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Cancer Research Communications Mar 2024Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed...
UNLABELLED
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.
Topics: Humans; Animals; Mice; Adrenocortical Carcinoma; Mitotane; Heterografts; Ubiquitin-Activating Enzymes; Adrenal Cortex Neoplasms; Cell Line, Tumor; Antineoplastic Agents; Organoids; Proto-Oncogene Proteins c-bcl-2; Nuclear Proteins; Bridged Bicyclo Compounds, Heterocyclic; Sulfides; Sulfonamides; Pyrimidines; Pyrazoles
PubMed: 38451783
DOI: 10.1158/2767-9764.CRC-24-0085 -
World Journal of Gastrointestinal... Feb 2024B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At...
BACKGROUND
B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear.
AIM
To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC.
METHODS
The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells.
RESULTS
In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells.
CONCLUSION
B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.
PubMed: 38425404
DOI: 10.4251/wjgo.v16.i2.475 -
Microbiology Spectrum Apr 2024A landmark study by Poore et al. showed intratumor bacteria (ITBs) playing a critical role in most cancers by reproduction of The Cancer Genome Atlas (TCGA)...
UNLABELLED
A landmark study by Poore et al. showed intratumor bacteria (ITBs) playing a critical role in most cancers by reproduction of The Cancer Genome Atlas (TCGA) transcriptome data. A recent study by Salzberg et al. argued that ITBs, being overstated as a methodology by Poore et al., were problematic. We previously reported that ITBs were prognostic in adrenocortical carcinoma (ACC), a highly aggressive rare disease using data by Poore et al., and here, we aimed to answer whether ITBs truly existed and were prognostic in ACC. ACC samples from our institutes underwent 16S rRNA sequencing [adrenocortical carcinoma blocks from Huashan Hospital and China Medical University (HS) cohort]. The ITB profile was compared to TCGA data processed by Poore et al. (TCGA-P) and TCGA data processed by Salzberg et al. (TCGA-S), respectively. The primary outcome was overall survival (OS). A total of 26 ACC cases (HS cohort) and 10 paraffin controls were sequenced. The TCGA cohort encompassed 77 cases. Two and four amid the top 10 abundant genera in HS cohort were not detected in TCGA-P and TCGA-S, respectively. Neither was alpha or beta diversity associated with survival nor could ACC be subtyped by ITB signature in the HS cohort. Notably, a five-genera ITB risk score (, , , , and ) for OS trained in the HS cohort was validated in both TCGA-P and TCGA-S cohorts and was independently prognostic. Whereas ITB signature on the whole may not be associated with ACC subtypes, certain ITB features are associated with prognosis, and a risk score could be generated and validated externally.
IMPORTANCE
In this report, we looked at the role of ITBs in ACC in patients with different race and sequencing platforms. We found a five-genera ITB risk score consistently predicted overall survival in all cohorts. We conclude that certain ITB features are universally pathogenic to ACC.
Topics: Humans; Adrenocortical Carcinoma; Prognosis; Adrenal Cortex Neoplasms; RNA, Ribosomal, 16S; Risk Factors; Bacteria
PubMed: 38421176
DOI: 10.1128/spectrum.03727-23 -
Case Reports in Oncology 2024Adrenocortical carcinoma (ACC) is an extremely rare and aggressive tumor, and its clinical characteristics are poorly defined because of its rarity.
Adrenocortical Carcinoma with a Renal Vein Thrombus Extending to the Inferior Vena Cava Successfully Resected with the Left Kidney and Distal Pancreatectomy: A Case Report.
INTRODUCTION
Adrenocortical carcinoma (ACC) is an extremely rare and aggressive tumor, and its clinical characteristics are poorly defined because of its rarity.
CASE PRESENTATION
We report a 64-year-old man who presented with upper abdominal pain and weight loss. Computed tomography revealed a 15 cm left adrenal tumor compressing the pancreas ventrally and a tumor thrombus in the inferior vena cava (IVC) originating from the left renal vein. Positron emission tomography-computed tomography revealed F-fluorodeoxyglucose uptake only in the tumor and tumor thrombus, and radical surgery was planned. Intraoperatively, the tumor was visible on the posterior stomach wall, and the tumor adhered to the pancreas and left kidney. We excised the tumor with part of the pancreas and the left kidney and excised the thrombus from the IVC after clamping. The final diagnosis was ACC, tumor-node-metastasis grade T3N1M0, stage III. The patient received chemotherapy and radiotherapy postoperatively; however, two liver metastases appeared 6 months after surgery. Chemotherapy was continued, and no exacerbation of the liver metastases was observed. Posterior segment resection of the liver was performed 16 months after the initial surgery.
CONCLUSION
This report of a rare case of ACC involving the pancreas with tumor thrombus extension to the IVC stresses that this combination of conditions does not preclude radical surgery. However, more data are needed regarding chemotherapy and radiotherapy, as well as relapse treatment, and further research on ACC is essential for a favorable prognosis.
PubMed: 38415268
DOI: 10.1159/000535367 -
Cancer Control : Journal of the Moffitt... 2024This study sought to explore the clinical value of matrix metalloproteinases 12 () in multiple cancers, including lung adenocarcinoma (LUAD).
OBJECTIVE
This study sought to explore the clinical value of matrix metalloproteinases 12 () in multiple cancers, including lung adenocarcinoma (LUAD).
METHODS
Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of . The expression of between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly.
RESULTS
mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) ( < .05). expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, < .05). The elevated expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, < .05). Some pan-cancer findings regarding are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels ( < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease ( < .05).
CONCLUSIONS
is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.
Topics: Humans; Female; Matrix Metalloproteinase 12; Adenocarcinoma; Prognosis; Retrospective Studies; Colonic Neoplasms; Adenocarcinoma of Lung; Breast Neoplasms; RNA, Messenger; Lung Neoplasms
PubMed: 38410859
DOI: 10.1177/10732748241235468 -
Cureus Jan 2024Adrenocortical carcinoma (ACC) is a very rare malignancy with a poor prognosis. It is predominantly noted in the fourth to fifth decades of life and is more common in...
Adrenocortical carcinoma (ACC) is a very rare malignancy with a poor prognosis. It is predominantly noted in the fourth to fifth decades of life and is more common in White females. ACC is most commonly detected as an incidental finding but may have other presentations, such as rapid-onset Cushing's syndrome or pulmonary embolism. In the current case, ACC was incidentally observed in a 24-year-old female during imaging, and the patient later developed a pulmonary embolism. Lab investigations were suggestive of hypercortisolism along with hyperandrogenism. Following preoperative treatment with beta-blockers, metyrapone, and therapeutic anticoagulation, she underwent left radical nephrectomy with left open adrenalectomy and inferior vena cava (IVC) resection and reconstruction. Surgery was uncomplicated, and she was discharged with plans for outpatient adjuvant chemotherapy. This case highlights the fact that a seemingly unprovoked pulmonary embolism may point to the possibility of an underlying occult malignancy and undetected ACC should be included in the differential diagnosis of such cases.
PubMed: 38406134
DOI: 10.7759/cureus.52929 -
Cancers Feb 2024International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation...
International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE ( < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.
PubMed: 38398097
DOI: 10.3390/cancers16040706 -
Cancers Feb 2024Adrenocortical carcinoma (ACC) commonly metastasizes to the lungs, and pulmonary metastasectomy (PM) is utilized due to limited systemic options.
BACKGROUND
Adrenocortical carcinoma (ACC) commonly metastasizes to the lungs, and pulmonary metastasectomy (PM) is utilized due to limited systemic options.
METHODS
All ACC patients with initially only lung metastases (LM) from a single institution constituted this observational case series. Kaplan-Meier and Cox proportional hazard analyses evaluated the association with potential prognostic factors and outcomes. Overall survival (OS) was calculated from the date of the PM or, in those patients who did not undergo surgery, from the development of LM.
RESULTS
A total of 75 ACC patients over a 45-year period met the criteria; 52 underwent PM, and 23 did not. The patients undergoing PM had a median OS of 3.1 years (95% CI: 2.4, 4.7 years) with the 5- and 10-year OS being 35.5% and 32.8%, respectively. The total resected LM did not impact the OS nor the DFS. The patients who developed LM after 11 months from the initial ACC resection had an improved OS (4.2 years; 95% CI: 3.2, NR; = 0.0096) compared to those developing metastases earlier (2.4 years; 95% CI: 1.6, 2.8). Patients who underwent PM within 11 months of adrenalectomy demonstrated a reduced OS (2.2 years; 95% CI: 1.0, 2.7) compared to those after 11 months (3.6 years, 95% CI: 2.6, NR; = 0.0045). PM may provide benefit to those patients with LM at presentation (HR: 0.5; = 0.2827), with the time to first PM as a time-varying covariate.
CONCLUSIONS
PM appears to have a role in ACC patients. The number of nodules should not be an exclusion factor. Patients developing LM within a year of primary tumor resection may benefit from waiting before further surgeries, which may provide additional insight into who may benefit from PM.
PubMed: 38398093
DOI: 10.3390/cancers16040702 -
Indian Journal of Nuclear Medicine :... 2023Paraneoplastic neurologic syndromes (PNSs) are rare in pediatrics and are understood to be consequences of cross-reactivity against various neuroendocrine antigens...
Paraneoplastic neurologic syndromes (PNSs) are rare in pediatrics and are understood to be consequences of cross-reactivity against various neuroendocrine antigens expressed on cancer cells. Here, we report a case of autoimmune encephalitis, a type of PNS associated with a case of adrenocortical carcinoma (ACC), that had a clinical response to immunosuppressive therapy. ACC is a rare tumor with controversial tissue of origin but expresses various neuroendocrine antigens that could be the possible mechanism for this rare yet interesting association.
PubMed: 38390536
DOI: 10.4103/ijnm.ijnm_26_23 -
Journal of the Endocrine Society Feb 2024Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on...
Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.
PubMed: 38384443
DOI: 10.1210/jendso/bvad170