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Sunday, January 7, 2018

Targeting the Warburg effect for Cancer Treatment: Ketogenic Diets for Management of Glioma

A promising approach to cancer control is to develop interventions to slow or halt progression of early stages of carcinogenesis to invasive disease as indicated by biomarkers of disease progression as well as related symptom burden. Our goal is to utilize a broad-spectrum approach targeting multiple signaling pathways that result in modulation of apoptosis, proliferation, inflammation and related pathologies, relevant to progression in early stage disease to advanced cancers. The metabolic pathways which support rapid growth of tumors represent a promising therapeutic target for cancer. Ketogenic therapies in the form of a KD and/or pharmacological modulators using exogenous KAs represent one potential tool to exploit the metabolic vulnerabilities of tumors. A number of distinct yet interrelated effects of ketosis may be implicated in the potential anti-tumor effects of ketosis (Fig. 2). Ketogenic therapy for CNS tumors, including glioma, extends far beyond the originally proposed mechanism of reducing glucose availability, and may work through multiple and yet distinct mechanisms such as reducing inflammation, altering in oxidative stress, enhancing anti-tumor immunity, altering gene expression, sensitizing tumors to standard of care and adjuvant therapies, among others (Fig. 5). Some of these mechanisms may depend directly on ketone signaling, supporting the notion that an elevation in blood ketones is a significant component of ketogenic therapy for CNS tumors. To date, case reports and pilot projects have reported moderate success evaluating KD in patients with advanced stage disease (HGG). However, it is important to acknowledge that advanced stage disease, including GBM, display significant increases in genomic complexity and a variety of cell-signaling redundancies. Thus, clinicians face multiple patient-related (due to illness, compliance and other co-morbidities) and metastatic disease- related challenges. It is possible that the KD would be more effective in earlier stage disease (LGG) and provide an opportunity to potentially increase the likelihood of pinpointing targets for transformational therapies. However, to date, there continues to be a paucity of research that exploits these mechanisms and systematically examines interventions such as the ketogenic diet, relevant to tumor progression in glioma. If successful, these novel treatments could provide a non-toxic, cost-effective adjuvant therapy to standard of care in a disease currently with a grim prognosis.

http://www.sciencedirect.com/science/article/pii/S1044579X17301244

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