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Lonidamine in malignant brain tumors
D Schiffer1, S Sales, R Soffietti
1II Department of Neurology, University of Torino, Italy.
Abstract:
Among new therapeutic modalities for both primary and secondary brain tumors, selective manipulation of metabolic pathways seems attractive. In human malignant gliomas and cell lines from a glioblastoma multiform, lonidamine has been shown to interfere with aerobic glycolysis with a decrease of lactate production by the inhibition of a mitochondrially-bound hexokinase; this selective reduction of the energetic capabilities of glioma cells would be a limiting factor for processes requiring energy, such as cell growth and recovery from potentially lethal damage after radiotherapy or chemotherapy. The activity of lonidamine in malignant gliomas after surgery in association with conventional radiotherapy is being investigated, while previous studies have suggested a limited, but clear therapeutic activity of the drug in recurrent malignant gliomas. In brain metastases lonidamine has not been effective as a radiation enhancer, but has been shown to potentiate systemic chemotherapy. Most common side effects were myalgias, testicular pain and ototoxicity with no serious organ toxicity or myelosuppression.
Insights
Lonidamine targets cancer cell energy production by inhibiting hexokinase in malignant gliomas. This metabolic interference may limit tumor growth and enhance treatment efficacy, with manageable side effects.
Area of Science:
- Oncology
- Cancer Metabolism
- Neuro-oncology
Background:
- Malignant gliomas and brain metastases present significant therapeutic challenges.
- Targeting cancer cell metabolism, specifically aerobic glycolysis, offers a promising therapeutic strategy.
- Lonidamine is a compound known to interfere with cellular energy production.
Purpose of the Study:
- To investigate the role of lonidamine in targeting metabolic pathways of human malignant gliomas and glioblastoma cell lines.
- To evaluate lonidamine's potential as a therapeutic agent in primary and secondary brain tumors, including its effects on radio/chemotherapy.
- To assess the efficacy and safety profile of lonidamine in brain tumor treatment.
Main Methods:
- In vitro studies on human malignant glioma and glioblastoma cell lines.
- Analysis of lonidamine's effect on aerobic glycolysis and lactate production.
- Investigation of lonidamine's impact on cellular energy-dependent processes.
- Clinical evaluation of lonidamine in combination with radiotherapy and chemotherapy for brain tumors.
Main Results:
- Lonidamine inhibits mitochondrially-bound hexokinase, decreasing lactate production and aerobic glycolysis in glioma cells.
- This metabolic inhibition reduces the energetic capacity of glioma cells, potentially limiting growth and recovery.
- Lonidamine shows limited but clear therapeutic activity in recurrent malignant gliomas and potentiates systemic chemotherapy in brain metastases.
- Common side effects include myalgias, testicular pain, and ototoxicity, with no significant organ toxicity or myelosuppression observed.
Conclusions:
- Lonidamine effectively targets the metabolic vulnerability of malignant gliomas by inhibiting hexokinase and aerobic glycolysis.
- The drug demonstrates potential as an adjunct therapy in managing brain tumors, particularly in recurrent settings and when combined with chemotherapy.
- Lonidamine presents a manageable side effect profile, making it a viable option for further clinical investigation in neuro-oncology.