Medulloblastoma targeted therapy: From signaling pathways heterogeneity and current treatment dilemma to the recent advances in development of therapeutic strategies

Wang, Qiyue; Xin, Xiaofei; Dai, Qihao; Sun, Mengjuan; Chen, Jinhua; Mostafavi, Ebrahim; Shen, Yan; Li, Xueming

doi:10.1016/j.pharmthera.2023.108527

Cited by 2 publications

(1 citation statement)

References 221 publications

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“…These two populations show a differential distribution within different subtypes of MB, with the SHH-activated subtype being notorious for the abundance of M2-M population [ 78 ]. The TME heterogeneity is not limited to that of myeloid cells but is also observed at the level of T-cells and non-immune components of the environment, such as fibroblasts [ 80 ]. As expected, these differences in the TME have implications when it comes to responses to therapy.…”

Section: Main Drivers Of Treatment Resistancementioning

confidence: 99%

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

Slika,

Shahani,

Wahi

et al. 2024

Cancers

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Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma’s response to therapeutic modalities.

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Section: Main Drivers Of Treatment Resistancementioning

confidence: 99%

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

Slika,

Shahani,

Wahi

et al. 2024

Cancers

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FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single‐cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK‐8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2‐related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH‐MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH‐MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH‐MB cells and sensitized SHH‐MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH‐MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH‐MB cell‐derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH‐MB and silencing FANCD2 could sensitize SHH‐MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

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Medulloblastoma targeted therapy: From signaling pathways heterogeneity and current treatment dilemma to the recent advances in development of therapeutic strategies

Cited by 2 publications

References 221 publications

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

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