RARE DISEASE
Adrenocortical carcinoma
Adrenocortical carcinoma
Adrenocortical carcinoma
Synonyms: ACC
Synonyms: ACC
Synonyms: ACC
Drug discovery
9
drugs
With orphan designations
Overview
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex with an incidence of 0.5–2 cases per million annually [2][7][16]. It primarily affects children and middle-aged adults (median age 55), showing female predominance (1.5–2.5:1 ratio) [4][9][16]. Hormonally active tumors may cause hypercortisolism or virilization. Prognosis remains poor due to high metastatic potential and recurrence rates, with 5-year survival <35% for advanced stages [2][9][14]. Treatment requires multidisciplinary care at specialized centers.
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
1,678 drug discovery papers about Adrenocortical carcinoma, with 5 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,678 drug discovery papers about Adrenocortical carcinoma, with 5 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Comprehensive Profiling of OTSSP167 Action in Adrenocortical Carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive malignancy with no approved targeted therapy and poor outcomes. Using multiple patient and cell line derived xenograft (PDX/CDX) models, and a newly developed PDX model (CUACC9), we investigated the potential action of the multikinase inhibitor OTSSP167 for treatment of ACC. OTSSP167 effectively reduced tumor growth in wild type TP53 (CUACC1) and mutant TP53 (H295R, CUACC9) in vivo tumor models. Immunohistochemical (IHC) analysis of treated tumors verified apoptosis via caspase activation as a mechanism of OTSSP167 action. Further evaluation of downstream effectors via RNA-seq and a Reverse Phase Protein Array (RPPA), using ACC cell lines matching the in vivo genetic diversity, demonstrated that OTSSP167 impeded cell cycle via G2/M arrest independent of TP53 status. In TP53 mutant lines, OTSSP167 enhanced DNA damage and inhibited protein synthesis. RSK1 was identified as a direct target of OTSSP167 activity in vitro. OTSSP167 also induced the G2/M checkpoint protein, WEE1, activation in all models, indicating an early adaptive response. Combining the WEE1 inhibitor AZD1775 with OTSSP167 significantly enhanced cytotoxicity in TP53 mutant lines, and reduced tumor growth in a TP53 mutant ACC model. Together these findings establish the feasibility of using OTSSP167 in ACC, especially in TP53 mutant ACC tumors. In addition, this study demonstrates the possibility of targeting the early adaptive response subsequent to exposure to OTSSP167 treatment. Our findings provide strong rationale for a future phase I clinical trial in ACC.
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.
2026-08-12 | Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas
Adrenocortical carcinomas (ACC) are aggressive cancers with limited therapeutic options. Cyclin-dependent kinases (CDKs) 1/2/4 and polo-like kinase 1 (PLK1) are upregulated in ACC, suggesting their role as potential targets. This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures. ACC cells showed marked CDK1/2/4 and PLK1 transcript and protein upregulation compared to normal adrenal gland. Dinaciclib reduced cell growth and induced apoptosis at low nanomolar doses. CurE induced weaker pro-apoptotic effects, whereas AT7519 and SNS-032 displayed activity only in JIL-2266 and MUC-1. Among PLK1i, plogosertib impaired proliferation and increased apoptosis in a nanomolar range. Dinaciclib-plogosertib combination produced the highest synergistic anti-proliferative effects in NCI-H295R and TVBF-7. In steroidogenic NCI-H295R cells, dinaciclib lowered cortisol secretion and downregulated CYP11A1, CYP17A1, CYP21A2, SF-1, and GR transcripts, as well as GR protein expression. In parallel, dinaciclib broadly suppressed CDK1/2 axis and their downstream signalling proteins, including cyclin E1, and p21Waf1/Cip1, consistent with G1/S blockade. Plogosertib increased p-CDK1(Tyr15), cyclin B1, and γ-H2AX levels, indicative of DNA damage and mitotic stress. These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo.
2026-08-12 | Frequent antecedent nodules and diagnostic gaps in adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare and often fatal malignancy currently only cured by surgery. Large-scale studies have failed to capture benign to malignant transition events, and patients often present with metastatic disease. These observations suggest ACC develops rapidly without a measurable precursor lesion, forming the basis of widely implemented adrenal incidentaloma guidelines. We aimed to characterize the prevalence of antecedent adrenal nodules, quality of preoperative diagnostic workup, and the impact on survival for adults with ACC. We analyzed clinical data from 108 consecutive patients referred to a single tertiary academic medical center from 2000 to 2025. Median follow-up was 86.7 months. Strikingly, 31.7% harbored antecedent nodules, indolent for a median 4.68 years before ACC presentation, and ultimately associated with a higher risk of death (adjusted hazard ratio [HR], 2.9; 95% CI, 1.39-6.0). Regarding preoperative evaluation, 46.4% were referred to endocrinology, associated with more complete hormonal assessment; 31.4% had adrenal biopsy, accompanied by increased risk of progression (adjusted HR, 2.53; 95% CI, 1.24-5.2) and death (adjusted HR, 2.22; 95% CI, 1.07-4.6). Patients with high-grade disease received more interventions; those who received mitotane and/or locoregional therapies had improved survival (adjusted HR, 0.31; 95% CI, 0.14-0.71, and adjusted HR, 0.47; 95% CI, 0.23-0.98, respectively). The unexpectedly high prevalence of indolent antecedent adrenal nodules suggests a prolonged, clinically premalignant phase in a subset of ACC. Initial diagnostic evaluation was often incomplete or inappropriately invasive, compromising the preoperative window and patient survival. These findings challenge current surveillance paradigms, revealing an extended but vulnerable window for surgical cure.
2026-08-06 | Real-world safety profile of mitotane in adrenocortical carcinoma: a retrospective cross-sectional study integrating pharmacovigilance and interpretable machine learning.
Mitotane remains the cornerstone of adrenocortical carcinoma. However, its real-world safety profile is poorly defined. This study systemically evaluated mitotane-associated adverse events (AEs) and characterized multivariable patterns of serious outcomes using a combined pharmacovigilance and machine learning approach. Mitotane-related AE reports (2004-2025) were extracted from the FDA Adverse Event Reporting System (FAERS). Disproportionality analyses were performed via four algorithms. Detected signals were categorized using a clinical priority scoring system based on signal strength, mortality, seriousness, and existing evidence. Time-to-onset was evaluated utilizing Kaplan-Meier methods. Elastic net logistic regression and Extreme Gradient Boosting (XGBoost) models characterized features associated with serious outcomes, with performance assessed by the area under the receiver operating characteristic curve (AUROC). Among 870 identified reports, 45.7% involved serious outcomes. We detected 75 safety signals, predominantly involving gastrointestinal, neurological, endocrine, and metabolic systems. Notably, 21 signals (28.0%) were assigned moderate clinical priority, with adrenal insufficiency as the highest-priority signal. Time-to-onset analysis showed that endocrine AEs had a significantly longer onset time than non-endocrine AEs. Both models demonstrated consistent characterization of multivariable patterns associated with serious outcomes (elastic net AUROC = 0.830, XGBoost AUROC = 0.869). Key contributors to serious outcomes included reporting country, medical event designation, organ system involvement, and medication complexity. This large-scale study provides a real-world safety assessment of mitotane. Integrating signal detection, clinical prioritization, and interpretable machine learning reveals multivariable patterns underlying serious AEs. These findings support a risk-stratified monitoring approach to enhance the clinical safety of mitotane therapy.
2026-08-14 | Comprehensive Profiling of OTSSP167 Action in Adrenocortical Carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive malignancy with no approved targeted therapy and poor outcomes. Using multiple patient and cell line derived xenograft (PDX/CDX) models, and a newly developed PDX model (CUACC9), we investigated the potential action of the multikinase inhibitor OTSSP167 for treatment of ACC. OTSSP167 effectively reduced tumor growth in wild type TP53 (CUACC1) and mutant TP53 (H295R, CUACC9) in vivo tumor models. Immunohistochemical (IHC) analysis of treated tumors verified apoptosis via caspase activation as a mechanism of OTSSP167 action. Further evaluation of downstream effectors via RNA-seq and a Reverse Phase Protein Array (RPPA), using ACC cell lines matching the in vivo genetic diversity, demonstrated that OTSSP167 impeded cell cycle via G2/M arrest independent of TP53 status. In TP53 mutant lines, OTSSP167 enhanced DNA damage and inhibited protein synthesis. RSK1 was identified as a direct target of OTSSP167 activity in vitro. OTSSP167 also induced the G2/M checkpoint protein, WEE1, activation in all models, indicating an early adaptive response. Combining the WEE1 inhibitor AZD1775 with OTSSP167 significantly enhanced cytotoxicity in TP53 mutant lines, and reduced tumor growth in a TP53 mutant ACC model. Together these findings establish the feasibility of using OTSSP167 in ACC, especially in TP53 mutant ACC tumors. In addition, this study demonstrates the possibility of targeting the early adaptive response subsequent to exposure to OTSSP167 treatment. Our findings provide strong rationale for a future phase I clinical trial in ACC.
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.
2026-08-12 | Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas
Adrenocortical carcinomas (ACC) are aggressive cancers with limited therapeutic options. Cyclin-dependent kinases (CDKs) 1/2/4 and polo-like kinase 1 (PLK1) are upregulated in ACC, suggesting their role as potential targets. This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures. ACC cells showed marked CDK1/2/4 and PLK1 transcript and protein upregulation compared to normal adrenal gland. Dinaciclib reduced cell growth and induced apoptosis at low nanomolar doses. CurE induced weaker pro-apoptotic effects, whereas AT7519 and SNS-032 displayed activity only in JIL-2266 and MUC-1. Among PLK1i, plogosertib impaired proliferation and increased apoptosis in a nanomolar range. Dinaciclib-plogosertib combination produced the highest synergistic anti-proliferative effects in NCI-H295R and TVBF-7. In steroidogenic NCI-H295R cells, dinaciclib lowered cortisol secretion and downregulated CYP11A1, CYP17A1, CYP21A2, SF-1, and GR transcripts, as well as GR protein expression. In parallel, dinaciclib broadly suppressed CDK1/2 axis and their downstream signalling proteins, including cyclin E1, and p21Waf1/Cip1, consistent with G1/S blockade. Plogosertib increased p-CDK1(Tyr15), cyclin B1, and γ-H2AX levels, indicative of DNA damage and mitotic stress. These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo.
2026-08-12 | Frequent antecedent nodules and diagnostic gaps in adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare and often fatal malignancy currently only cured by surgery. Large-scale studies have failed to capture benign to malignant transition events, and patients often present with metastatic disease. These observations suggest ACC develops rapidly without a measurable precursor lesion, forming the basis of widely implemented adrenal incidentaloma guidelines. We aimed to characterize the prevalence of antecedent adrenal nodules, quality of preoperative diagnostic workup, and the impact on survival for adults with ACC. We analyzed clinical data from 108 consecutive patients referred to a single tertiary academic medical center from 2000 to 2025. Median follow-up was 86.7 months. Strikingly, 31.7% harbored antecedent nodules, indolent for a median 4.68 years before ACC presentation, and ultimately associated with a higher risk of death (adjusted hazard ratio [HR], 2.9; 95% CI, 1.39-6.0). Regarding preoperative evaluation, 46.4% were referred to endocrinology, associated with more complete hormonal assessment; 31.4% had adrenal biopsy, accompanied by increased risk of progression (adjusted HR, 2.53; 95% CI, 1.24-5.2) and death (adjusted HR, 2.22; 95% CI, 1.07-4.6). Patients with high-grade disease received more interventions; those who received mitotane and/or locoregional therapies had improved survival (adjusted HR, 0.31; 95% CI, 0.14-0.71, and adjusted HR, 0.47; 95% CI, 0.23-0.98, respectively). The unexpectedly high prevalence of indolent antecedent adrenal nodules suggests a prolonged, clinically premalignant phase in a subset of ACC. Initial diagnostic evaluation was often incomplete or inappropriately invasive, compromising the preoperative window and patient survival. These findings challenge current surveillance paradigms, revealing an extended but vulnerable window for surgical cure.
2026-08-06 | Real-world safety profile of mitotane in adrenocortical carcinoma: a retrospective cross-sectional study integrating pharmacovigilance and interpretable machine learning.
Mitotane remains the cornerstone of adrenocortical carcinoma. However, its real-world safety profile is poorly defined. This study systemically evaluated mitotane-associated adverse events (AEs) and characterized multivariable patterns of serious outcomes using a combined pharmacovigilance and machine learning approach. Mitotane-related AE reports (2004-2025) were extracted from the FDA Adverse Event Reporting System (FAERS). Disproportionality analyses were performed via four algorithms. Detected signals were categorized using a clinical priority scoring system based on signal strength, mortality, seriousness, and existing evidence. Time-to-onset was evaluated utilizing Kaplan-Meier methods. Elastic net logistic regression and Extreme Gradient Boosting (XGBoost) models characterized features associated with serious outcomes, with performance assessed by the area under the receiver operating characteristic curve (AUROC). Among 870 identified reports, 45.7% involved serious outcomes. We detected 75 safety signals, predominantly involving gastrointestinal, neurological, endocrine, and metabolic systems. Notably, 21 signals (28.0%) were assigned moderate clinical priority, with adrenal insufficiency as the highest-priority signal. Time-to-onset analysis showed that endocrine AEs had a significantly longer onset time than non-endocrine AEs. Both models demonstrated consistent characterization of multivariable patterns associated with serious outcomes (elastic net AUROC = 0.830, XGBoost AUROC = 0.869). Key contributors to serious outcomes included reporting country, medical event designation, organ system involvement, and medication complexity. This large-scale study provides a real-world safety assessment of mitotane. Integrating signal detection, clinical prioritization, and interpretable machine learning reveals multivariable patterns underlying serious AEs. These findings support a risk-stratified monitoring approach to enhance the clinical safety of mitotane therapy.
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Drug Discovery Landscape
9 orphan drug designations for Adrenocortical carcinoma.
9 orphan drug designations for Adrenocortical carcinoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Acetyl-D-tyrosylglycyl-D-arginyl-D-lysyl-D-lysyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D arginyl-D-arginylglycyl-D-lysyl-D-threonyl-D-leucyl-D-arginyl-D-valyl-D-alanyl-D-lysyl-D-alanyl-D-isoleucyl-D-tyrosyl-D-lysyl-D-arginyl-D-tyrosyl-D-isoleucyl-D-isoglutamine, acetate salt | peptides | FDA | 2024-07-01 | — | Cytovation AS |
N-[2,6-bis(1-methylethyl)phenyl]-N’-[[1-[4-(dimethylamino) phenyl]cyclopentyl]methyl]urea, hydrochloride salt | small molecules | EMA | 2013-06-07 | — | Millendo Therapeutics SAS |
Linsitinib | small molecules | EMA | 2012-04-02 | — | Astellas Pharma Europe B.V. |
nevanimibe HCL | small molecules | FDA | 2012-03-09 | — | Millendo Therapeutics, Inc. |
linsitinib | small molecules | FDA | 2012-03-09 | — | Astellas Pharma Global Development, Inc. |
Mitotane [Mitotane AP-HP 500 mg, capsules] | small molecules | EMA | 2002-09-11 | — | AGEPS |
Mitotane [Lysodren] | small molecules | EMA | 2002-06-12 | — | [INACTIVE] Laboratoire Hra Pharma |
Gossypol | small molecules | FDA | 1990-10-22 | — | Reidenberg, Marcus M. M.D. |
Iodine 131 6B-iodomethyl-19-norcholesterol | small molecules | FDA | 1984-08-01 | — | David E. Kuhl, M.D. |
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