small molecules

2026-09-27 | Antineoplastic effect of block-and-replace strategy for managing hypercortisolism caused by adrenal cortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy frequently associated with cortisol hypersecretion, which confers substantial morbidity and a worse prognosis. In metastatic ACC, rapid control of Cushing syndrome is essential to allow systemic therapy. Although the block-and-replace strategy using steroidogenesis inhibitors is well established for cortisol control, its potential antineoplastic effects have not been previously reported. We describe 2 patients with metastatic ACC and severe Cushing syndrome treated with block-and-replace using osilodrostat or metyrapone. In both, cortisol normalized rapidly and safely, with marked clinical improvement. Unexpectedly, both experienced significant radiological tumor responses before exposure to effective cytotoxic chemotherapy and before therapeutic mitotane plasma concentrations were achieved. These cases suggest that steroidogenesis inhibition within a block-and-replace strategy may exert a direct or indirect antineoplastic effect in ACC. Although causality cannot be established, the temporal association between cortisol blockade and tumor response is compelling and warrants further prospective and translational investigation.

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2026-09-26 | Adrenocortical Carcinoma: An Exceptional Survival Span Across a Tailored Management.

Adrenocortical carcinoma (ACC) represents a very rare (an incidence of 1-2 cases per million) and aggressive malignancy (an overall 5-year survival of 15%). Less than 15-20% of cases involve a single metastatic disease. In this presentation, we documented a most exceptional survival span in a case of ACC, between the female patient's age of 50 and the current age of 66. The subject underwent an open right adrenalectomy three times (at first diagnosis, after recurrence 2 years later, and, most recently, 15 years after the initial diagnosis amid a multi-visceral resection). She initially displayed Cushing syndrome, which remitted post-surgery. While the first pathological report established an adrenocortical adenoma, after relapse, low-grade ACC was confirmed and the first tumor mass was re-assessed as ACC based on a similar pathological profile. Following the second surgery and ACC recognition, she started mitotane therapy for 5 years (which she tolerated well, although she developed primary adrenal insufficiency). During this period, a single metastatic disease was detected at the pulmonary level, and she underwent a successful thoracic surgical resection of a 2.5 cm metastasis in the left inferior lobe (2 years after the second adrenalectomy). After this 5-year course of mitotane, the disease was stable, and a 4-year withdrawal period was followed by a relapse with local adrenal recurrence and growth of several lung nodules. Mitotane was re-started, and the en bloc resection included the right adrenal tumor (of 12 cm), right kidney, three liver segments, retro-hepatic inferior vena cava, and (partial) left renal vein. The reconstruction of the inferior vena cava required a Dacron graft of 12 cm in addition to a synthetic graft, which was placed between the left renal vein and the first graft. During surgery and in the following weeks, she presented with several episodes of acute adrenal insufficiency despite continued prompt replacement. A peak ACTH of 369 (Normal: 7.2-63.3) pg/mL was reached at one point. Renal function remained stable. In the meantime, she continued levothyroxine replacement (50 to 75 µg/day) for mitotane-induced primary hypothyroidism. Postoperative, low-grade ACC was confirmed with a Ki67 of 15%, as previously found. She re-started mitotane in month 3 and completely recovered following 9 months, while an abdominal CT scan confirmed no adrenal remnants. Further close surveillance was mandatory. A particular aspect involves the patient's options (personalized management), as she declined chemotherapy, immunotherapy or radiotherapy at any point in life and delayed the third adrenalectomy during the COVID-19 pandemic and early post-pandemic years. This case highlights an exceptional survival span across two decades with an ailment with a generally poor prognosis. Another particular aspect involves a complex multi-segmental resection, which requires a highly skilled surgical team; only a limited number of cases have previously been published, and, to the best of our knowledge, there is no previous data with respect to a third intervention after 15 years of surviving with ACC.

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2026-09-23 | Efficacy and safety of the CAPTEM regimen in patients with advanced adrenocortical carcinoma.

The purpose of this study was to evaluate the activity and tolerability of the CAPTEM regimen (capecitabine + temozolomide) in patients with advanced, heavily pretreated adrenocortical carcinoma (ACC). A retrospective analysis of 15 patients with metastatic ACC who received at least two lines of systemic therapy, including the CAPTEM regimen, between 2017 and 2022. Clinical characteristics, treatment outcomes (PFS, OS), and toxicities were collected and analysed. Treatment response was assessed using RECIST 1.1 criteria. Survival outcomes were estimated using the Kaplan-Meier method. Among the 15 patients, CAPTEM was administered in the first line therapy in three patients (20%), in the second-line therapy in 53.3%, and in further lines in the remaining cases. The overall disease control rate was 26.6% (all stable disease). Median progression-free survival (PFS) was 3 months (95% CI: 2-6), and median overall survival (OS) was 8 months (95% CI: 6-13). Patients who achieved disease stabilization had improved outcomes (mPFS 9.5 months, mOS 16.5 months) compared to those with progression (mPFS 2 months, mOS 7 months). Treatment-related adverse events occurred in 86.7% of patients, mostly mild; grade 3 toxicity was observed in one patient. The CAPTEM regimen demonstrated modest activity and acceptable toxicity in a heavily pretreated ACC population. While not recommended as a standard treatment, CAPTEM may be considered in select patients, particularly those who achieve disease stabilization. Further prospective studies are needed to better define its role and identify predictive biomarkers.

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2026-09-23 | SPP1+ macrophage-induced CD74+ tumor cells promote adrenocortical carcinoma tumor thrombus via the SPP1/CD44/JAK/STAT signaling.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited treatment options and poor prognosis. Venous tumor thrombus (VTT) is a common complication associated with ACC progression, yet the cellular and molecular mechanisms driving VTT formation remain largely unknown. We performed integrated single-cell RNA sequencing and spatial transcriptomics on paired samples of primary tumor, VTT tail, and VTT head obtained from one ACC patient, followed by in vitro and in vivo functional validation. Our results identified a distinct CD74+ tumor cell subcluster enriched in the VTT head region, and functional assays demonstrated that CD74 significantly enhances ACC cell migration, invasion, and proliferation through activation of the JAK-STAT signaling pathway. Moreover, spatial and ligand-receptor analyses revealed that SPP1+ macrophages closely interact with CD74+ tumor cells via the SPP1-CD44 axis. Functional experiments confirmed that SPP1 secreted by macrophages potentiates CD74-induced JAK-STAT activation and malignant phenotypes. Collectively, we found that CD74+ tumor cells drive ACC progression under the regulation of the SPP1-CD44 signaling pathway in the vicinity of SPP1+ macrophages, thereby revealing a novel mechanistic axis with therapeutic potential.

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2026-09-17 | A decade of survival in recurrent nonfunctioning oncocytic adrenocortical carcinoma in a young Filipina.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with high recurrence risk and limited long-term survival, particularly after metastatic spread. Oncocytic ACC is an uncommon variant that may behave more indolently but can still recur. We report a 30-year-old Filipina with a nonfunctioning oncocytic ACC initially treated with laparoscopic adrenalectomy (R1 margin; Ki-67 10%-20%). She developed local recurrence at 2.5 years, underwent open resection (R1; Ki-67 20%) followed by adjuvant tumor-bed radiotherapy and mitotane, which was discontinued because of intolerance and cost. After a lapse in follow-up, she developed a solitary hepatic metastasis resected with negative margins; planned etoposide, doxorubicin, and cisplatin chemotherapy was stopped after 3 cycles because of ototoxicity. Subsequent surveillance identified a paraumbilical nodal/subcutaneous metastasis resected with negative margins. More than 10 years from diagnosis, she remains under active surveillance without radiographic evidence of active disease. This case highlights the potential for prolonged survival in selected patients with recurrent/metastatic ACC through iterative multidisciplinary decision-making, medical management, and repeat metastasectomy when feasible.

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proteins

2026-07-07 | OncoMimic peptide-based immunotherapy EO2401 induces shared T cell clusters in patients with adrenal cancer.

Patients with advanced malignant adrenal tumors face poor prognoses with limited treatment options. Emerging data suggest that these rare tumors exhibit immunogenicity, potentially benefiting from intensified immunotherapy. The SPENCER trial (NCT04187404) evaluates EO2401, an off-the-shelf in vivo peptide immunotherapy containing three synthetic HLA-A*02 restricted-peptides called OncoMimic and derived from human gut commensals that exhibit molecular mimicry to tumor-associated antigens (BIRC5, FOXM1, IL13RA2) combined with nivolumab in patients with locally advanced or metastatic adrenocortical carcinoma (ACC) or malignant pheochromocytoma/ paraganglioma (PPGL). We performed T cell receptor (TCR) repertoire sequencing to profile the TCR architecture in ACC and characterize vaccination imprints. Here we show that ACC patients are characterized by a restricted peripheral T cell richness. EO2401 does not expand highly shared TCR clones across patients but diversifies pre-existing T cell clusters. These clusters are not converging on known neoantigen-specific TCRs but exhibit generation probabilities characteristic of public clones some of which being shared across patients. These findings suggest that EO2401-based peptide immunotherapy combined with checkpoint inhibition can broaden and activate public, pre-existing T cell clusters, potentially enhancing tumor-specific immune responses.

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2025-12-16 | Exploring the causal relationship between matrix metalloproteinases and adrenocortical carcinoma: A Mendelian randomization study.

The precise relationship between adrenocortical carcinoma (ACC) and matrix metalloproteinases (MMP) remains unclear. In this 2-sample Mendelian randomization (MR) study, exposure data regarding serum MMP levels were obtained from genome-wide association studies that included 21,758 individuals across 13 cohorts of European ancestry. The outcome data related to ACC were sourced from the FinnGen research project. The inverse-variance weighting method was employed as the primary analytical approach and was further verified using a variety of statistical techniques, including MR-Egger, weighted median, weighted mode, Bayesian weighted Mendelian randomization, constrained maximum likelihood, contamination mixture method and debiased inverse-variance weighted method. A Steiger directionality test was applied to avoid a reverse causation association. To assess pleiotropy and heterogeneity, we conducted the MR-Egger intercept test, Cochran Q test, and leave-one-out analyses. Using the IVW and Bonferroni-corrected approach, we observed that elevated serum levels of MMP-12 were associated with a reduced risk of ACC, with an odds ratio of 0.699 (95% confidence interval: 0.544-0.895; P = .005). Sensitivity analyses indicated the absence of significant heterogeneity and pleiotropy within our study. Additionally, the Steiger directionality test did not detect a significant reverse causation effect. The causal relationship between MMP-12 levels and ACC could have significant implications for the diagnostic and therapeutic approaches employed in the management of ACC.

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2025-10-22 | SorCS3 suppresses adrenocortical carcinoma progression by enhancing IGF2R-mediated endocytic trafficking and signaling attenuation.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited treatment options and poor prognosis. Identifying novel molecular regulators is essential for improving therapeutic strategies. In this study, we identified Sortilin-related VPS10 domain-containing receptor 3 (SorCS3) as a novel tumor suppressor candidate in ACC. Through expression detection and functional validation, we investigated the role of SorCS3, a member of the VPS10p-domain receptor family, in ACC. Expression data from TCGA and clinical tissue samples were analyzed. Endocytic activity, protein interactions, and downstream signaling were examined using immunofluorescence, co-immunoprecipitation (Co-IP), and western blotting in ACC cell lines. SorCS3, previously regarded as CNS-specific, was detected in ACC tissues and cell lines. Low SorCS3 expression was associated with reduced overall survival (OS) and disease-specific survival (DSS). Functional assays showed that SorCS3 enhanced endocytosis and colocalized with early endosomes. Co-IP revealed a physical or indirect interaction between SorCS3 and Insulin-like growth factor 2 receptor (IGF2R), a multifunctional receptor involved in IGF-II degradation and signal attenuation. SorCS3 overexpression (OE-SorCS3) increased IGF2R protein levels and suppressed PI3K/Akt and MAPK/Erk signaling. Blocking endocytosis partially reversed these effects, supporting a receptor trafficking-dependent mechanism. In this study, we identified SorCS3 as a novel tumor suppressor candidate in ACC. Although previously thought to be CNS specific, SorCS3 was found to be expressed in ACC tissues and cell lines. Low SorCS3 levels correlated with poor patient survival in the TCGA cohort. Functionally, SorCS3 enhanced endocytosis in ACC cells and physically or indirectly interacted with IGF2R. OE-SorCS3 increased IGF2R protein levels and reduced phosphorylation of Akt/Erk, suggesting tumor-suppressive effects through IGF2R stabilization and signaling inhibition. Overall, our findings highlight the SorCS3-IGF2R axis as a previously unrecognized regulatory mechanism in ACC progression and suggest that receptor trafficking could be a viable therapeutic target in this malignancy.

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2025-04-28 | Bimodal genomic approach predicting Semaphorin 7A (SEMA7A) as prognostic biomarker in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome data of 112 ACC tumor samples from patients enrolled in the TCGA and NCI. Among 72 bimodally expressed genes stratifying patients into prognostic groups, we focused on SEMA7A, as it encodes a glycosylphosphatidylinositol-anchored membrane glycoprotein (Semaphorin 7a) regulating integrin-mediated signaling, cell migration and immune responses. We find that high SEMA7A gene expression is associated with poor prognosis (hazard ratio = 4.27; p-value < 0.001). In hormone-producing ACCs, SEMA7A expression is elevated and positively correlated with genes driving steroidogenesis, aldosterone and cortisol synthesis, including CYP17A1, CYP11A1, INHA, DLK1, NR5A1 and MC2R. Correlation analyses show that SEMA7A is co-expressed with the integrin-β1, FAK (focal adhesion kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal regulated kinases) signaling pathways. Immunohistochemistry (IHC) staining demonstrates the feasibility of evaluating SEMA7A in ACC tissues and shows significant correlation between gene expression (RNA-Seq) and protein expression (IHC). These findings suggest SEMA7A as a candidate for further research in ACC biology, a candidate for cancer therapy, as well as a potential prognosis biomarker for ACC patients.

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2025-03-23 | Exploring currently available fibroblast activation protein targeting molecules in adrenocortical carcinoma: Navigating theranostic pathways.

Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) in the adrenocortical carcinoma (ACC) microenvironment may be used as potential therapeutic targets. This study investigated the diagnostic potential of four FAPi derivatives i.e. DOTA-FAPi-46 (FAPi46), DOTA.SA.FAPi (SA.FAPi), DATA5m.SA.FAPi (DATA.FAPi) and DATA5m.C4.FAPi (C4.FAPi) and compared with standard-of-care 18F-FDG (FDG) in ACC. Thirty histopathological proven cases of localized or metastatic ACC were recruited for both FDG and FAPi PET (number of patients (n) = 5 for SA.FAPi, n = 5 for DATA.FAPi, n = 5 for C4.FAPi and n = 15 for FAPi46). For biodistribution, standardized uptake values (SUV's) were computed by delineating region-of-interest on various body organs. For comparative analysis in disease identification, lesion tracer uptake was quantified using standardized uptake values corrected for lean body mass (SUL), tumor-to-background ratio (TBR), total lesion glycolysis (TLG for FDG) and total lesion FAP expression (TLF for FAPi). In overall analysis, both FAPi and FDG PET exhibited comparable mean SULpeak [FAPi 4.3 (8.0-1.7) vs FDG 3.9 (8.1-2.5), p-0.271], mean SULavg [2.2 (4.3-1.2) vs 2.2 (3.4-1.3), p-0.897] and mean TBR [1.8 (3.2-1.2) vs 1.9 (2.7-1.2), p-0.696]. In volumetric analysis, comparable mean TLF and mean TLG was noted for the cohort [9.3 (53.7-4.5) vs 11.8 (33.0-4.3), p-0.107]. Sub-categorical analysis demonstrated complete concordant findings for both radiotracers in detection of all primary lesions, nodal lesions and distant metastases in lung and peritoneum with discordant findings in liver (22%) and skeletal lesions (33%). For lesion detection, DATA.FAPi and FAPi46 showed 100% concordance with FDG scan findings in metastatic disease. SA.FAPi exhibited 33% discordance by detecting an additional skeletal lesion, while C4.FAPi had 10% discordance, missing one liver lesion identified by FDG. Three 68 Ga-FAP derivatives (SA.FAPi, DATA.FAPi, and C4.FAPi) exhibited similar biodistribution, with uptake in the salivary glands, thyroid, liver, pancreas, muscles, and kidneys, and variable uptake in the lacrimal glands, extra-ocular muscles, oral mucosa, and uterus. In contrast, FAPi46 physiological expression was noted in salivary glands and muscles, with no uptake in other organs. Pancreatic uptake was highest for SA.FAPi (SUVmean 11.8), DATA.FAPi (12.1), and C4.FAPi (10.8), while FAPi46 had the lowest (1.7). Conversely, FAPi46 exhibited the highest muscle uptake (SUVmean 4.3) compared to SA.FAPi (1.7), DATA.FAPi (1.4), and C4.FAPi (1.0). All the existing FAP inhibitor molecules were comparable to FDG PET for mapping disease spread and appeared as potential theranostic targets for the management of ACC.

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antibodies

2026-09-19 | Beyond mitotane: next-generation therapeutic landscapes in adrenocortical carcinoma.

The clinical management of adrenocortical carcinoma (ACC) has long been defined by its resistance to conventional therapies. Since the FIRM-ACT trial established the combination of etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) as the frontline standard, overall survival for metastatic patients has remained stubbornly low. This plateau in efficacy with cytotoxic regimes has necessitated a shift towards precision oncology and immunotherapy. However, translating the success of immune checkpoint inhibitors seen in other malignancies to ACC has proven exceptionally difficult. The primary challenge in the present therapeutic landscape of immunotherapy is the unique biology of the adrenal cortex, which creates an intrinsic immunologically privileged site. This review will address these current immunological hurdles but also explore novel strategies designed to bypass this barrier entirely. By shifting focus towards mechanisms that do not solely rely on the traditional engagement of adaptive immune system - such as the targeted delivery of cytotoxic payloads via antibody-drug conjugates (ADCs) or the androgen-mediated activation of myeloid cells to clear pro-tumoural populations - the field is moving towards a future where the 'cold' nature of the tumour microenvironment may no longer dictate the limits of therapeutic success.

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2026-08-01 | EP1733 - LBA_ECE_1473 - The role of pembrolizumab immunotherapy in metastatic adrenocortical carcinoma: a case series study

Abstract Background Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis in advanced stages. Standard first-line treatment for metastatic disease involves mitotane and cytotoxic chemotherapy (EDP-M); however, therapeutic options following progression are limited. Immunotherapy with immune checkpoint inhibitors, such as the anti-PD-1 agent pembrolizumab, has shown potential in solid tumors, particularly those with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). This study presents the clinical experience, safety, and outcomes of patients treated with pembrolizumab at a specialized Endocrine Unit of a University Hospital. Methods This retrospective observational case series study analyzed a cohort of seven adult patients with metastatic ACC followed between 2020 and 2026. Among them, three patients receiving pembrolizumab as salvage therapy for advanced disease were evaluated. Data collection included demographic profiles, clinical and histopathological characteristics, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. Results Case 1: A 30-year-old female with functional, symptomatic ENSAT stage IV ACC (pulmonary, hepatic, bone metastases) and Ki-67 35%-40% (Weiss score 8). Following surgery, adrenolytic therapy, and chemotherapy, pembrolizumab was initiated three years post-diagnosis. Treatment was discontinued after a single administration due to severe drug-induced hepatitis. Although a partial reduction in pulmonary metastases occurred, the brief treatment duration precluded a definitive attribution of this response to immunotherapy. Case 2: An 89-year-old female with functional ENSAT stage IV ACC (pulmonary, diaphragmatic, nodal, perirenal involvement) and a Ki-67 index of 50% (Weiss score 8), received pembrolizumab postoperatively alongside mitotane as salvage therapy. Efficacy could not be assessed as the patient succumbed shortly after initiation; death was attributed to rapid disease progression. Case 3: A 56-year-old female with symptomatic ENSAT stage IV oncocytic ACC (renal, hepatic, IVC involvement) with low grade malignancy (Weiss score 4, Ki-67 15%). Following surgery and standard therapies, she received pembrolizumab for two years. She achieved a sustained initial response with disease progression occurring 2 years later. Conclusion Pembrolizumab demonstrates heterogeneous outcomes in metastatic ACC. While it may provide prolonged disease control in selected patients. The risk of severe immune-related adverse events, should be considered. Immunotherapy remains a viable second/third line option, though, optimal patient selection and predictive biomarker identification are essential.

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2026-07-16 | IGF2R: a new player in the IGF2 loop sustaining adrenocortical carcinogenesis.

Most of adrenocortical carcinomas (ACC) are characterized by IGF2 overexpression; therefore, several studies have focused on its two oncogenic effectors, the tyrosine-kinase receptors IGF1R and IR. However, the specific IGF2 receptor, IGF2R, due to its scavenging activity, was considered a tumour suppressor and has never been fully investigated in this context. Nevertheless, recent evidence from other tumours identified IGF2R as a pro-tumorigenic actor able to exert its function through the downstream activation of the pro-mitotic sphingosine kinases (SphK) enzymes responsible for sphingosine phosphorylation. Hence, the main aims of this study were to elucidate the role of IGF2R in ACC cells, investigate its action mechanism, and test IGF2R and SphK inhibitors as possible novel therapies for ACC. The present study was conducted in vitro in 4 different ACC cell lines and in 3 ACC primary cultures, to reflect the heterogeneity of ACC. Target protein and transcript expression were evaluated on normal and tumoral adrenal tissues and cell lines, while the effects of IGF2R downregulation and overexpression, along with IGF2R and SphK inhibition, were tested on cell viability, proliferation, and apoptosis as well as cortisol secretion. ACC tissue analysis demonstrated the IGF2R overexpression compared to normal adrenal cortex, which was also positively correlated with IGF2 and IGF1R expression in ACC. In vitro assays proved the pro-mitotic involvement of IGF2R and its role in the downstream activation of SphK. Finally, we observed the anti-tumoral efficacy of three different inhibitors of this pathway on ACC cell lines and primary cultures: a specific neutralizing anti-IGF2R antibody was tested for its anti-proliferative action, while two SphK inhibitors, safingol (SAF) and fingolimod (FTY), were able to decrease cell proliferation, viability, and cortisol secretion, while promoting cell apoptosis. Overall, this comprehensive in vitro evaluation of the role of IGF2R in ACC demonstrates its tumorigenic effect through SphK activation. Moreover, the three pharmacological strategies here employed successfully controlled in vitro ACC growth, suggesting IGF2R/SphK pathway represents a novel therapeutic target for ACC.

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2026-06-28 | Study protocol: targeted delivery of interleukin-12 in combination with hepatic artery infusion pump therapy for patients with adrenocortical carcinoma liver metastases.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy often detected at an advanced stage with limited effective treatment options beyond first-line chemotherapy. The liver is a common site of metastasis, and patients frequently present with substantial hepatic disease burden that precludes complete resection. Locoregional therapies, including hepatic artery infusion pump (HAIP) delivery of floxuridine, have not been thoroughly evaluated for treatment of ACC liver metastasis, likely due to its rare incidence and highly aggressive nature. PDS01ADC (previously referred to as NHS-IL12) is a novel antibody-drug conjugate designed to deliver the immunomodulatory cytokine interleukin-12 to areas of tumor necrosis and modulate the tumor microenvironment to support immune surveillance and cytotoxic tumor responses. Combination of PDS01ADC with HAIP therapy (HAIP-delivered floxuridine plus systemic chemotherapy) was recently found to be feasible for clinical evaluation by an interim analysis in patients with colorectal liver metastases. Patients who received PDS01ADC with HAIP therapy had extended overall survival compared to patients who received HAIP therapy alone in a nonrandomized prior sequential study. We discuss herein the rationale and initiation of a new clinical trial arm to evaluate HAIP therapy with PDS01ADC for patients with ACC liver metastasis who have failed standard of care therapy. Patients with unresectable ACC liver metastasis and either resectable or no progressive extrahepatic disease will receive combination therapy including HAIP floxuridine and subcutaneous injection of PDS01ADC administered concurrently with systemic gemcitabine and oxaliplatin in 28-day cycles. The primary outcome measured is overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria. Secondary outcomes measured in this study include intrahepatic and extrahepatic progression-free survival, overall survival, and safety of PDS01ADC combination therapy with HAIP-delivered floxuridine. For select patients with ACC liver metastasis, HAIP therapy with PDS01ADC may improve disease control and thereby prolong survival. Study ID NCT05286814 version 2026-05-04; https://clinicaltrials.gov/study/NCT05286814.

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2026-06-15 | Pan-cancer expression, methylation, and prognostic significance of α7 nicotinic acetylcholine receptor in tumor immunology.

The α7 nicotinic acetylcholine receptor (α7nAChR), functioning as a critical ligand-gated ion channel in the nervous system, has recently been implicated to play a role in various non-neuronal tissues. Nonetheless, a comprehensive understanding of its expression patterns, mechanisms of epigenetic control, and functions within the tumor microenvironment (TME) across various malignancies is still lacking. To address this gap, we performed an extensive multi-cancer investigation of CHRNA7 spanning 31 tumor types, leveraging datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases, including its expression patterns, methylation characteristics, genomic instability, and prognostic significance. Additionally, the potential immunomodulatory effects of α7nAChR were investigated through integration of multiple algorithms. The results revealed that CHRNA7 is significantly overexpressed in 11 cancer types, including cholangiocarcinoma, glioblastoma, and lung squamous cell carcinoma, whereas it is underexpressed in 11 other cancer types, including breast cancer (BRCA) and lung adenocarcinoma (LUAD). A noteworthy finding was the inverse correlation between CHRNA7 expression levels and the staging system recommended by the World Health Organization for specific cancers, such as cervical squamous cell carcinoma and thyroid carcinoma. Another interesting finding is that CHRNA7 plays dual prognostic roles [1] as a protective factor in low-grade glioma and rectal adenocarcinoma and [2] as a risk factor in adrenocortical carcinoma, BRCA, and LUAD. Genomic analyses revealed that copy number variations and single nucleotide variations of CHRNA7 are significantly associated with survival outcomes in cancers such as liver hepatocellular carcinoma (LIHC) and kidney renal clear cell carcinoma. Moreover, these genetic variations exhibit cancer type-specific correlations with tumor mutational burden and microsatellite instability, with positive associations in colon adenocarcinoma and esophageal squamous cell carcinoma. Epigenetic studies indicated that methylation of the CHRNA7 promoter is inversely correlated with its mRNA expression level in certain cancers such as BRCA and LUAD. Additionally, CHRNA7 promoter methylation shows significant interactions with DNA mismatch repair genes and cancer stemness characteristics. Analysis of the TME revealed a positive association between high CHRNA7 expression and immune cell infiltration and immune checkpoint molecule expression in cancers such as BRCA and LIHC, suggesting its potential role in modulating tumor immune evasion and influencing treatment responses. Functional enrichment analysis confirmed that CHRNA7 is involved in key biological pathways, including cholinergic signaling, DNA damage repair, and cell proliferation regulation. In conclusion, this study provides a comprehensive pan-cancer characterization of CHRNA7, offering novel insights into its potential role as a prognostic biomarker and immunotherapeutic target. These findings could facilitate the development of personalized cancer treatment strategies customized according to the expression level and functional status of CHRNA7.

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oligonucleotides

2023-08-16 | miRNAs orchestration of adrenocortical carcinoma - Particular emphasis on diagnosis, progression and drug resistance.

Adrenocortical carcinoma (ACC) is an uncommon aggressive endocrine malignancy that is nonetheless associated with significant mortality and morbidity rates because of endocrine and oncological consequences. Recent genome-wide investigations of ACC have advanced our understanding of the disease, but substantial obstacles remain to overcome regarding diagnosis and prognosis. MicroRNAs (miRNAs, miRs) play a crucial role in the development and metastasis of a wide range of carcinomas by regulating the expression of their target genes through various mechanisms causing translational repression or messenger RNA (mRNA) degradation. Along with miRNAs in the adrenocortical cancerous tissue, circulating miRNAs are considered barely invasive diagnostic or prognostic biomarkers of ACC. miRNAs may serve as treatment targets that expand the rather-limited therapeutic repertoire in the field of ACC. Patients with advanced ACC still have a poor prognosis when using the available treatments, despite a substantial improvement in understanding of the illness over the previous few decades. Accordingly, in this review, we provide a crucial overview of the recent studies in ACC-associated miRNAs regarding their diagnostic, prognostic, and potential therapeutic relevance.

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2023-06-28 | What is the role of CHCHD2 in adrenal tumourigenesis?

CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal tumourigenesis are scarce. We studied the expression of CHCHD2, BCL2, and BAX in human adrenocortical tissues and SW13 cells. mRNA and protein levels were analyzed through qPCR and immunoblotting, respectively, in 16 benign adrenocortical neoplasms (BANs), along with their adjacent normal adrenal tissues (controls), and 10 adrenocortical carcinomas (ACCs). BCL2/BAX mRNA expression was also analyzed in SW13 cells after CHCHD2 silencing. MTS, flow cytometry and scratch assays were performed to assess cell viability, apoptosis, and invasion, respectively. BCL2 and CHCHCD2 mRNA and protein expression was increased in BANs compared to normal adrenal tissues whereas BAX was decreased. BAX and CHCHD2 mRNA and protein levels were significantly downregulated and upregulated, respectively, in ACCs compared with either BANs or controls. Expression of the studied genes was not different among cortisol-secreting and nonfunctional ACAs. No significant association was found between genes' expression and other established prognostic markers of ACCs patients. In vitro analysis showed that CHCHD2 silencing resulted in reduced cell viability and invasion as well as increased SW13 cells apoptosis. CHCHD2 expression seems to be implicated in adrenal tumourigenesis and its absence resulted to increased apoptosis in vitro. However, the exact mechanism of action and particularly its association with the BAX/BCL2 pathway needs to be further studied and evaluate whether it could be a protentional therapeutic target.

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2022-12-16 | Multi-genomic analysis of 260 adrenocortical cancer patient tumors identifies novel network BIRC5-hsa-miR-335-5p-PAX8-AS1 strongly associated with poor survival.

Adrenocortical carcinoma is a rare endocrine cancer with poor overall survival. Linking survival outcomes to a common target across multiple genomic datasets incorporating microRNA-long non-coding RNA dysregulation have not been well described. We hypothesized that a multi-database analysis of microRNA-long noncoding RNA-messenger RNA regulatory networks associated with survival will identify novel biomarkers. Significantly dysregulated genes or microRNA in adrenocortical carcinoma compared to normal adrenal was identified from sequencing data for 260 human adrenocortical carcinomas using GEO2R. The miRnet identified hub microRNA and genes and long noncoding RNA and microRNA associated with survival genes. The R2 generated Kaplan-Meier curves. The database miRTarBase linked genes associated with poor survival and dysregulated microRNA. Analysis of genes and microRNAs differentially regulated in >50% of datasets revealed 75 genes and 12 microRNAs were upregulated, and 167 genes and 12 microRNAs were downregulated (bonf. P < .05). Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed cell cycle, P53 signaling, arachidonic acid and innate immune response, and PI3/Akt are altered in adrenocortical carcinoma. A microRNA-target interaction network of differentially regulated microRNAs identified upregulated miRNA107, 103a-3p and 27a-3p, 16-5p, and downregulated 335-5p to have the highest degree of interaction with upregulated (ie, TPX2, CDK1, BIRC5, PRC1, CCNB1, GINS1) and downregulated (ie, RSPO3, NR2F1, TLR4, HOXA5, USP53, SLC16A9) hub genes as well as hub long noncoding RNAs XIST, NEAT1, KCNQ1OT1, and PAX8-AS1. Survival analysis revealed that the hub genes are associated with poor overall survival (P < .05) of adrenocortical carcinoma in the Cancer Genome Atlas data. A messenger RNA-microRNA-long noncoding RNA network analysis identified the BIRC5-miR335-5p-PAX8-AS1 network as one that was associated with poor overall survival in adrenocortical carcinoma, warranting further validation as a potential therapeutic target.

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2022-11-01 | 516 Clinical tier grading of cancer stem cells according to clinical characteristics for immune checkpoint inhibitors guided by mRNA stemness index

Background

Cancer stems cells are cells in tumors that have self-renewing capabilities and proliferation, and are partly responsible for tumor growth, metastasis and drug resistance, and have been associated with multidrug resistance and epithelial-mesenchymal transition. Recent studies have shown that cancer stemness is capable of being targeted by immunotherapies.1 mRNAsi, or mRNA stemness index, is a tool that has been developed to analyze prognostic significance for immunotherapy response for cancer stemness in lung adenocarcinoma, adrenocortical carcinoma and gastric cancer, among other carcinomas2,3,4 This abstract proposes to apply the prognostic signatures as determined by mRNAsi to create a clinical tier grading system that categorizes cancer stemness presenting characteristics based on studies by for ICI (nivolumab, (anti-PD-1) ipilumumab (anti-CTLA-4), pembrolizumab (anti-PD-L1), atezolizumab (anti-PD-L1)) treatment. 5

Methods

A literature search will be conducted using the keywords "cancer stem cells" OR "cancer stemness" AND "immunotherapies" AND "mRNAsi" AND "immune checkpoint inhibitors efficacy". Additional keywords include "prognostic signatures" AND "metastasis" AND "clinical features" AND "clinical presentation." Results mRNAsi-guided tools determined differentially expressed genes in tumors and generated prognostic signatures which in turn reflected clinical characteristics that could be grouped into a tiered list, creating grading categories for ICI treatment efficacy (table 1). Low-risk and high-risk survival groups, tumor mutational burden, TNM pathological stages, overall survival were generated from prognostic gene signatures through mRNAsi. They also could predict 1-year, 3-year, and 5-year overall survival in certain cancers. Based on this clinical presentation, guidance for ICI therapy could be developed.

Conclusions

A clinical tier grading list may be an effective way to guide oncologists in applying mRNAsi tools to cancer stemness for treatment through ICIs. Future studies could focus on stratifying patients through the prognostic signatures generated by these tools.

References

Qin P, Li Q, Liu S, Ning N, Zhang X, Xu Y, Chang AE, Wicha MS. Targeting cancer stem cells using immunologic approaches. Stem Cells. 2015 July ; 33(7): 2085–2092. Li N, Li Y, Zheng P, Zhan Z. Cancer Stemness-Based Prognostic Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma. Front. Endo. 2021. Mao D, Zhou Z, Song S, Li D, He Y, Wei Z, Zhang C. Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer. Front Onc 2021. Shi X, Liu Y, Cheng, S, Hu H, Zhang J, Wei M, Lin Zhao L, Xin S. Cancer stemness associate with prognosis and the efficacy of immunotherapy in adrenocortical carcinoma. Front Onc. 2021, Santoro S. Clinical phenotype and management data in down syndrom regression disorder. American College of Medical Genetics and Genomics Annual Meeting 2022.

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2022-08-31 | Identification of an immune-related gene signature as a prognostic target and the immune microenvironment for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Even with complete tumor resection and adjuvant therapies, the prognosis of patients with ACC remains unsatisfactory. In the microtumor environment, the impact of a disordered immune system and abnormal immune responses is enormous. To improve treatment, novel prognostic predictors and treatment targets for ACC need to be identified. Hence, credible prognostic biomarkers of immune-associated genes (IRGs) should be explored and developed. We downloaded RNA-sequencing data and clinical data from The Cancer Genome Atlas (TCGA) data set, Genotype-Tissue Expression data set, and Gene Expression Omnibus data set. Gene set enrichment analysis (GSEA) was applied to reveal the potential functions of differentially expressed genes. GSEA indicated an association between ACC and immune-related functions. We obtained 332 IRGs and constructed a prognostic signature on the strength of 3 IRGs (INHBA, HELLS, and HDAC4) in the training cohort. The high-risk group had significantly poorer overall survival than the low-risk group (p < .001). Multivariate Cox regression was performed with the signature as an independent prognostic indicator for ACC. The testing cohort and the entire TCGA ACC cohort were utilized to validate these findings. Moreover, external validation was conducted in the GSE10927 and GSE19750 cohorts. The tumor-infiltrating immune cells analysis indicated that the quantity of T cells, natural killer cells, macrophage cells, myeloid dendritic cells, and mast cells in the immune microenvironment differed between the low-risk and high-risk groups. Our three-IRG prognostic signature and the three IRGs can be used as prognostic indicators and potential immunotherapeutic targets for ACC. Inhibitors of the three novel IRGs might activate immune cells and play a synergistic role in combination therapy with immunotherapy for ACC in the future.

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2026-08-13 | ELAVL1-KO Affects Steroid Synthesis in ACC Cell Line NCI-H295R and Reduces Colony-Forming Abilities.

Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal gland for which no curative treatment options exist in advanced stages. Analyzing the ACC cohort of The Cancer Genome Atlas, we identified that expression of the mRNA-stabilizing protein Embryonic-Lethal-Abnormal-Vision-Like RNA-Binding Protein 1 (ELAVL1) was negatively associated with patient survival. To investigate the functional role in ACC, we generated a CRISPR/Cas9-mediated ELAVL1 knockout (KO) in the ACC cell lines NCI-H295R and HAC15 and performed Next-Generation RNA Sequencing (NGS) to characterize transcriptomic changes. In NCI-H295R, NGS analysis revealed 3468 upregulated genes and 3458 downregulated genes in ELAVL1-deficient cells compared with controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified significant enrichment of aldosterone biosynthesis-related genes and enriched downregulation of genes associated in with "pathways in cancer." Functionally, ELAVL1-KO cells exhibited impaired colony-forming ability, indicating reduced proliferative or clonogenic potential. Steroid profiling of cell culture supernatants further demonstrated increased aldosterone synthesis and decreased cortisol and androgen production in the KO cells, consistent with the observed transcriptional changes. Given that hypercortisolism is an established negative prognostic factor in ACC, these data suggest that ELAVL1 may represent a potential therapeutic target worth further investigation for modulating steroidogenesis in ACC patients.

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2026-07-02 | ENPP3 CAR T cells combined with CD206 modulation suppress adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited curative treatment options. While chimeric antigen receptor (CAR) T cells have shown some promise in solid tumors, ACC remains largely unexplored in this context. Here, we used patient-derived xenograft (PDX) models of ACC to identify immunotherapeutic targets and develop novel CAR T-cell strategies. Target identification and tumor microenvironment (TME) profiling were conducted using publicly available bulk and single-cell RNA sequencing data from patients with ACC samples. Surface proteomic analysis and flow cytometry of PDXs were conducted to validate antigen candidates. CAR T cells were engineered and tested for cytotoxicity in vitro and in vivo and profiled using flow cytometry and cytokine analysis. We identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as a shared immunotherapy target in 4/7 (57%) ACC PDXs. ENPP3-targeted CAR T-cells eradicated >85% of ENPP3+ ACC cells in vitro but showed attenuated efficacy in PDX mouse models. Restrained ENPP3 CAR T-cell activity correlated with immunosuppressive features of the TME, particularly the presence of CD206+ tumor-associated macrophages (TAMs). Co-treatment with an agent modulating CD206+ TAMs restored CAR T-cell function and improved antitumor responses in ENPP3high and ENPP3low PDX models (difference between mean tumor weights -270.1 mg±117.4; p<0.05). ENPP3 is a novel target for CAR T-cell therapy in ACC. ENPP3 CAR T cells, when combined with CD206 modulation to overcome immune suppression within the TME, have therapeutic efficacy in ACC by mediating robust tumor growth suppression. This combinatorial strategy, which includes CAR T cells alongside therapies that recalibrate immunosuppressive CD206+ TAMs, may be a novel approach for improved immunotherapy of solid cancers beyond ACC.

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2026-01-16 | Establishment of a patient-derived adrenocortical carcinoma 3D tumor construct platform for evaluation of therapeutic strategies.

Adrenocortical carcinoma (ACC) is an under-studied, aggressive cancer of the adrenal glands where surgical resection is currently the only effective curative option. However, after surgery the majority of patients experience tumor progression. The median overall survival of 12 months has not improved since approval of mitotane in 1970. The lack of effective therapies in ACC is partially due to the lack of preclinical models that accurately represent human ACC. Most attempts to generate ACC cell lines or animal models have been unsuccessful. The few existing models do not adequately reflect the oncogenic signaling pathways or intratumoral heterogeneity of human ACC. These limited model systems have hindered identification of drivers of tumor progression and immune escape mechanisms, thereby limiting development and testing of novel therapeutic approaches such as targeted therapies or immunotherapies. We developed human ACC patient-derived tumor constructs (PTCs) encapsulated in synthetic extracellular matrix. Our ACC PTCs exhibit hallmarks of ACC: proliferation, expression of key ACC biomarkers, such as SF1, and production of cortisol. We provide characterization in the form of immunofluorescence staining for ACC biomarkers, and confirmation of PTC proliferation and cortisol production - a hallmark of ACC. We then demonstrate the utility of ACC PTCs for evaluation of chemotherapies currently used clinically (mitotane) with and without experimental cocktails of etoposide, doxorubicin, and cisplatin, experimental targeted therapies, and cellular immunotherapies, primarily in the form of natural killer (NK) cell therapy. In particular, the latter - cellular immunotherapies - are cutting edge studies demonstrating potential to evaluate immunotherapies in ACC clinical scenarios. Together these data provide evidence that patient-derived ACC models can serve as an important tool for identification of future points of intervention and testing of novel therapeutic strategies to improve ACC clinical care.

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2026-01-14 | Chemo-immunotherapy with cisplatin and nivolumab as second-line approach in metastatic adrenocortical carcinoma.

No effective therapies are available for patients with advanced adrenocortical carcinoma (ACC) progressing after standard therapy: EDP (etoposide, adriamycin, and cisplatin) and mitotane (EDP-M regimen). These patients have poor prognosis with a median life expectancy of 6-7 months. Immunotherapy in this setting is promising. Concomitant chemotherapy administration can enhance the efficacy of immunotherapy, as demonstrated in other malignancies. This retrospective study aims to explore the activity of a combination of cisplatin and nivolumab administered to patients with ACC who have previously undergone chemotherapy and mitotane treatment. Cisplatin, 25 mg/m2 on day 1, and nivolumab, 240 mg on day 2, every 2 weeks, were administered to advanced/metastatic ACC with disease progression to EDP-M regimen plus/minus other chemotherapeutic regimens. The primary endpoint was the disease response according to RECIST. Secondary endpoints were clinical benefit, disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety. Twenty-three patients were enrolled between January 2023 and March 2025. The median follow-up was 15.1 months. Eight patients [34.8% (95% CI, 15.3%-54.2%)] obtained a partial response and 4 patients (17.3%) a stable disease; therefore, 12 patients (52.2%) obtained a clinical benefit. The DCR after 6 months was obtained in 39.1% [95% CI, 19.7%-61.5%] of patients. The median PFS was 4.3 months [95% CI, 3.9-13.0], and the median OS was 18.9 months [95% CI, 15.8-not reached]. Chemo-immunotherapy combination was well tolerated, and most toxicities were limited to grade G1-2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria. One patient discontinued treatment after 1 cycle, due to grade 3 immune-related hepatitis. The combination of cisplatin and nivolumab is an active regimen in advanced, previously treated, ACC patients. The long survival achieved in this patient population with a poor prognosis is promising.

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2025-12-19 | A genome-wide RNAi screen for novel CIN genes using human artificial chromosome.

Chromosome instability (CIN) remains among the most important problems in modern cancer research. In this study, we conducted a genome-wide RNAi screen to identify genes that contribute to CIN. To achieve this, we used a human artificial chromosome in a novel sensitized screen to measure CIN. We screened 18,658 genes for their roles in maintaining chromosomal stability and identified 834 candidates as potential CIN genes. A secondary RNAi screen identified 44 genes with the most pronounced CIN phenotypes. In guilt-by-association analysis using a published set of 8,498 proteins across a panel of 949 cancer cell lines, this cohort of 44 genes displayed a striking correlation with mitotic regulators. Furthermore, altered expression of these proteins was associated with a poor prognosis across multiple cancer types. Specifically, downregulation of AMY2B, ALAD, PDGFRA, PPIE, VEZ1, and TTC19 is associated with poor survival in two or more of the following: small cell lung cancer, lung adenocarcinoma, adrenocortical carcinoma, ovarian cancer, and breast cancer. The genes identified in this screen hold potential as prognostic markers for patient survival across several cancer types and could potentially serve as targets for the development of new therapeutic approaches aimed at mitigating CIN.

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