Press-pulse: a novel therapeutic strategy for the metabolic management of cancer 癌症代謝管理的新治療策略

Calorie restriction used with glutamine targeting for metastatic cancer

Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging [265]. Glutamine targeting should have therapeutic benefit against those tumors that depend on glutamine for growth and survival. We found that the highly metastatic VM-M3 tumor cells are dependent primarily on availability of glutamine for growth and ability to spread systemically [108]. The glutaminase inhibitor DON (6-diazo-5-oxo-L-norleucine) has shown therapeutic benefit in the clinic, as long as toxicity can be managed [186, 266]. DON could work best when combined with inhibitors of glycolysis such as lonidamine [186]. In addition to DON, other glutamine inhibitors ((bis-2-(5-phenylacetamido-1,2, 4-thiadiazol-2-yl)ethyl sulfide, BPTES, or CB-839) could also be therapeutic in targeting glutamine-dependent tumors [267]. A greater attention to possible adverse effects will be needed for glutamine targeting than for glucose targeting, as glutamine is involved with several essential physiological functions especially for cells of the immune system [268, 269]. It might therefore be necessary to also periodically schedule glutamine supplementation with glutamine targeting to obtain maximum therapeutic benefit while protecting immune system function.

The VM-M3 tumor is an excellent model system for evaluating the role of glutamine as a metabolic driver of invasive and metastatic cancer. The VM-M3 tumor arose spontaneously in the brain of its syngeneic immunocompetent VM/Dk inbred mouse host [270]. The tumor was classified as a glioblastoma (GBM) based on histological appearance, invasive growth behavior in brain, and systemic metastasis when give access to extraneural sites [271, 272, 273, 274, 275, 276, 277]. The neoplastic VM-M3 tumor cells share several characteristics with mesenchymal microglia/macrophages, which are abundant in GBM and use glutamine as a major fuel [278, 279]. Although calorie restriction could partially reduce distal invasion of VM-M3 tumor cell in brain and reduce primary tumor growth in flank, CR did not prevent systemic metastasis despite causing reduction in blood glucose and elevation of ketone bodies [108, 280]. However, DON had a major effect in reducing both primary tumor size and systemic metastasis indicative of the importance of glutamine in driving this tumor [108]. A synergistic interaction was also seen when DON was combined with calorie restriction [281]. Modifications of DON scheduling, timing, and dosing would be needed to improve efficacy and reduce toxicity. In this example, CR is the press and DON is the pulse. As glutamine is a major fuel of immune cells, glutamine targeting should be effective in reducing most metastatic cancers that have characteristics of macrophages and other immune cells [121].

Optimization of scheduling, timing, and dosing

The success of the press-pulse therapeutic strategy for the metabolic management of cancer will depend on optimization of the scheduling, dosing, and timing of the various diets, drugs, and procedures used in order to achieve maximum synergistic interactions (Fig. 2). Scheduling will involve the order in which the chosen pulses are delivered to the subject while under dietary therapy. Timing will determine when and for how long the presses and pulses are given (number/day,/week,/month etc.). Dosing will identify the optimal drug dosages needed to kill tumor cells while preventing or minimizing systemic toxicity. Scheduling for each of these variables can be adjusted for the age, sex, and general health status of the subject. The strategy should degrade tumor cell populations gradually to prevent tumor lysis syndrome, which could cause excessive toxicity. Tumor imaging procedures involving FDG-PET, magnetic resonance imaging (MRI), and computed tomography perfusion (CTP), as well as analysis of serum cancer biomarkers should be helpful in assessing therapeutic success. The goal of the press-pulse therapeutic strategy is to improve progression-free and overall survival from cancer without producing adverse effects from the treatment.