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Unlocking the Role of Metabolic Pathways in Brain Metastatic Disease
Madalena Pinto1, Sara Violante1, Rita Cascão1
1GIMM-Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035 Lisboa, Portugal.
Abstract:
The dissemination of malignant cells to the brain is a late-stage complication of cancer, leading to significant morbidity and mortality. Brain metastases (BM) affect 20-30% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of ≤12 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood-brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM.
Insights
Brain metastases (BM) are a severe complication of cancer. This review explores how cancer cell metabolism and genetic changes drive brain metastasis, highlighting new therapeutic strategies targeting these pathways.
Area of Science:
- Oncology
- Neuroscience
- Metabolic Research
Background:
- Brain metastases (BM) are a significant cause of cancer morbidity and mortality, affecting 20-30% of patients.
- Current treatments for BM remain largely ineffective due to the blood-brain barrier and tumor heterogeneity.
- Understanding the mechanisms of brain dissemination is crucial for developing better therapies.
Purpose of the Study:
- To review the role of metabolic adaptations in cancer cell dissemination to the brain.
- To discuss current preclinical models and clinical trials for brain metastases.
- To highlight therapeutic strategies targeting metabolic reprogramming in BM.
Main Methods:
- Literature review of studies on cancer metabolism, brain metastases, and therapeutic targets.
- Analysis of preclinical models and ongoing clinical trials.
- Synthesis of information on metabolic pathways relevant to brain cancer dissemination.
Main Results:
- Metabolic reprogramming is critical for cancer cells to survive and proliferate in the brain's nutrient-poor environment.
- Genetic alterations in BM contribute to their unique biological characteristics.
- Targeting metabolic pathways shows promise in preclinical studies for treating BM.
Conclusions:
- Metabolic adaptations are key drivers of brain metastasis.
- Further research into the interplay of metabolism and genetics in BM is needed.
- Targeting metabolic reprogramming offers a promising avenue for novel therapeutic strategies against brain metastases.
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