Cancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 million deaths in 2015 [1, 2]. In the US, it is estimated that 1,688,780 new cancers will be diagnosed in 2017 [3] and 600,920 people will die...
moreCancers are one of the leading causes of morbidity and mortality worldwide, accounting for 8.8 million deaths in 2015 [1, 2]. In the US, it is estimated that 1,688,780 new cancers will be diagnosed in 2017 [3] and 600,920 people will die from this disease in 2017. Gliomas are a
highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. In 2017, an estimated 23,800 new cases of brain tumors will be diagnosed, and 16,700 will die from a brain tumor, most attributed to glioma [3]. Gliomas are neuroepithelial
tumors that originate from the supporting glial cells of the central nervous system (CNS). Glial tumors mostly consist of astrocytomas and oligodendrogliomas. The 2016 WHO classification of CNS tumors uses molecular genetic parameters in addition to histology to define many tumor entities [4]. The routine assessment of isocitrate dehydrogenase (IDH) mutation status, which are frequent in grade II and III infiltrating gliomas and small subset of glioblastomas (GBM) improves histological diagnostic accuracy and has been observed to have a favorable prognostic implication for all glial tumors [5-7] and to be predictive for chemotherapeutic responses in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q, also defined as tumors of oligodendroglial lineage, have favorable prognosis. GBM typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alternations and TERT prompter mutations [5]. The revised classification thus provides a model that reflects malignant characteristics based on histopathlogical and molecular features of the tumors, offering additional opportunities for improved diagnosis, treatment, and estimating prognosis in
the molecular era. Lower grade diffuse gliomas (LGGs) (WHO Grade II-III) have fewer malignant characteristics than high-grade gliomas (WHO Grade IV), and a relatively better clinical prognosis. However, the majority of LGGs eventually progress to high grade gliomas
(HGG, WHO Grade III or IV), with death an inevitable outcome [8]. The life expectancymfollowing diagnosis with Grade IV glioblastoma multiforme is 2-4 months without treatment. Survival at 5 years for patients with GBM who receive treatment with concurrentchemoradiotherapy followed by maintenance temozolomide is around 8-14% [9]. Progression free survival for low grade glioma with standard treatment (LGG, WHO Grade I or II) is 8-35 months depending on patient age, tumor size, functional scores, and symptoms [8]. Treatment for LGG includes surgical resection followed by either radiation and chemotherapy or chemotherapy alone, but average survival is still approximately seven (7) years from diagnosis
[8]. Although LGG have a less aggressive course than do high-grade gliomas, both tumor, its treatment and the ultimate poor prognosis contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and compromised quality of life [8]. Significant gaps exist in how best to manage LGG during active surveillance, a period when patients report significant anxiety, eagerness to reduce disease progression, treatment-related symptoms, and demonstrate significant interest in interventions that can extend their years and quality of survival. Patients with LGG may thus represent an ideal cohort for the evaluation of interventions for secondary chemoprevention and symptom management. Although the current WHO grading system (2016) [4] demonstrates promise towards
identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically
targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. Although LGG have a less aggressive course than do high-grade gliomas, both tumor and its treatment contribute to increased patient burden with disabling morbidity including decline in neurocognitive functions, seizures and ultimately to progression to HGG. There is thus an
urgent need and opportunity for the development of novel, adjunct, secondary chemopreventative strategies targeting patients with LGG to slow or halt progression of LGG to HGG. The recognition and broad applicability of the concepts described by Hanahan and Weinberg [10] – identifying the hallmarks of cancer – has transformed the landscape of cancer prevention and treatment. The hallmarks of cancer constitute an organizing principle for rationalizing the complexities and multi-step development of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling
replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Additional hallmarks include genome instability, which underlies these hallmarks and generates the genetic diversity that is permissive for their acquisition, and inflammation, which fosters
multiple hallmark functions. Based on the conceptual progress made in the last decade, two emerging hallmarks of potential generality were added to this list: reprogramming energy metabolism and evading immune destruction [11]. Abnormal energy metabolism is a consistent
feature of most tumor cells across all tissue types [12]. The characteristic metabolic phenotype of tumor cells as compared to non-transformed cells has been well documented. In the 1930s, Otto Warburg observed that tumors exhibit a unique metabolic phenotype characterized by high rates of aerobic glycolysis, or fermentation in the presence of oxygen [13]. Following glycolysis, pyruvate is primarily fermented to lactate despite availability of oxygen. This feature, known as the Warburg effect, is characterized by tumor hypoxia, genetic mutations, and mitochondrial abnormalities within proliferating cancer cells [14]. The rapid and unbridled proliferation characteristic of tumor growth is an energy and resource-consuming process, and thus
predictably, metabolism is significantly altered during neoplastic transformation and tumor progression [15]. The Warburg effect confers multiple growth promoting effects onto the tumor, including provision of ATP in the face of hypoxia, acidification of the tumor microenvironment,
regeneration of endogenous antioxidants, and provision of carbon sources for biomass production, among others [15].