Albumin-bound paclitaxel augment temozolomide treatment sensitivity of glioblastoma cells by disrupting DNA damage repair and promoting ferroptosis.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism. METHODS: A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models. RESULTS: ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy. CONCLUSION: Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.

BACKGROUND: The incidence of osteosarcoma as a secondary neoplasm in glioblastoma patient is extremely rare. The genetic characteristic still remains unclear until now. CASE DESCRIPTION: We reported a 47-year-old female patient with multiple intracranial disseminations and infiltrations (splenium of the corpus callosum and lateral ventricular wall) of a rapid progressive glioblastoma underwent occipital craniotomy and total resection of all the enhancing lesions. Whole-exome sequencing and pathological examination revealed glioblastoma, IDH1 wild type, PTEN deficient, TERT mutated, NF1mutated, MGMT unmethylated. After surgery, the patient received combined therapeutic regimen of TTFields (tumor-treating fields) plus pembrolizumab plus temozolomide and TTFields plus everolimus, which displayed significant clinical benefits. During the combined therapeutic course, an extremely rare secondary malignant neoplasm occurred, femur MR and pathological detection of biopsy tissue demonstrated osteosarcoma. The result of whole-exome sequencing revealed 7 germline mutated genes (EPAS1, SETD2, MSH3, BMPR1A, ERCC4, CDH1, AR). Bioinformatic analysis showed the two germline mutations (MSH3 and ERCC4) induced deficiency in the DNA repair machinery, which resulting in the accumulation of mutations and may generate neoantigens contributing to the development of a secondary osteosarcoma in this case. CONCLUSION: Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.

The Ependymal Region Prevents Glioblastoma From Penetrating Into the Ventricle via a Nonmechanical Force.

BACKGROUND: Intraventricular penetration is rare in glioblastoma (GBM). Whether the ependymal region including the ependyma and subventricular zone (SVZ) can prevent GBM invasion remains unclear. METHODS: Magnetic resonance imaging (MRI) and haematoxylin-eosin (HE) staining were performed to evaluate the size and anatomical locations of GBM. Binary logistic regression analysis was used to assess the correlation between tumor-ependyma contact, ventricle penetration and clinical characteristics. Cell migration and invasion were assessed via Transwell assays and an orthotopic transplantation model. RESULTS: Among 357 patients with GBM, the majority (66%) showed ependymal region contact, and 34 patients (10%) showed ventricle penetration of GBM. GBM cells were spread along the ependyma in the orthotopic transplantation model. The longest tumor diameter was an independent risk factor for GBM-ependymal region contact, as demonstrated by univariate (OR = 1.706, p < 0.0001) and multivariate logistic regression analyses (OR = 1.767, p < 0.0001), but was not associated with ventricle penetration. Cerebrospinal fluid (CSF) could significantly induce tumor cell migration (p < 0.0001), and GBM could grow in CSF. Compared with those from the cortex, cells from the ependymal region attenuated the invasion of C6 whether cocultured with C6 or mixed with Matrigel (p = 0.0054 and p = 0.0488). Immunofluorescence analysis shows a thin gap with GFAP expression delimiting the tumor and ependymal region. CONCLUSION: The ependymal region might restrict GBM cells from entering the ventricle via a non-mechanical force. Further studies in this area may reveal mechanisms that occur in GBM patients and may enable the design of new therapeutic strategies.