Combined carboplatin and etoposide chemotherapy for patients with recurrent glioma

Chen, Jianxin; Zhao, Yuze; Hou, Xinyu; Gao, Xiaoyan; Shi, Qi; Li, Shan; Huang, Hongyan

doi:10.21037/apm-21-3382

“…Among the BBB+ cohort, we found that many drugs that have been used as salvage therapy for TMZ-refractory recurrent gliomas, such as cyclophosphamide, fluorouracil, and cisplatin, exhibit higher predicted efficacy than TMZ in GBM patients. Despite the model was not conclusive about the ability of Etoposide to cross the BBB, this drug has been used in GBM patients alone or in combination with TMZ, cisplatin and other drugs [22,[35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…TMZ, carmustine, cyclophosphamide, fluorouracil, and cisplatin were predicted to cross the BBB, while contradictory results were obtained for Etoposide BBB permeability, our analyses predicted that GBM will exhibit high sensitivity to this drug. Moreover, Etoposide has been utilized for intracranial neoplasia in clinical settings [22]. While carmustine and TMZ exhibited the highest predicted IC50, i.e.…”

Section: Identification and Experimental Validation Of Chemotherapeut...mentioning

confidence: 99%

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

Gonzalez,

Pérez Küper,

Garcia Fallit

et al. 2024

Preprint

0

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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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“…6a), our analyses predicted that GBM will exhibit high sensitivity to this drug. Moreover, Etoposide has been utilized for intracranial neoplasia in clinical settings [13]. While carmustine and TMZ exhibited the highest predicted IC50, i.e.…”

Section: Drug Sensitivity Prediction Modelmentioning

confidence: 99%

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

Gonzalez,

Küper,

Fallit

et al. 2024

Preprint

0

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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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“…Instead, they observed that this combination treatment resulted in a high level of toxicity [ 80 ]. In 2021, Chen et al [ 81 ] applied etoposide and carboplatin (alkylating drug) to treat patients with recurrent glioma, as this combination of drugs is widely used in the treatment of malignant tumors. Unfortunately, their results showed that this combination therapy did not offer any advantages compared to the use of high doses of temozolomide, as demonstrated in the RESCUE Study [ 82 ].…”

Section: Topoisomerase-ii Inhibitorsmentioning

confidence: 99%

“…Unfortunately, their results showed that this combination therapy did not offer any advantages compared to the use of high doses of temozolomide, as demonstrated in the RESCUE Study [ 82 ]. However, the studies of Chen et al resulted in one significant observation: the disease control rate (DCR)—which is the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response, and stable disease to a therapeutic intervention in clinical trials of anticancer agents—time to progression (TTP), and overall survival (OS) were significantly longer in patients with grade 2 and 3 gliomas compared to patients with grade 4 gliomas [ 81 ].…”

Section: Topoisomerase-ii Inhibitorsmentioning

confidence: 99%

Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies

Gaca-Tabaszewska,

Bogusiewicz,

Bojko

2022

Cancers

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In addition to being the most common primary brain tumor, gliomas are also among the most difficult to diagnose and treat. At present, the “gold standard” in glioma treatment entails the surgical resection of the largest possible portion of the tumor, followed by temozolomide therapy and radiation. However, this approach does not always yield the desired results. Additionally, the ability to cross the blood-brain barrier remains a major challenge for new potential drugs. Thus, researchers continue to search for targeted therapies that can be individualized based on the specific characteristics of each case. Metabolic and lipidomic research may represent two of the best ways to achieve this goal, as they enable detailed insights into the changes in the profile of small molecules in a biological system/specimen. This article reviews the new approaches to glioma therapy based on the analysis of alterations to biochemical pathways, and it provides an overview of the clinical results that may support personalized therapies in the future.

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Combined carboplatin and etoposide chemotherapy for patients with recurrent glioma

Cited by 5 publications

References 25 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

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

Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies

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