Adrenal Cortex Carcinoma

PAK4 is significantly overexpressed in ACC, and it may play a carcinogenic role, showing great application potential as a potential therapeutic target and an independent prognostic biomarker of ACC.

Clinicians should maintain a high index of suspicion for paragangliomas in patients with suggestive symptoms, regardless of blood pressure status. A multidisciplinary approach and long-term follow-up are vital, particularly for extra-adrenal tumors, with consideration of genetic counselling in all cases.

P2/3, N=100, Active, not recruiting, Changi General Hospital | Recruiting --> Active, not recruiting | Trial completion date: Jul 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> May 2025

This includes work that led to the FDA approvals of immune checkpoint inhibitors in multiple rare pediatric tumor types, the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions, the ALK inhibitor crizotinib in children and adults with ALK-positive inflammatory myofibroblastic tumors, and the radioligand LUATHERA for adolescents and adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Despite these advances, the study of rare pediatric cancers faces multiple challenges including a limited number of patients for efficient and well-powered clinical trials and a dearth of financial incentives. Ongoing, coordinated efforts are needed to continue the advancement of novel treatments and improve survival and minimize late effects.

Our study provides a comprehensive single-cell atlas of APA, uncovering key tumorigenic mechanisms and identifying potential biomarkers (e.g., CAPS, VWF, UPK3B) and therapeutic targets, including mTOR and Hedgehog/Wnt pathways. These findings advance the genomic understanding of adrenal tumors and support precision medicine development.

Furthermore, all models demonstrated key properties of cancer stem cells, although with varying degrees of expression of progenitor and stem cell markers, which could be dynamically modulated by treatments and therapies. Overall, our results draw parallels between canonical and noncanonical Wnt signaling, differential cytoskeletal remodeling, stemness properties and various cellular plasticities in primary tumor and metastasis-derived models of ACC.

Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

Quantitative high-throughput drug combination screening identified potent synergy between phosphatidylinositol-3-kinase (PI3K) inhibitor, PIK75 and heat shock protein 90 (HSP90) inhibitors, Ganetespib (STA9090), HSP990, or Luminespib (NVP-AUY922). Further antitumor efficacy was confirmed by the BGT226-STA9090 combination in human ACC xenograft model and five PDOs with different pathogenic mutations. Conclusively, the combinations of PI3K and HSP90 inhibitors were highly effective in preclinical studies, warranting a clinical trial in patients with advanced ACC.

Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multi-omics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.

Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.

P1, N=40, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

Our findings highlight a central role for B cells and TLSs in shaping the immune microenvironment of NB. Their presence and maturation status are linked to clinical outcome, suggesting their potential as prognostic biomarkers and targets for novel immunotherapeutic strategies in pediatric oncology.