Neuro-oncology advances最新文献

Background: Glioblastoma (GBM) is the most common primary brain tumor with an overall survival under 21 months. Despite extensive research effort, patient outcomes have improved minimally over the past several decades. The Inhibitor of Apoptosis (IAP) proteins are critical survival factors implicated in both immune regulation and gliomagenesis. Small molecule IAP antagonists called SMAC mimetic compounds (SMCs) are under investigation as cancer therapeutics across multiple malignancies, including GBM. SMCs induce GBM cell death in the presence of inflammatory cytokines, synergize with immune checkpoint inhibitors (ICI), and induce death of microglia and macrophages. Although SMCs show significant efficacy in murine models, complete eradication is not achieved. Here, we aimed to understand the limitations of SMCs in murine GBM and identify strategies to enhance efficacy of combination treatment with ICIs with the goal of informing future translational efforts.

Methods: We use animal models, co-culture systems, flow cytometry, and multiplex immunohistochemistry to optimize SMC dosing and delivery, uncovering resistance mechanisms that address key unmet research needs.

Results: We demonstrate that although GBM cells are immunologically recognizable, their location within the central nervous system (CNS) limits effective anti-GBM immunity following SMC and ICI combination therapy. Increasing SMC dose potently improves overall survival, which is associated with reduced intratumoral macrophage content, increased microglial involvement, and peripheral immunoactivation. Given the immunosuppressive role of TGFβ, the incorporation of TGFβ blockade further enhances survival outcomes.

Conclusion: We comprehensively outline how SMCs can be used in conjunction with ICIs to treat GBM and propose strategies to maximize SMC efficacy.

Background: Non-germinomatous germ cell tumors (NGGCTs) occur 3.5 times more frequently in Chinese children than in western populations. This study aimed to evaluate treatment outcomes, prognostic factors, and diagnostic challenges in a Chinese cooperative group, with particular focus on the roles of pathology and surgical intervention.

Methods: We retrospectively analyzed 62 consecutively diagnosed pediatric patients with NGGCT (September 2018-June 2023) from Shanghai Children's Medical Center and Huashan Hospital. NGGCT was diagnosed by histopathology with/without elevated tumor markers (n = 46) or by elevated markers alone (n = 16). All patients received standardized treatment according to Children's Oncology Group ACNS0122 protocol. Whole-exome sequencing was performed on 12 paired tumor-blood samples to characterize molecular alterations.

Results: The study cohort included 49 males and 13 females (median age, 9.8 year). Primary locations were mainly pineal (58%) and suprasellar (29%). Treatment delays (>6 mo) occurred in 21% of patients, particularly those with non-pineal locations and endocrine symptoms. The 3 years event-free survival and overall survival rates were 81.9 ± 5.4% and 91.3 ± 3.7%, respectively. Univariate analysis identified poor prognostic factors: elevated AFP >200 ng/mL, spinal metastases, and lack of complete/partial response after induction chemotherapy. Surgical resection of small residual tumors (<2 cm) provided no survival benefit. Molecular analysis revealed KRAS and KIT as the most frequent mutations, with chromosome 12p abnormalities in 50% of cases.

Conclusions: Standardized multidisciplinary treatment achieves favorable outcomes comparable to international benchmarks. Aggressive surgery does not improve survival when tumor markers normalize. Diagnostic delays remain common, emphasizing the need for improved awareness and referral systems in China.

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, extensive inter- and intra-tumoral heterogeneity, and resistance to standard-of-care, including radiotherapy. Radiotherapy remains a cornerstone of GBM management, but its efficacy is limited by complex tumor biology and mechanisms of radioresistance. This review explores the advances in radiotherapy for GBM, focusing on the interplay between tumor biology and emerging treatment strategies. Hallmarks of GBM biology, including hypoxia, the robust DNA repair mechanisms, the immunosuppressive tumor microenvironment (TME), and the extensive plasticity contribute to therapeutic resistance. Innovative approaches in radiotherapy may allow to address these challenges. Charged particle therapies (CPTs), including proton and carbon ion therapy, offer superior precision and enhanced biological effectiveness by delivering lethal doses to tumor cells while sparing surrounding healthy tissue. FLASH therapy, using ultra-high dose rates, could reduce normal tissue toxicity without compromising tumor control. Furthermore, targeted radionuclide therapy harnesses tumor-specific targets to systemically deliver radiopharmaceuticals carrying therapeutic radionuclides directly to cancer cells, improving specificity and reducing off-target effects. This review highlights the promise of these novel radiotherapy modalities to address GBM's inherent heterogeneity and treatment resistance. By integrating advancements in technology with novel insights into GBM biology, these approaches may significantly improve patient outcomes.

Background: Sex differences in glioblastoma (GBM) are recognized, but their treatment implications remain unclear. Recent preclinical studies have characterized mechanisms of sex-biased anti-tumor immunity in GBM, and have found in murine models that males derive greater survival benefit from immune checkpoint inhibitor (ICI). We evaluated sex differences associated with ICI in GBM patients.

Methods: We retrospectively evaluated consecutive patients with newly diagnosed GBM (nGBM) or recurrent GBM (rGBM) treated with ICI on clinical trials at one institution from 2014 to 2022. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis, univariate and multivariable regression models. Sex-by-treatment interactions were assessed relative to a concurrent reference group treated on non-ICI clinical trials.

Results: 296 patients with nGBM (58% male, 19% ICI) and 458 patients with rGBM (60% male, 40% ICI) were evaluated. In nGBM, ICI was not associated with sex difference in PFS (HR_male 1.35; 95% CI, 0.62-2.95; P = .446; P _interaction = .142) or OS (HR_male 1.15 [0.53-2.53], P = .722; P _interaction = .438) compared to non-ICI treatment. In rGBM, males receiving ICI had worse OS (HR_male 1.64 [1.09-2.47], P = .017) and trended towards worse PFS (HR_male 1.41 [0.94-2.11], P = .095), but sex differences with ICI were not significantly different compared to non-ICI treatment (PFS P _interaction = .610; OS P _interaction = .361). No sex differences were observed when all immunotherapies were analyzed collectively.

Conclusion: In nGBM and rGBM, ICI therapy was not associated with sex difference in PFS or OS. Clinically meaningful sex-based outcome differences may be better understood by prospective evaluation in clinical trials.

Background: Glioblastoma represents one of the most aggressive and fatal primary brain tumors in adults. Chemotherapeutic agents, while integral to management, frequently induce varying levels of myelotoxicity. The aim is to investigate the clinical impact of myelotoxicity in patients treated with the CeTeG versus the Stupp regimen which has not yet been systematically investigated under real-world conditions.

Methods: This retrospective study included patients with newly diagnosed glioblastoma who underwent radiochemotherapy. Peripheral blood counts were systematically assessed throughout first-line therapy, starting at the initiation of radiation and continuing until either first disease progression or death, whichever occurred earlier.

Results: Among 161 identified patients, 133 (83%) were assigned to the myelotoxicity cohort and 28 (17%) to the non-myelotoxicity cohort. Female sex was independently associated with a higher incidence of myelotoxicity (p = 0.007). In multivariate analysis leukopenia ≥ grade 2 was significantly associated with improved progression-free and overall survival in both the overall and CeTeG cohorts. Neutropenia ≥ grade 2 similarly correlated with improved survival outcomes in the overall cohort. Prophylaxis against pneumocystis jiroveci pneumonia was associated with a significant survival advantage in both the overall and Stupp cohorts, as was lymphopenia grade 3-4.

Conclusion: Myelotoxicity at the time of glioblastoma diagnosis does not seem to be detrimental to patient outcomes. Our findings highlight the importance of pneumocystis jiroveci prophylaxis in the Stupp regimen. This raises the intriguing question of whether future chemotherapy dosages could be tailored based on individual blood values, potentially exceeding current standard doses. Prospective studies are needed to explore these possibilities, including the feasibility of high-dose therapies similar to those used in leukemia treatment.

Background: Glioblastoma (GBM) prognosis remains poor, and although immune checkpoint inhibitors (ICI) have transformed the treatment of many tumors, they are ineffective in GBM. However, response to ICIs occurs in high-tumor-mutational-burden (TMB) GBMs. To address the immunological impact of high TMB in GBM, we created a high TMB syngeneic mouse model from the low TMB SB28 GBM cell line.

Methods: We used CRISPR-Cas9 to target murine Msh2, Mlh1, CXCL10, and CCL5. Single-cell-sorted clones were characterized by whole exome, bulk RNA-sequencing, and neoantigen prediction. Clones were injected subcutaneously or intracranially with or without anti-PD-1/anti-CTLA4 and dexamethasone.

Results: Loss of mismatch repair (MMR) proteins Msh2 or Mlh1 increased nonsynonymous mutations. A fraction of mice with intracranial Msh2KO but not Mlh1KO SB28 showed long-term survival with anti-PD-1/anti-CTLA4 treatment plus dexamethasone. Long-term surviving mice from Msh2 KO SB28 rejected rechallenged subcutaneous tumors. Subcutaneous tumors from clones with increased TMB grew more slowly. This was fully abrogated in Rag1 null mice for Msh2KO but only partially for Mlh1KO SB28. Hypermutant Msh2KO clones spontaneously secreted CXCL10, CCL5, and increased pro-inflammatory chemokines after IFN-γ stimulation. Knockout of CXCL10 or CCL5 in the highest TMB Msh2KO clone restored flank tumor growth, indicating loss of immune response despite elevated TMB.

Conclusion: Mismatch repair-deficient SB28 tumors were more immunogenic, but this was not completely correlated with TMB. Rather, rejection depended on increased secretion of pro-inflammatory chemokines. Msh2 and Mlh1 loss was not equivalent, suggesting that additional studies are needed to elucidate germline and somatic mismatch repair gene-specific immune alterations.

Background: The intra- and inter-tumoral heterogeneity of glioblastoma (GBM) represents a significant therapeutic challenge and barrier to the generation of reliable and accurate models for in vitro studies. Three-dimensional models, such as patient-derived neurospheres (PDN) and organoids (PDO), recapitulate complex cellular states. However, the direct comparison of models derived in parallel from the same primary tumor tissue has never been performed. The aim of this study was to determine the tumor cell composition of PDN and PDO models relative to matched primary GBM tissue.

Methods: Four GBM surgical samples were used to establish matched PDO and PDN models, which were genomically verified using single nucleotide polymorphism array. DNA methylation, histology, and transcriptome were examined for intra-tumoral heterogeneity correlating with the matched GBM tissue. PDN lines were used to investigate the tumor cell composition response to temozolomide chemotherapy over time, maximizing their utility.

Results: We find that both patient-derived models recapitulate the genomic, epigenomic, and tumor cell heterogeneity of the primary tissue at similar capacity. Furthermore, single-nuclei RNA sequencing revealed a subset of organoids containing small numbers of non-malignant cells from neuron and immune cell lineages. Harnessing the intra-tumoral heterogeneity of PDN models, we reveal the impact of temozolomide chemotherapy on individual cell states, altering composition of tumors over time in response to treatment.

Conclusions: Our data confirms that both PDN and PDO patient-derived models recapitulate patient intra-tumoral heterogeneity providing a platform for tumor cell state refined therapeutic studies.

Abstract: BackgroundStudies suggest that high intensities of tumor treating fields (TTFields) correlate with prolonged survival in newly diagnosed glioblastoma. However, no randomized clinical studies have tested different doses of TTFields, and the treatment remains controversial for recurrent glioblastoma. This study examined the clinical efficacy of dose-enhanced TTFields in first recurrence glioblastoma (rGBM).

Methods: This open-label, randomized, multicenter, phase 2 clinical trial was conducted nationwide in Denmark (2020-2024) with planned enrollment of 84 rGBM patients. Inclusion criteria were focal disease, KPS ≥ 70, and eligibility for resection. Patients were randomized (1:1) to receive standard or dose-enhanced TTFields in addition to standard-of-care. Dose enhancement (25%-70%) in the tumor was achieved by placing five small cranial burr holes over the tumor bed with overlapping TTFields transducer arrays. The primary outcome was the overall survival (OS) rate at 12 months (OS12). Secondary outcomes included progression-free survival, toxicity, steroid use, objective response rate (ORR), and quality of life.

Results: We enrolled 58 participants with a mean (SD) age of 59.2 (11.1) years and a median (IQR) KPS of 90 (10). Preplanned interim analysis of the first 52 patients resulted in early trial termination due to futility. Intent-to-treat analysis of the complete cohort showed an OS12 of 56% vs 46% (P = .38) and a median OS of 12.3 vs 11.1 months (P = .93) for intervention and control, respectively. Differences in the secondary outcomes were insignificant.

Conclusion: Dose-enhanced TTFields utilizing burr holes over the resection cavity were not associated with improved survival in rGBM, with low study power as the primary limitation.

Background: Lysine-specific demethylase 1 (LSD1) is overexpressed in glioblastoma, contributing to tumor growth and treatment resistance. LSD1 inhibitors have shown preclinical promise but have had limited clinical development for glioblastoma. Given the frequent kinase pathway alterations seen in glioblastoma, the interplay between LSD1 inhibition and kinase signaling pathways was investigated.

Methods: Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. The effect on cell viability, proliferation, and neurosphere formation was assessed, and synergy scores were calculated using Bliss synergy models. Kinase signaling was analyzed and in vivo efficacy was evaluated in orthotopic xenograft models.

Results: LSD1 knockdown and seclidemstat reduced kinase signaling, while catalytic LSD1 inhibitors increased kinase activity or had no effect. Catalytic LSD1 inhibitors combined with kinase inhibitors, synergistically reduced GSC viability and proliferation while sparing NHAs. Combination treatment consistently reduced phospho-S6 ribosomal protein levels in three different GSC lines, and basal phospho-S6 ribosomal protein levels across the GSCs and the NHAs were negatively correlated with a synergistic response. The generation of an NCD38-resistant GSC showed increased kinase activity and was associated with enhanced osimertinib sensitivity. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes.

Discussion: These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

Background: The impact of systemic therapy (ST) on outcomes for patients with brain-only metastases (BrM) in the absence of extracranial disease (ECD) is not well established. We compared outcomes between patients with BrM treated with stereotactic radiosurgery (SRS) who received ST ≤3 months (mos), >3 mos, or not at all after SRS.

Methods: We identified BrM patients who completed SRS across two institutions from 1/2015 to 12/2020. Intracranial progression after SRS was determined by brain MRI radiographic recurrence. Overall survival (OS) and intracranial progression free survival (iPFS) estimates were also generated.

Results: In total, 342 patients with BrM were identified. Primary sites included lung (73%), breast (12%), and additional sites (15%). Almost half, 169 (49%), received no ST, 80 (23%) received ST ≤3 mos, and 93 (27%) received ST >3 mos after SRS. Median age was younger in the ST >3 mos cohort (60.5years) compared with ST <3mo (67.7years) and no ST (67.0years), P = .0002. Median OS differed significantly between groups: ST ≤3 mos with 24.9mos (95%CI: 16.6-51.1), ST >3 mos with 27.5mos (95% CI: 20.6-37.5), and no ST with 11.0mos (95%CI: 9-17.5), P = .002. Median iPFS differed significantly between groups: ST ≤3 mos 16.1mos (95% CI: 9.5-33.7), ST >3 mos 8.9mos (95% CI: 6.9-13.5), and no ST 10.0mos (95% CI: 6.7- 15.1). However, timing of ST was not significant multivariate analysis.

Conclusions: In our cohort of BrM patients, ST after SRS improves OS regardless of timing. ST ≤3 mos may improve iPFS compared with ST >3 mos after SRS, which warrants further investigation. Appropriate patients with BrM should be referred for a multi-disciplinary discussion of ST following SRS.