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ImmunoTargets and Therapy 2024Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of...
PURPOSE
Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described.
MATERIALS AND METHODS
Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated.
RESULTS
NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome.
CONCLUSION
Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.
PubMed: 38948503
DOI: 10.2147/ITT.S458278 -
Cureus May 2024Medulloblastoma, an embryonal tumor located in the posterior fossa of the brain, originates from the neuro-epidermal layer of the cerebellum. It is the most prevalent...
Medulloblastoma, an embryonal tumor located in the posterior fossa of the brain, originates from the neuro-epidermal layer of the cerebellum. It is the most prevalent malignant tumor in children, while it is rare in adults and predominantly affects males. Multimodal therapeutic interventions, such as surgery, radiotherapy, and chemotherapy, have substantially enhanced the prognosis of this condition. Extraneural metastases are infrequent. We present a case of medulloblastoma relapse with nodal metastasis in a 28-year-old adult.
PubMed: 38947611
DOI: 10.7759/cureus.61339 -
Neuro-oncology Advances 2024Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with...
BACKGROUND
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with posterior fossa boost (PFB), underpins treatment for non-infants; however, radiotherapeutic insult to the normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated aging/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.
METHODS
We have developed a clinically relevant in vivo model system that recapitulates the radiotherapy dose, targeting, and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received computerized tomography image-guided CRT (human-equivalent 37.5 Gy EQD2, = 12) ± PFB (human-equivalent 48.7 Gy EQD2, = 12), via the small animal radiation research platform and were longitudinally assessed for > 12 months.
RESULTS
CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group ( = 12), irradiated mice were significantly frailer following irradiation (frailty index; = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; = .026) and grip strength ( = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; = .009) and exhibited spatial memory deficits (Barnes maze; = .029). Receipt of PFB did not induce a more severe late-effect profile.
CONCLUSIONS
Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late effects and the development of novel interventions for their amelioration.
PubMed: 38946880
DOI: 10.1093/noajnl/vdae091 -
Brain Pathology (Zurich, Switzerland) Jun 2024The prognosis for many pediatric brain tumors, including cerebellar medulloblastoma (MB), remains dismal but there is promise in new therapies. We have previously...
Intracerebellar administration of the chemokine Cxcl3 reduces the volume of medulloblastoma lesions at an advanced stage by promoting the migration and differentiation of preneoplastic precursor cells.
The prognosis for many pediatric brain tumors, including cerebellar medulloblastoma (MB), remains dismal but there is promise in new therapies. We have previously generated a mouse model developing spontaneous MB at high frequency, Ptch1/Tis21. In this model, reproducing human tumorigenesis, we identified the decline of the Cxcl3 chemokine in cerebellar granule cell precursors (GCPs) as responsible for a migration defect, which causes GCPs to stay longer in the proliferative area rather than differentiate and migrate internally, making them targets of transforming insults. We demonstrated that 4-week Cxcl3 infusion in cerebella of 1-month-old mice, at the initial stage of MB formation, forces preneoplastic GCPs (pGCPs) to leave lesions and differentiate, with a complete suppression of MB development. In this study, we sought to verify the effect of 4-week Cxcl3 treatment in 3-month-old Ptch1/Tis21 mice, when MB lesions are at an advanced, irreversible stage. We found that Cxcl3 treatment reduces tumor volumes by sevenfold and stimulates the migration and differentiation of pGCPs from the lesion to the internal cerebellar layers. We also tested whether the pro-migratory action of Cxcl3 favors metastases formation, by xenografting DAOY human MB cells in the cerebellum of immunosuppressed mice. We showed that DAOY cells express the Cxcl3 receptor, Cxcr2, and that Cxcl3 triggers their migration. However, Cxcl3 did not significantly affect the frequency of metastases or the growth of DAOY-generated MBs. Finally, we mapped the expression of the Cxcr2 receptor in human MBs, by evaluating a well-characterized series of 52 human MBs belonging to different MB molecular subgroups. We found that Cxcr2 was variably expressed in all MB subgroups, suggesting that Cxcl3 could be used for therapy of different MBs.
PubMed: 38946128
DOI: 10.1111/bpa.13283 -
British Journal of Cancer Jun 2024Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential...
BACKGROUND
Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches.
METHODS
We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected BCL-2 family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing.
RESULTS
Group 3 medulloblastoma (MB) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MB and BCL2 in neuroblastomas. Co-treatments with RA and BCL-2/X inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of BIM to BCL-X in MB and to BCL-2 in neuroblastoma, inducing apoptosis in vitro and in vivo.
CONCLUSIONS
RA treatment primes MB and NB cells for apoptosis, triggered by navitoclax cotreatment.
PubMed: 38942989
DOI: 10.1038/s41416-024-02740-5 -
Cancer Cell Jun 2024Global investigation of medulloblastoma has been hindered by the widespread inaccessibility of molecular subgroup testing and paucity of data. To bridge this gap, we...
Global investigation of medulloblastoma has been hindered by the widespread inaccessibility of molecular subgroup testing and paucity of data. To bridge this gap, we established an international molecularly characterized database encompassing 934 medulloblastoma patients from thirteen centers across China and the United States. We demonstrate how image-based machine learning strategies have the potential to create an alternative pathway for non-invasive, presurgical, and low-cost molecular subgroup prediction in the clinical management of medulloblastoma. Our robust validation strategies-including cross-validation, external validation, and consecutive validation-demonstrate the model's efficacy as a generalizable molecular diagnosis classifier. The detailed analysis of MRI characteristics replenishes the understanding of medulloblastoma through a nuanced radiographic lens. Additionally, comparisons between East Asia and North America subsets highlight critical management implications. We made this comprehensive dataset, which includes MRI signatures, clinicopathological features, treatment variables, and survival data, publicly available to advance global medulloblastoma research.
PubMed: 38942025
DOI: 10.1016/j.ccell.2024.06.002 -
Journal of Clinical Medicine Jun 2024: Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic...
: Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising treatment for recurrent cases. Our study provides a comprehensive analysis of the long-term efficacy and safety of SRS in recurrent medulloblastomas across both pediatric and adult patients at a single institution. : We retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for recurrent cranial medulloblastomas at our institution between 1998 and 2023. Follow-up data were available for 15 medulloblastomas in 10 patients. The cohort comprised eight pediatric patients (ages 3-18) and two adult patients (ages 19-75). The median age at the time of SRS was 13 years, the median tumor volume accounted for 1.9 cc, the median biologically equivalent dose (BED) was 126 Gy, and the single-fraction equivalent dose (SFED) was 18 Gy. The SRS was administered at 75% of the median isodose line. : Following a median follow-up of 39 months (range: 6-78), 53.3% of the medulloblastomas progressed, 13.3% regressed, and 33.3% remained stable. The 3-year local tumor control (LTC) rate for all medulloblastomas was 65%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67%). The 3-year overall survival (OS) rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival (PFS) rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away. : Our study provides a complex perspective on the efficacy and safety of CyberKnife SRS in treating recurrent cranial medulloblastomas across pediatric and adult populations. The rarity of adverse radiation events (AREs) underscores the safety profile of SRS, reinforcing its role in enhancing treatment outcomes. The intricacies of symptomatic outcomes, intertwined with factors such as age, tumor location, and prior surgeries, emphasize the need for personalized treatment approaches. Our findings underscore the imperative for ongoing research and the development of more refined treatment strategies for recurrent medulloblastomas. Given the observed disparities in treatment outcomes, a more meticulous tailoring of treatment approaches becomes crucial.
PubMed: 38930121
DOI: 10.3390/jcm13123592 -
International Journal of Molecular... Jun 2024Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological...
Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition-time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations.
Topics: Humans; Neurons; Proteomics; Proteome; Cell Line, Tumor; Heat-Shock Response; Tandem Mass Spectrometry; Chromatography, Liquid; Cell Differentiation; Proteotoxic Stress
PubMed: 38928492
DOI: 10.3390/ijms25126787 -
Cancers Jun 2024Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection,... (Review)
Review
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.
PubMed: 38927954
DOI: 10.3390/cancers16122249 -
Cancers Jun 2024Medulloblastoma (MB) is the most frequent malignant brain tumor in children with extensive heterogeneity that results in varied clinical outcomes. Recently, MB was...
Medulloblastoma (MB) is the most frequent malignant brain tumor in children with extensive heterogeneity that results in varied clinical outcomes. Recently, MB was categorized into four molecular subgroups, WNT, SHH, Group 3, and Group 4. While SHH and Group 4 are known for their intermediate prognosis, studies have reported wide disparities in patient outcomes within these subgroups. This study aims to create a radiomic prognostic signature, medulloblastoma radiomics risk (mRRisk), to identify the risk levels within the SHH and Group 4 subgroups, individually, for reliable risk stratification. Our hypothesis is that this signature can comprehensively capture tumor characteristics that enable the accurate identification of the risk level. In total, 70 MB studies (48 Group 4, and 22 SHH) were retrospectively curated from three institutions. For each subgroup, 232 hand-crafted features that capture the entropy, surface changes, and contour characteristics of the tumor were extracted. Features were concatenated and fed into regression models for risk stratification. Contrasted with Chang stratification that did not yield any significant differences within subgroups, significant differences were observed between two risk groups in Group 4 ( = 0.04, Concordance Index (CI) = 0.82) on the cystic core and non-enhancing tumor, and SHH ( = 0.03, CI = 0.74) on the enhancing tumor. Our results indicate that radiomics may serve as a prognostic tool for refining MB risk stratification, towards improved patient care.
PubMed: 38927953
DOI: 10.3390/cancers16122248