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Targeting pediatric adrenocortical carcinoma: Molecular insights and emerging therapeutic strategies
Michaela Kuhlen İD Maximilian Schmutz “, Marina Kunstreich a,d, Antje Redlich d, Rainer Claus b,e
a Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany
b Bavarian Cancer Research Center (BZKF), Augsburg, Germany
” Hematology and Oncology, Faculty of Medicine, University of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany
d Department of Pediatrics, Pediatric Hematology/Oncology, Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany
e Pathology, Faculty of Medicine, University of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany
ARTICLE INFO
Keywords:
Children and adolescents Adrenocortical carcinoma Therapy Overview
ABSTRACT
Pediatric adrenocortical carcinoma (pACC) is an exceptionally rare and aggressive malignancy, accounting for only 0.2-0.3% of childhood cancers. Characterized by significant endocrine activity and often associated with genetic syndromes such as Li-Fraumeni syndrome, pACC exhibits distinct clinical and molecular profiles compared to adult adrenocortical carcinoma (ACC). Current treatment approaches, largely adapted from adult protocols, center on surgery and chemotherapy, including mitotane. However, the lack of pediatric-specific data and major clinical trials underscores a pressing need for tailored therapeutic strategies.
Advances in molecular profiling have unveiled actionable targets, such as alterations in the Wnt/ß-catenin and MAP/ERK pathways, overexpression of IGF2, and epigenetic dysregulation. Emerging therapies, including im- mune checkpoint inhibitors, CAR T-cell therapy, and radiopharmaceuticals, hold promise but remain largely untested in pediatric populations. Targeting metabolic vulnerabilities, such as steroidogenesis and lipid meta- bolism, offers additional avenues for therapeutic innovation. Furthermore, improved diagnostic tools like liquid biopsy and steroid profiling may enhance disease monitoring and early detection.
Despite progress in understanding pACC biology, significant challenges remain in translating these insights into effective treatments. Collaborative efforts, such as the European Cooperative Study Group for Pediatric Rare Tumors (EXPERT), and the development of pediatric-specific clinical trials are vital for advancing the field. Multidisciplinary care and international research initiatives will be pivotal in addressing the unmet needs of pACC patients.
By leveraging molecular insights and fostering global collaboration, the field can move toward personalized medicine, improving outcomes and quality of life for children with this challenging disease. Expanding clinical trials, refining diagnostic tools, and integrating novel therapies into treatment regimens will be critical in bridging the gap between pediatric and adult ACC treatment success.
Pediatric adrenocortical carcinoma - A rare and unique entity
Pediatric adrenocortical tumors (pACTs) are a spectrum of neo- plasms originating from the adrenal cortex, ranging from benign ade- nomas to carcinomas [1,2]. Among these, pediatric adrenocortical carcinoma (pACC) is an exceptionally rare and aggressive malignancy, accounting for just 0.2-0.3 % of childhood cancers, with an incidence of 0.3-0.7 cases per million children annually [3,4].
pACC shows two distinct age-related peaks: early childhood (before
age 4) and adolescence, with a marked female predominance [3,5-7]. A hallmark feature is excessive steroid hormone secretion (cortisol, aldo- sterone, androgens, estrogens), leading to clinical manifestations like virilization and Cushing syndrome [5,7,8].
Genetic predisposition is pivotal in pACC pathogenesis, with ~ 60 % of cases linked to syndromes such as Li-Fraumeni (LFS) and Beckwith- Wiedemann (BWS) [9,10].
Complete surgical resection remains the primary treatment and key prognostic factor [2,7,11,12]. In advanced disease stages, including
* Corresponding author at: Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany. E-mail address: Michaela.Kuhlen@uk-augsburg.de (M. Kuhlen).
https://doi.org/10.1016/j.ctrv.2025.102942
stage III, stage IV tumors, and unresectable disease, (neo)adjuvant or palliative therapies, including chemotherapy and mitotane, show limited efficacy with 5-year survival rates of 20-50 % which highlights the urgent need for novel, effective therapies [2,3,11,13-15].
The rarity of pACC poses a major challenge, as evidence from treatment trials is limited; phase III data are almost entirely lacking and unlikely to emerge. Thus, pACC may serve as a model disease for very rare cancers, where mechanistic understanding can guide therapeutic strategies despite the absence of high-level clinical evidence. Deep molecular insights inform urgently needed improvements in therapy, not only for pACC but also for other rare and difficult-to-treat cancers lacking standardized treatment approaches [16].
Molecular and genetic insights
Molecular subgroups
Pinto et al. identified common tumorigenic mechanisms in 37 pACTs, including overexpression of insulin-like growth factor 2 (IGF2), dysregulation of the Wnt/B-catenin pathway (CTNNB1), and telomere maintenance dysfunction via ATRX mutations [17] (Fig. 1).
These findings delineate molecular subgroups defined by specific genetic alterations driving tumor development and progression. The primary alterations include:
TP53 mutations: Germline TP53 mutations are found in a high proportion of pACC cases, [17] particularly in children under age 12,
with reported rates of 50 %-80 %. This frequency drops to 25 % in pa- tients aged 12-20 years [10]. Additionally, somatic TP53 mutations occur in ~ 25 % of tumors with wild-type germline TP53 [17]. TP53 plays a pivotal role in cell cycle regulation and tumor suppression.
ATRX mutations: Somatic ATRX mutations, identified in 32 % of ACTs, are exclusively associated with germline TP53 mutations. ATRX encodes a helicase involved in chromatin remodeling and telomere maintenance.
ß-Catenin activation: CTNNB1 mutations are present in ~ 18 % of pACTs, leading to dysregulated Wnt/ß-catenin signaling. These muta- tions are only seen in tumors with wild-type germline TP53.
Based on these alterations, Pinto et al. [17] classified pACTs into three molecular subgroups, with Group 1 showing significant poorer survival compared to Groups 2 and 3:
Group 1: Germline TP53 and somatic ATRX mutations.
Group 2: Germline TP53 mutations and no ATRX mutation
Group 3: Both wild-type TP53 and ATRX.
DNA methylation studies further refined these classifications. Clay et al. identified two DNA methylation-based subgroups, pACT-1 and pACT-2, associated with clinical outcomes [18]. pACT-1 tumors, enriched for CTNNB1 mutations, were associated with poor prognosis, while pACT-2 tumors, enriched for TP53 germline variants, showed favorable outcomes and earlier onset. This contrasts with Pinto et al., where TP53 germline alterations were associated with poorer survival [17]. These discrepancies may reflect differences in TP53 variant types, patient age, or tumor biology. Notably, the CpG-island hypermethylator
Wnt Signaling Pathway Dysregulation
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phenotype observed in adult ACC was absent in pACT.
Expanding on these findings, recent methylation- and transcriptome- based analyses revealed four molecularly distinct subgroups [19,20]. A high-risk subgroup demonstrated significantly reduced 5-year overall survival (OS; 27 %) compared to 81 %-95 % in other subgroups. These tumors were diagnosed at higher ages and exhibited heightened prolif- eration programs.
Together, these molecular insights define the genetic underpinning of pACC and help guide efforts toward developing targeted therapies tailored to specific molecular subgroups.
Non-Coding RNA dysregulation
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are increasingly recognized as critical regulators in the pathogenesis of pACT [21-23]. miRNAs, which post- transcriptionally regulate gene expression by targeting mRNA 3’ un- translated regions (UTRs), are implicated in oncogenesis and tumor suppression. While distinct miRNA expression patterns are well- characterized in adult ACC (reviewed in [18,19]), their role in pACC is now emerging, with significant implications for prognosis and ther- apeutic development.
Three pivotal studies have shed light on miRNA dysregulation in pACT. In the first, miR-149-3p was overexpressed in 67 pACT samples compared to non-neoplastic adrenal tissues. This miRNA was associated with unfavorable outcomes and promoted tumor cell viability, prolif- eration, and colony formation in vitro. Mechanistically, it down- regulated CDKN1A (p21), disrupting normal cell cycle control. These findings highlight miR-149-3p as a potential therapeutic target [21].
A second study identified miR-99a and miR-100 as regulators of the IGF-mammalian target of rapamycin(mTOR)-raptor signaling pathway in pACT. These miRNAs modulate mTOR signaling by binding 3’ UTRs of target genes, influencing tumor proliferation and survival. Inhibition of mTOR with everolimus reduced tumor growth in vitro and in vivo, underscoring the therapeutic relevance of targeting miRNA-mTOR in- teractions [22].
The third study profiled miRNA expression in 37 pACT samples and nine non-neoplastic tissues, identifying 98 differentially expressed miRNAs. A 17-miRNA signature strongly correlated with clinical out- comes, including relapse and mortality. Higher expression of hsa-miR- 630, -139-3p, and -125a-3p, and lower levels of hsa-miR-377-3p, -126-3p, and -410, stratified patients into two prognostic groups with distinct 5-year event-free survival (EFS) rates. This signature was an independent prognostic factor, offering a robust biomarker for risk stratification [23].
lncRNAs, another major ncRNA class, function as epigenetic regu- lators, scaffolds, and decoys, modulating chromatin remodeling and gene expression. In adult ACC, specific lncRNAs such as ASB16-AS1 have been implicated in tumor suppression via promoting of HuR ubiquiti- nation [24].
Other ncRNA classes, including piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs), are also dysregulated in ACC and influence genomic stability and tumor suppressor pathways [25]. Although their role in pACC is less well defined, they likely contribute to the regulatory networks underlying tumorigenesis.
Collectively, these findings underscore the importance of ncRNA dysregulation, particularly miRNAs, in pACC biology. Emerging evi- dence supports their value in prognosis and therapy, with miR-149-3p and the 17-miRNA signature offer promising diagnostic and therapeu- tic avenues.
Cancer predisposition syndromes
pACC is frequently associated with cancer predisposition syndromes (CPS), highlighting a strong link between tumor development and
hereditary genetic factors.
Li-Fraumeni syndrome (LFS)
LFS is caused by pathogenic variants in TP53, a key tumor suppressor involved in cell cycle regulation and apoptosis [26]. It is strongly associated with pACC, which represents the second most common ma- lignancy in children with LFS, accounting for ~ 27 % of cases [27]. Notably, the TP53 p.R337H (c.1010G > A, p.Arg337His) founder variant is highly prevalent in Brazilian populations, where 80-100 % of pACT cases are linked to LFS [28,29,30].
Beckwith-Wiedemann syndrome (BWS)
BWS is an overgrowth syndrome associated with epigenetic abnor- malities of chromosome 11p15.5, including IGF2 dysregulation. pACTs account for ~ 3 % of tumors in BWS and typically occur in early childhood [31-33].
Familial Adenomatous Polyposis (FAP)
FAP has also been associated with ACTs, including ACC [34,35]. APC mutations and subsequent activation of the Wnt/ß-catenin pathway may contribute to adrenal tumorigenesis [34].
Other syndromes occasionally linked to pACTs include Multiple Endocrine Neoplasia type 1 (MEN1) [36,37] and Carney Complex (CNC) [38], though these associations are less well established.
Hormonal and metabolic Aspects
Steroid hormones and metabolomics are central to recent adult ACC research, reflecting the adrenal gland’s pivotal role in steroid produc- tion. These hormones arise through steroidogenesis, a cascade con- verting cholesterol into cortisol, aldosterone, androgens, and estrogens [39]. In ACC, dysregulated steroidogenesis-marked by altered ste- roidogenic enzymes and receptors-not only drives tumor biology but also offers diagnostic and prognostic biomarker potential.
Plasma steroid hormone profiling
Plasma steroid hormone profiling shows promise as a diagnostic tool in adult ACC. In one LC-MS/MS-based study, 15 steroid hormones were measured in 66 ACA and 42 ACC patients [40]. ACC cases showed elevated levels of 11-deoxycorticosterone, progesterone, 17-hydroxy- progesterone, 11-deoxycortisol, DHEA, DHEAS, and estradiol. Logistic regression identified six steroids that improved diagnostic accuracy, with positive predictive values of 92 % in men and 96 % in women, and negative predictive values of 90 % and 86 %, respectively.
Serum steroid profiling has also been explored for monitoring disease progression and recurrence. In a cohort of 89 patients, markers like 11- deoxycortisol and testosterone detected “endocrine progress” before radiological evidence by a median of 32 days, underscoring the potential of LC-MS/MS for early disease detection [41].
Urine steroid hormone profiling
Urine steroid hormone profiling also shows utility in adult ACC. Several studies report significantly increased urinary excretion of androgen, mineralocorticoid, and glucocorticoid metabolites in ACC compared to ACA [42,43]. One study demonstrated that urinary profiling could distinguish malignant tumors in Cushing syndrome and adrenal neoplasms with over 90 % sensitivity and 100 % specificity [44]. Combining urinary profiling with imaging, (e.g., CT) and tumor diameter has enhanced diagnostic performance in evaluating adrenal incidentalomas [45].
A proof-of-concept study using GC-MS and machine learning detected recurrent ACC with 81 % sensitivity and specificity. Recurrent cases shared urinary profiles with their primary tumors, suggesting that preoperative profiling may aid in early recurrence detection [46].
Hormonal and metabolic insights in pediatric ACC
Data on steroid hormone metabolism in pACC remain limited, but recent GC-MS urinary steroid hormone profiling has yielded promising diagnostic insights. In one study, pACT patients showed elevated 5-ene- steroid metabolites (e.g., pregnenolone, 17-hydroxypregnenolone, DHEA) along with reduced activity of enzymes like 36-hydroxysteroid dehydrogenase and 11-hydroxylase.
Importantly, GC-MS profiling distinguished pACCs from pACAs through metabolic signatures, including decreased corticosterone me- tabolites, increased 17-hydroxylase activity, and reduced 5x-reductase activity. These biomarkers achieved diagnostic accuracies exceeding 0.7 (ROC), supporting the potential of metabolic profiling as a non-invasive tool for pediatric ACC diagnosis [47]. Crucially, these metabolic profiles differ significantly from those observed in adult ACC, where distinct steroidogenic patterns and biomarker profiles have been reported.
A direct comparison between plasma and urinary steroid hormone profiling, as well as LC-MS/MS and GC-MS methodologies, remains largely unexplored in pACC. While LC-MS/MS-based plasma profiling is more accessible, its diagnostic performance relative to GC-MS urinary profiling in children is currently unknown. Standardizing steroid hor- mone profiling in pACC could substantially improve diagnosis, surveil- lance, and clinical management of pACC, enabling earlier detection, better risk stratification, and more personalized care.
Pediatric versus adult adrenocortical carcinoma
Pediatric and adult ACC exhibit distinct clinical, hormonal, genetic, and molecular characteristics, highlighting the need for age-specific management strategies. These differences influence not only presenta- tion but also underlying biology and therapeutic approaches. (reviewed in [48,49]).
pACC typically shows significant endocrine activity, with symptoms such as virilization and Cushing syndrome commonly observed. In contrast, adult ACC often presents with non-functional tumors or iso- lated Cushing syndrome. Hormonal profiles in pACC are generally more pronounced, primarily driven by excess androgen production, whereas adult ACC exhibits a greater hormonal heterogeneity [8,50].
The genetic landscape of pACC also differs markedly. Pediatric cases are more frequently associated with inherited syndromes, most notably LFS, whereas adult ACC more often involves somatic mutations in genes such as CTNNB1 and ZNRF3, reflecting alterations in the Wnt/ß-catenin pathway. pACC also shows a higher prevalence of somatic chromosomal alterations and a distinct set of driver mutations [17,49].
In adult ACC, genomic profiling has identified actionable mutations in a subset of cases., approximately 10 % in unselected cohorts and up to 50 % in metastatic tumors. In contrast, only ~ 3 % of pACC cases harbor potentially actionable alterations, further underscoring the unique mo- lecular landscape of pACC [49].
Prognosis is generally more favorable in pACC, likely due to differ- ences in tumor biology and the greater effectiveness of surgical resection in younger patients [2,14,51-53]. Treatment approaches reflect these differences: surgery remains central to management in both groups, but in pACC, it is more commonly combined with chemotherapy [14,52,54-56]. Mitotane is more frequently used in adults [54,56,57]. Pediatric strategies prioritize balancing efficacy with long-term out- comes, while adult ACC often necessitates aggressive chemotherapy and is increasingly exploring targeted therapies [57-59].
While pACC and adult ACC share some overlapping features, their distinct genetic, hormonal, and clinical profiles necessitate tailored diagnostic and treatment approaches. Recognizing and addressing these differences is essential to improving outcomes and delivering age- appropriate care.
Current conventional therapeutic approaches in pACC
The clinical management of pACC follows a multimodal approach, combining surgical resection, chemotherapy, and mitotane therapy based on disease stage. The overarching goal is complete tumor removal and effective control of residual or metastatic disease.
The Children’s Oncology Group (COG) classifies pACC into four stages according to disease extent and tumor characteristics (Table 1), guiding treatment and prognostic assessment [14].
Surgery
Surgical resection remains the cornerstone of localized pACC treat- ment. Adrenalectomy with R0 resection offers the best chance for long- term survival [2,3,11,13,14]. Michalkiewicz et al. reported a 5-year event-free survival (EFS) of 54 % with complete resection vs. 15 % with incomplete resection, a finding confirmed in subsequent studies [2,3,7,11-13]. Given the rarity and complexity of pACC, treatment at specialized pediatric oncology centers is recommended.
Chemotherapy
Chemotherapy is essential in advanced, residual, or metastatic dis- ease, especially when initial resection is not feasible. Neoadjuvant chemotherapy may help downstage tumors and facilitate surgery [2,3,13-15]. The EDP regimen (etoposide, doxorubicin, cisplatin) plus mitotane is standard, though significant toxicity occurs in about one- third of patients [14]. Similar outcomes and toxicity have been re- ported with the alternating NN I/II regimen combined with mitotane [2,60].
Streptozotocin, in combination with mitotane, demonstrated efficacy in adult ACC in the FIRM-ACT trial [51]. However, its role in pACC remains undefined due to lack of pediatric-specific evidence.
Mitotane requires close monitoring due to its narrow therapeutic index and potential side effects, including adrenal insufficiency, gastrointestinal symptoms, and neurotoxicity [14,15,61].
The COG ARAR0332 trial stratified treatment by stage: Stage I pa- tients fared well with surgery alone; stage III patients receiving EDP- mitotane had excellent outcomes; stage IV patients continued to have poor prognosis despite aggressive therapy [14]. However, stage II pa- tients experienced high recurrence rates despite RPLND. This may reflect tumors with more aggressive biology, such as high Ki67 index, - not captured by conventional staging systems [57,62].
Radiation therapy
Radiation therapy is selectively used for local control in cases of incomplete resection, recurrence, or palliative treatment in metastatic disease [63,64]. Due to potential long-term side effects, especially in genetically predisposed children (e.g., LFS), its use is limited by the risk of secondary malignancies.
Challenges in treating pACC
pACC poses significant clinical challenges due to its aggressive behavior, high metastatic potential, and frequent relapse. Current treatment strategies often fall short, highlighting the urgent need for improved approaches informed by molecular insights.
Metastatic Disease: Obstacles and Limitations
Metastatic pACC progresses rapidly and most commonly spreads to the liver, lungs, and lymph nodes [2,14,63]. Management is difficult: complete surgical resection is rarely feasible, and debulking, while reducing tumor burden, is not curative and carries surgical risk [7]. Standard systemic therapies - mitotane, etoposide, doxorubicin, and
| COG stage | Definition | Treatment according to COG ARAR0332 protocol [14] | Treatment according to GPOH-MET 97 protocol [60]# | Therapeutic recommendations according to EXPERT/ PARTNER [1] |
|---|---|---|---|---|
| Stage I | Completely resected, small tumors (<100 g and < 200 cm3) with normal postoperative hormone levels. | Tumor resection | Stage I-III: T1-3, N0, M0 Tumor resection | Tumor resection |
| Stage | Completely resected, large tumors (≥100 g and ≥ 200 cm3) | Tumor resection plus | Tumor resection | |
| II | with normal postoperative hormone levels. | retroperitoneal lymph node dissection (RPLND) | Consider mitotane | |
| Stage III | Unresectable tumors, presence of gross or microscopic residual disease, tumor spillage, patients with stage I and II tumors who do not achieve normal hormone levels postoperatively, or patients with nodal involvement | 8 cycles of EDP chemotherapy | Stage III: T1-2, N1, MO* Tumor resection 4 cycles of adjuvant NN I/ | Tumor resection 6 cycles of (neo)adjuvant chemotherapy |
| Mitotane for 8 months, Tumor resection plus RPLND | ||||
| NN I chemotherapy Mitotane for 9 months | Mitotane for 1-2 years* | |||
| Stage IV | Presence of distant metastases. | 8 cycles of EDP chemotherapy | Tumor resection and resection of metastases as | Tumor resection and resection of |
| Mitotane for 8 months* | metastases as clinically indicated | |||
| Resection of primary tumor plus | clinically indicated | 6-8 cycles of (neo)adjuvant | ||
| RPLND and of metastases as | 8 cycles of (neo)adjuvant NN I/NN I chemotherapy Mitotane for 18 months | chemotherapy (EDP or NN I/ | ||
| clinically indicated | NNII) | |||
| Mitotane for 1-2 years* |
# according to American Joint Committee Cancer 7th edition.
cisplatin - achieve modest control, with median progression-free sur- vival (PFS) of 5-9 months. Resistance frequently develops, limiting long- term efficacy [2,14,60,65].
Resistance mechanisms, such as genetic alterations and dysregulated signaling, remain poorly understood and present major barriers to progress [63]. Additionally, current imaging and biomarker tools fail to detect small metastases or early relapse, underscoring the need for better monitoring strategies.
High risk for relapse and refractory disease
Relapse and refractory disease are common, even after aggressive multimodal treatment [14,63]. Recurrence occurs in 37-50 % in stage II patients and exceeds 70 % in advanced stages (III and IV). Risk factors include positive margins, tumor spillage, large tumor size, and older age [2,3,13,14,66]. Management of refractory disease is complicated by rapid progression and resistance to conventional therapies.
Surgical re-resection can be critical for long-term survival in select relapsed cases [63]. Molecular drivers of resistance, such as alterations in the Wnt/B-catenin pathway, highlight the need for targeted strategies [9,18,19]. While imaging and hormone monitoring are standard, there is growing interest in circulating tumor DNA (ctDNA) as a more sensitive tool for early relapse detection.
Unmet needs and future Directions
The lack of standardized second-line treatment protocols in pACC often necessitates individualized treatment, made more challenging by limited first-line options. No validated biomarkers currently exist to guide therapy or predict outcomes. The scarcity of actionable molecular targets further limits development of precision therapies. Most available treatment data are derived from adult populations, creating uncertainty in pediatric care.
Moving forward, several priorities must be addressed: comprehen- sive molecular profiling to identify novel therapeutic targets; develop- ment of predictive biomarkers to guide individualized therapy; evaluation of targeted treatments aimed at key drivers of resistance and progression; and exploration of novel strategies including immuno- therapies and rational drug combination. Crucially, more pediatric- specific data are needed to inform clinical decisions in this unique pa- tient population.
In conclusion, overcoming the challenges of metastatic, relapsed, and refractory pACC will require a deeper understanding of its biology and the development of innovative, multimodal treatment strategies.
Preclinical models in pACC research
The development of targeted therapies for pACC is significantly hindered by the lack of robust preclinical models. In contrast to adult ACC, where human-derived cell lines and patient-derived xenografts (PDX) support translational research, pediatric equivalents are extremely limited or absent. The scarcity of pACC-specific cell lines and PDX models restricts functional studies of disease biology, evaluation of drug efficacy, and the translation of preclinical findings into clinical practice [67-70].
Advanced targeted therapies
Managing pACC remains challenging due to its aggressive nature and resistance to conventional therapies. Comprehensive genomic and multi-omics profiling is crucial to identify actionable mutations and tailor therapies that improve outcomes in high-risk cases [71,72].
This section reviews promising targeted therapies and the current state of research, most of which is derived from adult ACC patients.
Genomic and molecular targets
Targeting p53
TP53 encodes the tumor suppressor p53, a key regulator of cell cycle arrest, DNA repair, and apoptosis. Given the high frequency of both germline and somatic TP53 mutations in pACC, [10,17] targeting p53 dysfunction represents a compelling therapeutic strategy. (Fig. 1).
Small molecules like PRIMA-1 and APR-246 (Eprenetapopt) aim to reactivate mutant p53 and induce apoptosis in cancer cell lines, though ACC-specific data remain limited [73,74].
MDM2 inhibitors prevent p53 by disrupting the p53-MDM2 inter- action. Preclinical studies, including those in adult ACC, show promise with agents like Nutlin-3. Although no MDM2 inhibitors are currently approved, newer compounds, with orphan or fast-track designations, seek to improve potency, pharmacokinetics, and toxicity [75-77].
Given the central role of p53 in pACC, developing therapies that restore or stabilize p53 function, ideally in pediatric-specific trials, should be a priority. Combining MDM2 inhibitors or p53-restoring agents with chemotherapy or other targeted strategies may offer future treatment options.
Insulin-like growth factor (IGF) pathway inhibitors
The IGF2 pathway is essential for cell growth and development, and IGF2 overexpression is observed in nearly all pACC cases [17,78]. Tar- geting this axis offers significant therapeutic potential, though efficacy
in pediatric settings remains uncertain. (Fig. 1).
Current efforts focus on insulin-like growth factor 1 receptor (IGF1R) inhibitors, such as linsitinib (OSI-906), which block downstream tumor proliferation signals. IGF1R overexpression, linked to mTOR activation, correlates with relapse and metastasis in pACC [78,79]. In adult ACC cell lines, linsitinib reduced viability and induced apoptosis; combining IGF1R inhibitors with mitotane enhanced tumor suppression in vitro and in xenografts [78,80].
A phase I study of linsitinib showed tolerability with two adult ACC patients achieving partial responses at specific doses, though overall response rates were limited [81]. A subsequent phase III trial in meta- static ACC found no significant benefit over placebo [82]. Similarly, in a phase II trial of cixutumumab, a monoclonal IGF1R antibody, one of ten children with refractory pACC achieved stable disease [83].
Ongoing research is exploring predictive biomarkers and rational combination therapies, including co-targeting IGF1R and mTOR. The mTOR pathway integrates IGF signals and contains feedback loops linking mTORC1 and IGF signaling [84,85]. Importantly, given IGF1Rs role in normal growth and development, particularly in children, po- tential adverse effects on linear growth must be carefully monitored in clinical trials. Co-targeting IGF1R and mTOR may enhance efficacy and overcome resistance, but further research is needed to establish safety and effectiveness.
Developmental pathways in tumorigenesis
Wnt/B-Catenin pathway inhibitors
The Wnt/ß-catenin pathway regulates cell proliferation, differentia- tion, and survival. Dysregulation is common in pACC and associated with high-risk disease [17,19]. Mutations in CTNNB1, which encodes ß-catenin, are associated with aggressive tumor behavior and poor outcomes [17]. Targeting this pathway to restore normal signaling and inhibit tumor growth holds therapeutic potential [86,87] (Fig. 1).
Preclinical studies support this strategy. Rottlerin reduced prolifer- ation, induced apoptosis, and caused G0/G1 arrest in adult ACC cell lines by downregulating LRP6 and ß-catenin. In a nude mouse ACC model, it inhibited tumor growth and promoted apoptosis [88]. Abduch et al. found that YAP1, a downstream target of Wnt/ß-catenin signaling, is overexpressed in pACT and correlates with poor prognosis, recur- rence, and lower survival. Interestingly, inhibition of Wnt/ß-catenin using PNU-74654, a Wnt/B-catenin inhibitor, paradoxically increased YAP1 mRNA in adult ACC cell lines, suggesting compensatory mecha- nisms that may limit the efficacy of pathway inhibitors [89].
Despite its promise, clinical translation of Wnt pathway inhibitors remains challenging due to the pathway’s complexity and vital physi- ological roles. Current approaches involve combining Wnt/ß-catenin inhibitors with agents targeting parallel pathways (e.g., Hedgehog/GLI inhibitors) or using AI-driven drug screening to identify optimal com- binations [90,91].
Hedgehog pathway inhibitors
The Hedgehog (Hh) signaling pathway is critical for embryogenesis and adrenal cortex development and remains active in both fetal and adult adrenal tissues. Its dysregulation has been observed in several cancers, including ACC. In pACTs, significantly reduced mRNA expres- sion of SHH, PTCH1, SMO, GLI1, and GLI3 has been reported compared to normal pediatric adrenal tissue [92] (Fig. 2).
Preclinical studies suggest that inhibiting Hh signaling has anti- tumor potential. Cyclopamine reduced cell viability in adult ACC cell lines, while NVP-LDE225 (a Smoothened inhibitor) reduced tumor growth and hormone secretion in ACC models [92,93].
Though promising, pediatric-specific data remain scarce. FDA- approved Hh pathway inhibitors, such as vismodegib and sonidegib, are effective in basal cell carcinoma. However, in a phase I trial including two adult ACC patients, vismodegib did not produce any clinical responses [94].
In summary, while preclinical data support Hh pathway inhibition, its therapeutic role in ACC-especially pACC- remains unclear and warrants further study.
Notch pathway inhibitors
The Notch signaling pathway governs cell differentiation, prolifera- tion, and apoptosis. Although widely implicated in cancer, effective clinical targeting remains limited. Emerging evidence suggests that antibody-drug conjugates (ADCs) targeting Notch ligands could be promising for ACC. (Fig. 2).
DLK1, a non-canonical Notch ligand, is overexpressed in adult ACC and represents a compelling target. Preclinical studies show that DLK1- directed ADCs like ADCT-701 exert potent cytotoxic effects in DLK1- positive ACC cell lines and patient-derived organoids by inducing DNA damage through receptor-mediated internalization [95].
Encouraged by these findings, a phase I trial (NCT06041516) is now evaluating ADCT-701 in adults with ACC and other tumor types, a step toward clinical translation [95].
Key challenges include confirming DLK1 specificity to avoid off- target toxicity and determing the feasibility of this approach in pACC.
Other Kinase pathways and enzymatic targets
Aurora Kinase inhibitors
Aurora kinases (AURKA and AURKB) regulate mitosis, including chromosome segregation and cytokinesis. Their dysregulation is impli- cated in various cancers, including ACC. Overexpression of AURKA/ B has been linked to poor prognosis in pACT, with higher expression correlating with reduced EFS and more aggressive phenotypes [96]. Targeting these kinases via Aurora kinase inhibitors (AKIs) may disrupt tumor cell proliferation and survival. (Fig. 2).
Preclinical studies have shown AKIs reduce proliferation and induce apoptosis in adult ACC models. AMG 900 increased apoptosis and enhanced chemosensitivity in the NCI-H295 cells [96,97]. Combined with PNU-74654 it produced greater tumor growth inhibition than
NOTCH signaling pathway Dysregulation
Hedgehog (Hh) signaling pathway dysregulation
Dysregulation and overexpression of Aurora kinase A and B
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either agent alone [97].
The AKI ZM447439 inhibited proliferation in a childhood ACT cul- ture with the TP53 p.R337H mutation [96]. However, the AKI VX-680 showed limited efficacy in the H295R cells, emphasizing the need for model-specific approaches [98].
In summary, AKIs show promise in preclinical ACC models, but their clinical utility in pACC remains to be defined.
(Multi) Tyrosine Kinase inhibitors
Tyrosine kinases (TKIs), including receptor tyrosine kinases (RTKs), regulate proliferation, survival, migration, and angiogenesis. Sorafenib, targeting VEGFR, PDGFR, RET, and others, showed activity in adult ACC models, but residual disease limited long-term efficacy [99]. Similarly, the SIRAC trial of sunitinib showed modest results [100]. Notably, mitotane’s CYP3A4 induction may reduce TKI efficacy and should be considered in treatment planning.
Combination strategies appear more effective. Sorafenib plus ever- olimus synergistically inhibited tumor growth and promoted apoptosis [101]. Cabozantinib (C-Met, VEGFR2, AXL, RET) achieved a 4-month PFS rate of 76 % and median OS of 24 months, though outcomes may be influenced by prior mitotane exposure [59].
TKIs paired with immune checkpoint inhibitors (ICIs) are also promising. Lenvatinib or cabozantinib plus pembrolizumab achieved a 58.8 % disease control rate and median PFS of 7.1 months in heavily pretreated adult ACC patients [58]. Although pediatric data are limited, a phase I study of cabozantinib in children with refractory solid tumors identified a safe dose of 40 mg/m2/day, providing basis for future studies [102].
In conclusion, while single-agent TKIs show limited efficacy, rational combinations hold greater therapeutic potential.
MAPK/ERK pathway inhibitors
The MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase) pathway downstream of many RTKs regulates cell proliferation, differentiation, and survival. In adult ACC, ERK acti- vation is frequently increased in malignant versus benign adrenal tissues [103].
Preclinical studies show that inhibitors such as PD184352 reduce proliferation and steroidogenesis in adult ACC cells, suggesting this pathway contributes to tumor growth and hormone production [103].
Despite its relevance in adult disease, studies on MAPK/ERK signaling and inhibition in pACC remain lacking.
Pi3K/AKT/mTOR pathway inhibitors
The PI3K/AKT/mTOR axis is central to survival and metabolic signaling and intersects with the IGF1R, MAPK/ERK and Wnt/ß-catenin pathways. It plays a pivotal role in tumor progression and therapeutic resistance.
Dual PI3K/mTOR inhibitors such as PI-103 reduce proliferation and induce apoptosis in primary ACC cultures, including mitotane-resistant tumors [104]. PIK75, combined with HSP90 inhibitor STA9090, induced spheroid disintegration and apoptosis, suppressed PI3K targets (AKT, mTOR) and inhibited epithelial-mesenchymal transition, reducing metastatic potential [105].
While preclinical results are encouraging, clinical exploration in pACC is still absent.
Polo-like Kinase 1 (PLK1) inhibitors
PLK1 is essential for mitotic progression and is overexpressed in 30-60 % of adult ACC cases [106,107]. Inhibitors such as BI-2536 and rigosertib showed significant anti-tumor activity in TP53-mutant adult ACC cells and xenograft models [106,107].
However, clinical trials in pACC are currently lacking.
DNA metabolism and cell cycle control
Alterations in DNA repair and cell cycle regulators contribute to tumor progression and resistance. Targeting these mechanisms offers a promising strategy for precision medicine, particularly in tumors with defects in DNA damage response or checkpoint signaling.
PARP inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors, such as rucaparib and olaparib, target enzymes involved in DNA repair via homologous recombination. Tumors with DNA repair deficiencies are particularly vulnerable, as PARP inhibition induces synthetic lethality in cancer cells.
In adult ACC, PARP inhibitors have shown mixed outcomes; for example, rucaparib showed limited efficacy in a patient with BRCA mutations post-chemotherapy [108]. However, in pediatric cancers, synthetic lethal interactions extent beyond BRCA alterations, indicating broader therapeutic potential [95]. A pediatric-specific synthetic lethal signature outperformed adult-derived signatures in predicting PARP inhibitor response across multiple pediatric tumor types [95],
Combining PARP inhibitors with standard chemotherapies also enhanced efficacy in preclinical pediatric cancer models. Moreover, ribosome biogenesis has been proposed as a predictive biomarker, potentially improving patient selection [109].
While data in pACC are lacking, the ability of PARP inhibitors to exploit DNA repair vulnerabilities makes them promising candidates. Further studies are needed to clarify their role and optimize their use in pACC.
Targeting the CDK4/6/Cyclin D/RB pathway
The CDK4/6/Cyclin D/RB axis regulates cell cycle progression. Cyclin-dependent kinases 4 and 6 (CDK4/6) complexes with Cyclin D to phosphorylate and inactivate the retinoblastoma (RB) protein, promot- ing from the G1-S phase transition. Dysregulation contributes to un- controlled proliferation, and elevated CDK6 expression has been linked to poor prognosis in adult ACC [110].
CDK4/6 inhibitors, such as palbociclib and ribociclib, halt the cell cycle in G1, suppressing tumor growth. Preclinical studies in adult ACC cells have shown these agents reduce viability and induce senescence. Notably, palbociclib also induced apoptosis in RB-deficient ACC cells [110].
In the Pediatric MATCH trial, palbociclib was well tolerated in pa- tients with solid tumors harboring CDK4/6 pathway alterations. How- ever, no objective responses were observed, suggesting limited efficacy as monotherapy [111].
Combination strategies are being explored to improve outcomes. For example, CDK4/6 inhibitors combined with MEK inhibitors (e.g., tra- metinib) may enhance anti-tumor activity by co-targeting complemen- tary pathways [112].
In conclusion, while CDK4/6 inhibitors offers a mechanistic ratio- nale for targeting pACC and show promise in preclinical models, their standalone clinical activity appears limited.
Metabolic pathways
Targeting lipid metabolism and/or steroidogenesis
Lipid metabolism plays a critical role in tumor biology, affecting the tumor microenvironment, cancer progression, and therapeutic response. In adult ACC, transcriptomic studies have revealed alterations in genes involved in lipid and cholesterol metabolism. Upregulation of sphingo- lipid and steroid synthesis genes, such as SGPL1, FDFT1, and SQLE, correlates with poor survival, while PIK3C2B and DGAT1, involved in phosphatidylinositol and glycerol phospholipid metabolism, are down- regulated [113]. These findings suggest that lipid metabolic reprog- ramming supports tumor progression and may offer exploitable vulnerabilities.
Sterol-O-acyl transferase 1 (SOAT1), also known as acyl-CoA acyl- transferase 1 (ACAT1), catalyzes cholesterol esterification, a process essential for maintaining intracellular cholesterol homeostasis. SOAT1 has been implicated in tumor cell growth and survival, making it an appealing therapeutic target [114].
The SOAT1 inhibitor nevanimibe was evaluated in a phase I study in metastatic ACC. While no partial or complete responses were observed, some patients achieved stable disease. Notably, pharmacologic adrenal insufficiency occurred due to reduced steroidogenesis and apoptosis of adrenocortical cells [115]. These findings underscore the dual impact of SOAT1 inhibition on both lipid metabolic and steroid hormone pro- duction. Cholesterol plays a vital role in numerous cellular functions, including membrane integrity, signaling, and energy production. Thus, broader physiological effects of SOAT1 inhibition warrant careful evaluation.
In conclusion, targeting lipid metabolism represents a promising but still exploratory avenue in pACC therapy.
Steroidogenesis
Steroidogenesis, the enzymatic conversion of cholesterol into steroid hormones, is dysregulated in pACC and contributes to both tumor growth and clinical symptoms [8,47]. Key enzymes in this pathway include CYP11A1, CYP17A1, CYP21A2, and CYP11B1, which offer po- tential targets to reduce hormone excess and inhibit tumor progression.
Abiraterone acetate, a CYP17A1 inhibitor approved for prostate cancer, shows anti-secretory effects and has demonstrated potential in preclinical ACC studies [116]. Mitotane, the only FDA- and EMA- approved drug for ACC, controls hormone excess and prolongs recurrence-free survival in adults after radical resection. However, the ADIUVO trial showed limited benefit in low-risk patients [56,117].
In pACC, mitotane’s role is less clearly defined; partial responses have been reported in about one-third of patients receiving neoadjuvant therapy [15].
Ketoconazole can rapidly normalize cortisol levels in adult ACC but does not significantly reduce tumor size; it may be combined with metyrapone to enhance inhibition of steroidogenesis [118-121].
Steroidogeneic factor-1 (SF-1), a transcription factor involved in steroidogenesis and cell proliferation, is often amplified in pACC, mak- ing it a potential therapeutic target [122,123]. SF-1 inverse agonists and combination strategies-including SOAT1 inhibitors or immune check- point inhibitors-may increase efficacy. Continued efforts to develop more selective and less toxic enzyme inhibitors and SF-1 modulators are essential to advance steroidogenesis-targeted therapies for pACC.
Immunotherapeutic approaches to pACC
Immunotherapy has revolutionized cancer treatment by mobilizing the immune system to recognize and attack tumor cells. Strategies that activate T-cells have shown potential in various malignancies.
Innovative immunotherapies
Immune checkpoint inhibitors (ICIs)
ICIs, such as pembrolizumab, avelumab, nivolumab, and ipilimu- mab, block checkpoint proteins (PD-1, PD-L1, and CTLA-4), used by cancer cells to evade immune surveillance. By inhibiting these check- points, ICIs restore T-cell-mediated tumor killing.
In adult ACC, response rates and PFS have been limited. (reviewed in [124]) Three biomarkers - PD-1 and PD-L1 expression, microsatellite instability (MSI), and tumor mutational burden (TMB) - may predict response and help guide patient selection.
Several ongoing trials are exploring ICIs as monotherapy or in combinations in adults. Pembrolizumab is being studied alone (NCT05563467) or with mitotane (NCT05634577) or lenvatinib (NCT05036434). Relacorilant, a glucocorticoid receptor modulator, is being tested with pembrolizumab to counter cortisol-mediated
immunosuppression (NCT04373265). A terminated nivolumab trial re- ported modest activity (median PFS: 1.8 months; NCT02720484). A phase II trial is evaluating cabozantinib and atezolizumab (NCT06006013).
In pACC, data remain sparse. A phase 1-2 trial of pembrolizumab in pediatric patients with advanced melanoma or PD-L1-positive tumors showed partial responses in eight of 136 patients, including one with ACC [125]. While limited, these data emphasize the need for further investigation in pediatric settings. Hypersecretion of cortisol in ACC contributes to immune suppression and may hinder ICI’s efficacy. Combination strategies, such as ICIs with multikinase inhibitors (e.g., lenvatinib, cabozantinib) or glucocorticoid receptor modulators (e.g., relacorilant) aim to enhance immune responsiveness.
Despite modest efficacy in adult ACC and limited pediatric data, ICIs remain a promising avenue. Expanding pediatric-specific trials, identi- fying predictive biomarkers, and evaluating combination regimens are key to optimizing their role in pACC.
CAR T-cell therapy
Chimeric Antigen Receptor (CAR) T-cell therapy uses genetically engineered T cells to specifically target tumor antigens. It has shown remarkable success in hematologic malignancies, and its application to solid tumors is under active exploration.
In pediatric ACC, B7-H3 has emerged as a promising target, expressed in over half of pACT. Preclinical studies with B7-H3-CAR T cells demonstrated potent antitumor effects. In PDX models of pACC, these cells achieved complete tumor eradication in some mice [126,127]. These results suggest CAR T-cell therapy could offer new hope for high-risk or chemotherapy-resistant pACC.
Challenges remain - off-tumor toxicity, immune suppression in the tumor microenvironment, and manufacturing scalability are significant barriers to clinical translation. Nonetheless, the strong preclinical foundation supports moving toward clinical trials of B7-H3-CAR T cells in pACC.
In conclusion, CAR T-cell therapy targeting B7-H3 presents a novel and highly promising approach for pACC. Continued preclinical work and well-designed clinical trials will be critical for realizing its thera- peutic potential.
Epigenetic modifications in pACC
Epigenetic modifications, including DNA methylation and histone modifications, regulate gene expression without changing the underly- ing DNA sequence. In ACC, these modifications contribute to tumori- genesis by silencing tumor suppressor genes, activating oncogenes, and disrupting cell differentiation.
Recent studies have identified high-risk molecular subgroups in pACC characterized by aberrant CpG island methylation and WNT/ B-catenin pathway activation, both associated with poor survival [19]. These findings underscore the potential of epigenetic therapies, partic- ularly in tumors with extensive methylation-driven dysregulation.
DNA methylation inhibitors such as 5-azacytidine (azacitidine) and 5-aza-2’-deoxycytidine (decitabine) inhibit DNA methyltransferases, leading to DNA hypomethylation and reactivation of silenced genes. In preclinical adult ACC models, decitabine reduced tumor proliferation and enhanced the effects of standard chemotherapies such as doxoru- bicin, cisplatin, and etoposide [128,129]. However, epigenetic therapies in ACC remains an emerging field, with most evidence drawn from adult ACC models. Combining epigenetic agents with standard treatments or immunotherapies may improve efficacy by reactivating tumor sup- pressor genes or reshaping the immune microenvironment.
Radiopharmaceuticals
Radiopharmaceuticals offer a novel approach for diagnosing and treating ACC by targeting adrenal cortex-specific enzymes. These agents
provide both imaging and therapeutic potential, with promising results in adult patients. However, their application in pACC remains unexplored.
The novel CYP11B-ligand [(123/131)I]IMAZA has shown strong potential as a theranostic agent for ACCs by targeting CYP11B1 and CYP11B2, enabling enhanced specificity for adrenocortical tissue. Pre- clinical studies demonstrate greater metabolic stability compared to earlier compounds like [(123/131)I]iodometomidate (IMTO), which is rapidly inactivated. In vitro and in vivo experiments confirm high- affinity binding and selective accumulation in adrenocortical cells, allowing precise tumor targeting [130,131]. Early clinical data support improved imaging quality and pharmacokinetics with [(123/131)I] IMAZA over IMTO. In one case report, endoradiotherapy with [(131)I] IMAZA resulted in a progression-free interval of 21 months in an adult patient with advanced ACC [132].
Beyond CYP11B-targeted compounds, other radiopharmaceutical strategies are emerging. The C-X-C motif chemokine receptor 4 (CXCR4) has been identified as a promising target for both imaging and therapy, with potential for stratifying patients and refining therapeutic ap- proaches [130,131]. Radiopharmaceuticals like [(123/131)I]IMAZA exemplify recent advancements in targeted diagnostics and treatment of ACC.
Although data are currently limited to adult cases, these findings pave the way for future investigation in pACC, particularly in high-risk or advanced settings.
Outlook and future Directions
pACCs present unique challenges due to its rarity, aggressiveness, and limited treatment options. Current strategies, largely adapted from adult protocols, rely on surgery, chemotherapy, and mitotane. However, the lack of robust pediatric-specific data and dedicated clinical trials underscores a critical gap in care and research.
Recent advances in molecular profiling have revealed actionable targets in signaling pathways (e.g., Wnt/ß-catenin, MAPK/ERK), im- mune regulation, and epigenetics. Future therapies will likely combine these novel approaches with existing regimens, tailored to the unique biology of pACC.
Additionally, maintenance strategies and precise disease monitoring, such as steroid profiling and liquid biopsies, offer opportunities to enhance patient care.
Key Areas for progress
1. Clinical Trials and Novel Therapies: Early-phase clinical trials are essential to evaluate emerging treatments, particularly in metastatic, relapsed, or refractory pACC. Ensuring pediatric participation is critical to advancing knowledge and expanding access to innovative therapies.
2. International Collaboration and Data Sharing: Cooperative initia- tives like the European Cooperative Study Group for Pediatric Rare Tumors (EXPERT) and the proposed Pan-European pACT trial are pivotal for pooling expertise, resources, and patient data to drive progress in rare pediatric cancers.
3. Molecular Research and Targeted Therapies: Continued investiga- tion into the molecular drivers of pACC, supported by improved preclinical models, will guide the development of combination reg- imens that integrate conventional therapies with targeted agents and immunotherapies.
4. Early Detection and Monitoring: Technologies such as liquid biopsy and comprehensive steroid hormone profiling enable earlier detec- tion and dynamic monitoring, offering potential for timely in- terventions and individualized treatment adaptations.
5. Multidisciplinary and Comprehensive Care: A coordinated, multi- disciplinary approach including oncologists, surgeons, geneticists,
endocrinologists, and psychosocial experts is essential to provide holistic, long-term care for children with pACC.
Call to Action
Progress in pACC requires collaboration, innovation, and advocacy. Policymakers and funding agencies must prioritize rare cancer research, recognizing that underlying molecular mechanisms often transcend specific diagnoses. Expanding clinical trials to pediatric patients, investigating in biomarker development, and embracing precision oncology approaches, such as liquid biopsies and multi-omic profiling, will be key to advancing outcomes for this vulnerable population.
Conclusion
The fight against pACC reflects broader challenges in pediatric oncology: limited clinical data, unmet therapeutic needs, and the urgent necessity of collaborative research [16].
Grounding treatment in molecular insights, targeted therapies, and multidisciplinary care paves the way for personalized medicine in pe- diatric patients. Global initiatives, data sharing, and dedicated advocacy offer hope for better outcomes and brighter futures for affected children and their families.
Although progress has been made in adult ACC, these advances have yet to translate fully to pediatric cases. The distinct biological and clinical features of pACC demand specifically tailored strategies. Current therapies remain inadequate to meaningful improve long-term survival in children and adolescents with pACC.
Closing this gap requires intensified research, identification of novel targets, and development of innovative therapeutic approaches. By prioritizing pediatric-focused trials and fostering international collabo- ration, we can ensure that children with pACC benefit from in the full potential of modern oncology, delivering not just optimal care, but renewed hope for the future.
Funding
The research of MK on pACC is supported by Deutsche Kinder- krebsstiftung, grant number DKS 2021.11 and DKS 2024.16, Mittel- deutsche Kinderkrebsforschung, and Medical Faculty, University of Augsburg (intramurale Forschungsförderung).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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