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Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma

ABSTRACT: To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280891 | GEO | 2025/01/22

REPOSITORIES: GEO

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Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma [patients]

Project description:To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits.

2025-01-22 | GSE280951 | GEO

Cytoplasmic Proteomics for Temozolomide Resistance in Glioblastoma

Project description:TMZ resistance is one of the main reasons why treatment of glioblastoma (GBM) fails. In order to investigate the underlying mechanism associated with TMZ resistance, we conducted a cytoplasmic proteome research of U87 cells treated with TMZ for 1 week. A total of 162 DEPs including 66 up-regulated proteins and 96 down-regulated proteins were identified.

2018-10-23 | PXD007759 | Pride

G0/G1 switch gene 2 modulates gliomagenesis and radiation response

Project description:Glioblastoma multiforme (GBM), a WHO grade IV glioma is the most common and malignant primary cancer of the central nervous system with a grim median survival of 16 to 17 months upon diagnosis. Radiotherapy is the standard first line treatment for newly diagnosed patients with gliomas, but its effectiveness is limited given their intrinsic resistance and propensity for recurrence. Although possible mechanisms have been attributed to GBM resistance to radiation treatments, the molecular mechanisms regulating radiation resistance of GBM are still unclear.

2019-07-23 | GSE86213 | GEO

RAPID RESISTANCE TO BET INHIBITORS IS MEDIATED BY FGFR1 IN GLIOBLASTOMA

Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

2024-06-16 | PXD043214 | Pride

The different expression of long non-coding RNAs and messenger RNAs in temozolomide-resistant glioblastoma cells and parental glioblastoma cells

Project description:Temozolomide (TMZ) resistance may contribute to the treatment failure in patients with glioblastoma (GBM). Hence, understanding the underlying mechanisms and developing effective strategies against TMZ resistance are highly desired in the clinic. long non-coding RNAs (lncRNAs) have emerged as new regulatory molecules with diverse functions in biological processes and been deregulated in many pathologies, involved in the therapeutic resistance. It is urgent to elucidate the underlying lncRNA-based mechanisms of TMZ resistance in GBM patients.

2019-04-12 | GSE113510 | GEO

Transcriptome analysis reveals malignant and hypoxic signature of glioblastoma

Project description:Purpose:Glioblastoma (GBM) is the most common primary brain tumor in adults with poor prognosis and short medial survival after therapy. we have utilized U87-MG cell line as a human GBM cell model and human brain HEB cell line as non-neoplastic brain cell cultured in normoxia and 1% O2 hypoxia for transcriptional profiling to gain further insight into the molecular underpinnings that maintained the properties of GBM andclarify the molecular mechanism of hypoxia resistance of GBM. Methods:We have utilized U87-MG cell line as a human GBM cell model and human brain HEB cell line as non-neoplastic brain cell cultured in normoxia and 1% O2 hypoxia for transcriptional profiling. And validating the analysis results with specimens of GBM patients. Results: Firstly, the resulting data set revealed previously unknown proteins, including AKR1B1, MT2A, UBC, EEF1A1 and MTRNR2l2 in U87-MG cells, which promoted GBM characters through MAPK pathway. Meanwhile, we found that toll-like pathway was a new avenue mediating the function of inflammatory response in GBM. Furthermore, The results suggested that cytokine TGF-β1 and HIFs’ targeted genes, including HMOX1 and STC1 could be regard as hypoxic markers for GBM. Conclusion:Taken together, our study identified new potential biomarkers and illustrated the genes associated with inflammation in GBM. More importantly, the unique pattern to hypoxia implied new insight for the GBM research of hypoxia resistance and recurrence in future.

2019-09-11 | GSE77307 | GEO

Uncovering small non-coding RNAs involved in carcinogenesis of Glioma

Project description:To determine which signalling pathways are affected by small RNAs (piRNAs, miRNAs) through target regulation in Glioblastoma Multiforme (GBM), we performed high-throughput next-generation sequencing in U87-MG GBM cell line. The RNA sequencing (RNA-Seq) of small RNAs and transcriptomes discovered both known and novel piRNAs and miRNAs as well other transcriptomes of protein-coding genes, lncRNAs and pseudogenes expressed in this GBM cell line. These small RNAs and target transcriptomes can be further investigated to decode novel molecular mechanisms underlying oncogenesis of this malignancy.

2023-04-04 | GSE197508 | GEO

Genotyping of humanglioblastoma tissue samples, cell lines and explants

Project description:glioblastoma multiforme genomic profiling by single nucleotide polymorphism microarray Human GBM (glioblastoma multiforme)cell lines (U87, U118, U138, U343, U373, T98G) were maintained in Dulbecco's modified Eagle's medium with 10 % fetal calf serum, 10 U/ml penicillin-G, and 10 mg/ml streptomycin. All cells were incubated at 37 oC in 5% CO2. Four primary GBM explants were established from patients with glioblastoma multiforme undergoing surgery as following described: Tumor specimens were immediately transported to the laboratory, finely minced to single cell suspension and cultured in complete medium [Ham's F-12/DME High Glucose medium containing 10% fetal calf serum, 10 U/ml penicillin-G, and 10 mg/ml streptomycin and 2 mM glutamax-1 into 100 cm2 tissue culture plastic dishes the second passage. All cells were incubated at 37 oC in 5% CO2. GBM (glioblastoma multiforme) tissue samples were quick frozen. Standard proteinase K-phenol-chloroform extraction method was used to extract DNA from GBM samples, cell lines and explants. The matched peripheral blood data can be used as normalized data for their matched tumor tissue data. The cell lines samples and two explants without normalized data, but they can be normalized by one of the peripheral blood DNA data.

2009-01-13 | E-MEXP-1330 | biostudies-arrayexpress

RAPID RESISTANCE TO BET INHIBITORS IS MEDIATED BY FGFR1 IN GLIOBLASTOMA

Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

2023-10-23 | GSE245624 | GEO

Transcriptomic changes induced by a new Src Family Kinase Inhibitor and proton radiation in glioblastoma cells

Project description:Glioblastoma multiforme (GBM) is a central nervous system tumour. The current standard care for GMB is surgical resection, followed by conventional radiotherapy (RT) often combined with daily drug (temozolomide) administration. However, these treatment modalities are not currently curative and the resistance to both chemotherapy and RT plans is the main cause of GBM care failures. In this scenario, proton therapy (PT) could be used as a successful strategy for GBM treatment, being able to regulate the balance between tumour control and the normal tissue tolerance. In addition, new drugs could be used as radiosensitizing agents combined with PT in order to optimize GBM care. In this work we analyzed the GEP of the U87 MG human glioblastoma cell line, after treatment with PT alone or in combination with a new targeted compound, named Si306 (property of Lead Discovery Siena, Siena, Italy). We described GEP induced by both treatments, highlighting for the first time, the cell pathways induced by Si306. Summarizing, our results suggesting this compound as a novel possible candidate to treat GBM in combination with PT.

2019-11-04 | GSE127989 | GEO

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