temozolomide (SI 053 / Temodex / SI053)

Achieving Stable Disease in an Adult with Malignant Gastrointestinal Tumor following Cabozantinib Treatment: Case Report.

Iverson Brianna Jo BJ, Milhem Mohammed M MM, Rieth John Markus JM

Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare and aggressive neoplasm that is characterized by EWSR1 rearrangements. Most patients present with metastatic disease. There are no established treatment guidelines, and systemic therapy options remain poorly defined. A woman in her late 30s presented initially with right upper quadrant pain and bloating. Endoscopic biopsy of a duodenal mass revealed a SOX10-positive malignant neoplasm. Molecular testing identified an EWSR1:CREB1 fusion, confirming GNET. Initial treatment with ipilimumab and nivolumab resulted in disease progression. Subsequent therapies included a selective interleukin-2 agonist clinical trial, nivolumab/relatlimab, and temozolomide, all associated with continued progression. Cabozantinib was initiated after further radiographic progression. Follow-up imaging demonstrated tumor regression, and the patient maintained stable disease for 15 months before mild progression. Metastatic GNET has a poor prognosis and lacks standardized systemic therapy. This case demonstrates durable disease stabilization with cabozantinib after progression on immunotherapy and chemotherapy. Tyrosine kinase inhibition may represent a promising therapeutic strategy in GNET and warrants further investigation.

Case Report: Supraorbital keyhole resection of IDH-mutant grade 3 astrocytoma of the medial orbitofrontal region.

Ashirov Nurali N, Pochivalov David D, Zhamoldin Daniyar D, Aleinikov Viktor V et al.

High-grade gliomas located in the medial orbitofrontal region present significant surgical challenges due to their deep location and proximity to critical neurovascular structures. While the supraorbital eyebrow approach is widely used for extra-axial skull base lesions, its application to intra-axial high-grade gliomas remains less frequently reported. We report the case of a 47-year-old female diagnosed with an isocitrate dehydrogenase (IDH)-mutant World Health Organization Grade 3 astrocytoma located in the medial orbitofrontal cortex. The patient underwent gross total resection via a minimally invasive supraorbital trans-eyebrow craniotomy. Early postoperative MRI performed within 72 hours confirmed gross total resection without residual contrast-enhancing tumor. Histopathological examination demonstrated microvascular proliferation consistent with Grade 3 astrocytoma, and molecular analysis confirmed IDH mutation. The patient subsequently received standard adjuvant radiochemotherapy with temozolomide. Follow-up demonstrated preserved neurological function and high cosmetic satisfaction. This case illustrates that, in carefully selected patients, the supraorbital keyhole approach can achieve oncologically adequate resection of medial orbitofrontal IDH-mutant high-grade gliomas while minimizing surgical morbidity and optimizing cosmetic outcomes.

DLK1-35 Contributes to Temozolomide Resistance in Glioblastoma Through the miR-140-3p/NHE1/ERK-MGMT Axis.

Guo Jianxiong J, Li Dan D, Sun Mingyang M, Wang Zhuo Z et al.

IGSF3 drives acquired temozolomide resistance in glioblastoma through ASNS-dependent asparagine biosynthesis.

Li Jie J, Lu Hongnian H, Xu Qianqian Q, Yin Ying Y et al.

Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system, and acquired resistance to temozolomide (TMZ) is a major cause of tumor recurrence and poor clinical outcome. However, the tumor-intrinsic drivers and metabolic adaptations underlying this process remain incompletely understood. In this study, we integrated transcriptomic data from established TMZ-sensitive and TMZ-resistant models with public bulk and single-nucleus sequencing datasets, and validated candidate genes using clinical specimens, cell-based drug-sensitivity assays, xenograft models, metabolic measurements, luciferase reporter assays, chromatin immunoprecipitation, and small-molecule binding assays. Immunoglobulin superfamily member 3 (IGSF3) was consistently upregulated in TMZ-resistant cells, resistant xenografts, and recurrent GBM samples, and was mainly enriched in malignant glioma cells. Functionally, IGSF3 overexpression promoted resistance to TMZ-related treatment, whereas IGSF3 knockdown restored drug sensitivity. Mechanistically, IGSF3 was detected in the nucleus, where it enhanced the activity of the asparagine synthetase (ASNS) promoter. Additionally, IGSF3 was found to be enriched at the ASNS promoter, thereby increasing ASNS expression and asparagine production, reduced reactive oxygen species accumulation, preserved glutathione redox balance, and limited DNA damage induced by treatment. ASNS gain- and loss-of-function rescue experiments showed that ASNS was required for the pro-resistance effect of IGSF3. Finally, Tucatinib bound to IGSF3, suppressed the IGSF3-ASNS pathway, and enhanced TMZ efficacy in vitro and in vivo. These findings identify the IGSF3-ASNS axis as a tumor-intrinsic metabolic adaptation that drives acquired TMZ resistance in GBM and suggest a potential therapeutic strategy for recurrent GBM.