Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

Yalamarty, Satya Siva Kishan; Filipczak, Nina; Li, Xiang; Subhan, Abdus; Parveen, Farzana; Ataide, Janaína Artem; Rajmalani, Bharat Ashok; Torchilin, Vladimir P.

doi:10.3390/cancers15072116

Cited by 65 publications

(38 citation statements)

References 224 publications

(251 reference statements)

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“…It is very unlikely to de ne a unique identity of GBM, given its high genomic heterogeneity (spatial, temporal, inter-and intra-tumor) [18,19]. Novel treatments have shown promising preclinical effects [20],…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Gonzalez,

Küper,

Fallit

et al. 2024

Preprint

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Purpose Glioblastoma (GBM) remains a formidable challenge in oncology due to its invasiveness and resistance to treatment, i.e. surgery, radiotherapy, and chemotherapy with temozolomide. This study aimed to develop and validate an integrated model to predict the sensitivity of GBM to alternative chemotherapeutics and to identify novel candidate drugs and combinations for the treatment of GBM. Methods We utilized the drug sensitivity response data of 272 compounds from CancerRxTissue, a validated predictive model, to identify drugs with therapeutic potential for GBM. Using the IC50, we selected 'potentially effective' drugs among those predicted to be blood-brain barrier permeable via in silico algorithms. We ultimately selected drugs with targets overexpressed and associated with worse prognosis in GBM for experimental in vitro validation. Results The workflow proposed predicted that GBM is more sensitive to Etoposide and Cisplatin, in comparison with Temozolomide, effects that were validated in vitro in a set of GBM cellular models. Using this workflow, we identified a set of 5 novel drugs to which GBM would exhibit high sensitivity and selected Daporinad, a blood-brain barrier permeant NAMPT inhibitor, for further preclinical in vitro evaluation, which aligned with the in silico prediction. Conclusion Our results suggest that this workflow could be useful to select potentially effective drugs and combinations for GBM, according to the molecular characteristics of the tumor. This comprehensive workflow, which integrates computational prowess with experimental validation, could constitute a simple tool for identifying and validating compounds with potential for drug repurposing in GBM and other tumors.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Gonzalez,

Küper,

Fallit

et al. 2024

Preprint

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“…Glioblastoma Multiforme is a rapidly progressing tumor that affects the brain or spinal cord and is the most prevalent form of primary malignant brain tumor in adults. GBM patients have a 5-year survival rate of 7.2% and an average survival duration of 15 months [ 23 , 24 ]. In this study, we examined the rs4940595 ( Serpinb11 ) expression in 63 GBM patients.…”

Section: Discussionmentioning

confidence: 99%

Exploring Genetic Determinants: A Comprehensive Analysis of Serpin B Family SNPs and Prognosis in Glioblastoma Multiforme Patients

Al-Khatib,

Al-Bzour,

Al-Majali

et al. 2024

Cancers

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Serpins are serine proteinase inhibitors, with several serpins being overexpressed in cancer cells. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of Serpinb11 and its association with GBM survival. A cohort of 63 GBM patients recruited from King Abdullah University Hospital in Jordan underwent polymorphism analysis and overall survival (OS) assessments. The Cancer Genome Atlas (GBM) cohort was useful for validation. We constructed a risk score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk groups based on the median cutoff. Univariable Cox models were used to study the survival outcomes. We identified a significant association between rs4940595 and survival. In the TCGA cohort, Serpinb3 alterations showed worse OS. Univariable Cox showed worse PFS outcomes with higher SERPINB5 and SERPINB6 expression. A Serpin B 5-gene risk score showed a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation, and the MAPK cascade. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Our findings showed a significant role of the Serpin B family in GBM survival in the Jordanian population.

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“…1 Currently, the treatment for glioma is restricted to surgical resection in combination with radiotherapy, chemotherapy, and other auxiliary means. 2 However, the overall prognosis remains poor and the long-term survival rate is low. 3 Temozolomide (TMZ) is an alkylating agent that readily penetrates the blood−brain barrier (BBB), making it an effective drug for the postoperative treatment of glioma, but it is prone to drug resistance.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation

Wen,

Gui,

Wang

et al. 2024

J. Med. Chem.

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The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC 50 = 14.93 nM) and NAMPT (IC 50 = 12.56 nM), leading to significant suppression of IDH1mutated glioma cell (U87 MG-IDH1 R132H ) proliferation. Significantly, compound 23h has the ability to cross the blood−brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1 R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

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Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

Cited by 65 publications

References 224 publications

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Exploring Genetic Determinants: A Comprehensive Analysis of Serpin B Family SNPs and Prognosis in Glioblastoma Multiforme Patients

Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation

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