoma. METHODS: The expression of signal transducer and activator of transcription 3 and insulin-like growth factor 2 as well as microvessel density was measured in a series of tissue samples from 44 human sporadic adrenocortical tumors by immunohistochemistry. These specimens were classified as adenomas (n = 20) and carcinomas (n = 24) according to the histological criteria defined by Weiss. RESULTS: A total of 19 of 24 (79.17 %) malignant cases showed positive staining for signal transducer and activator of transcription 3 and 4 of 20 (20.00 %) benign cases showed positive, the difference of signal transducer and activator of transcription 3 expression between adrenocortical adenomas and adrenocortical carcinomas was statistically significant (P < 0.001). Similarly, insulin-like growth factor 2 staining was seen in 70.83 % (17/24) of the malignant cases versus 25.00 % (5/20) of the benign, the difference of insulin-like growth factor 2 expression among two groups was statistically significant (P = 0.002). Malignant cases showed higher microvessel density compared to benign tumors (84.70 ± 12.44 vs 21.05 ± 8.07, P < 0.001). Signal transducer and activator of transcription 3 and insulin-like growth factor 2 expression were positively correlated with microvessel density in all specimens (r_s = 0.832, P < 0.001; r_s = 0.703, P = 0.001). CONCLUSIONS: This study has confirmed that adrenocortical carcinoma overexpress signal transducer and activator of transcription 3 and insulin-like growth factor 2; these results suggest that angiogenesis of human adrenocortical carcinoma may be mediated by these proteins and they could represent selective targets for the molecularly targeted treatments of adrenocortical carcinoma (AU)
No disponible
Assuntos
Humanos , Masculino , Feminino , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/radioterapia , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/secundário , Indutores da AngiogêneseRESUMO
O tumor do córtex adrenal (TCA) na infância é raro. Entretanto, no Paraná sua incidência é 15 vezes maior do que a observada em outros países. A mutação germinativa R337H TP53, presente em mais de 95 por cento dos nossos pacientes, provavelmente está relacionada à maior incidência. Cento e vinte e cinco pacientes foram tratados no período de 1966 a 2003. A cirurgia é o único tratamento curativo. Em nossa experiência, tumores no estádio I, ausência de spillage durante a cirurgia e ausência de trombo são parâmetros relacionados à maior sobrevida. Dados preliminares mostram que a associação de etoposídeo, doxorrubicina, cisplatina e mitotano produziu remissão completa do tumor e/ou das metástases em alguns pacientes. Os efeitos colaterais destas drogas são comuns e pode ocorrer insuficiência adrenocortical. As doses de reposição de glicocorticóides e mineralocorticóides devem ser 2 a 3 vezes maiores que as doses fisiológicas.
Assuntos
Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Estadiamento de Neoplasias , Prognóstico , Análise de SobrevidaRESUMO
El carcinoma de la corteza suprarrenal en un tumor poco frecuente, y el diagnóstico por lo regular se realiza cuando la enfermedad se encuentra avanzada debido a la localización de la glándula suprarrenal y a su carácter silencioso, especialmente si es no funcionante. El tratamiento quirúrgico sigue siendo la única posbilidad de curación cuando se encuentra localizado, y el pronóstico generalmente es ominoso. Se presenta la experiencia de cuatro casos, dos de los cuales eran funcionantes. El promedio de edad fue de 44 años, la relación entre varón y mujer de 1:1, y el tiempo promedio de inicio de los síntomas al momento del diagnóstico de 13 meses. Los síntomas y signos principales fueron dolor abdominal, adinamita, tumoración palpable, pérdida de peso e hipertensión arterial. Tres casos presentaban metástasis a distancia al momento del diagnóstico. El tratmiento en tres casos consistió en cirugía radical, y uno recibió quimioterapia con respuesta parcial de corta duración. El peso promedio de las neoplasias fue de 500 g. Tres pacientes fallecieron por la enfermedad dentro del primer año después del diagnóstico