Res Sq [Preprint]. 2025 May 5:rs.3.rs-6508597. doi: 10.21203/rs.3.rs-6508597/v1.

ABSTRACT

BACKGROUND: High-grade gliomas (HGGs), including diffuse midline glioma (DMG), represent the most aggressive and deadly pediatric brain cancers. Despite recent advances in understanding their molecular underpinnings, these tumors remain universally fatal. A hallmark feature of pediatric HGGs is the frequent presence of mutations and amplifications in components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathway. These alterations drive unchecked tumor growth, confer resistance to standard therapies, and contribute to the dismal survival outcomes observed in affected children.

MAIN BODY: While the PI3K/mTOR axis has been recognized as a critical dependency in DMG and other pediatric HGGs, clinical translation of pathway inhibitors has been limited by several major barriers. Most notably, the blood-brain barrier (BBB) restricts the delivery of conventional PI3K and mTOR inhibitors, many of which lack sufficient central nervous system (CNS) penetration. Furthermore, even when delivered to the tumor site, these agents often encounter rapid adaptive resistance through activation of compensatory pathways, reducing their therapeutic benefit. Treatment-related toxicities, including hyperglycemia, rash, and mucositis, further limit tolerability and patient adherence.Emerging brain-penetrant PI3K/mTOR inhibitors represent a new generation of targeted therapies with the potential to overcome these pharmacological limitations. However, increasing drug exposure does not necessarily equate to improved outcomes, particularly when used in combination with immunotherapies or other targeted agents. Achieving optimal therapeutic efficacy while minimizing systemic toxicity remains a central challenge, requiring careful consideration of drug dosing, timing, and combination strategies tailored to each individual patient.

CONCLUSION: This review explores the current landscape of PI3K/mTOR targeting in DMG, highlighting both the therapeutic promise and inherent challenges. We discuss known resistance mechanisms, the need for better CNS-optimized compounds, and the importance of individualized treatment strategies. Finally, we propose a roadmap for future research, emphasizing rational drug combinations, refined patient stratification, and the development of next-generation therapies aimed at improving outcomes for children with these devastating malignancies.

PMID:40386392 | PMC:PMC12083663 | DOI:10.21203/rs.3.rs-6508597/v1

Cell. 2025 Jun 12;188(12):3238-3258.e25. doi: 10.1016/j.cell.2025.03.041. Epub 2025 May 12.

ABSTRACT

Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.

PMID:40359942 | PMC:PMC12176077 | DOI:10.1016/j.cell.2025.03.041

Neuro Oncol. 2025 May 13:noaf120. doi: 10.1093/neuonc/noaf120. Online ahead of print.

NO ABSTRACT

PMID:40355627 | DOI:10.1093/neuonc/noaf120