A phase I dose-escalation trial of 2-deoxy- d -glucose alone or combined with docetaxel in patients with advanced solid tumors
TL;DR: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects, and this phase I trial found this to be the clinically tolerable dose.
Abstract: Purpose
This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-d-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors.
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TL;DR: The PI3K–AKT signalling network is discussed and its control of cancer cell metabolism through both direct and indirect regulation of nutrient transport and metabolic enzymes, thereby connecting oncogenic signalling and metabolic reprogramming to support cancer cell survival and proliferation.
Abstract: The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
860 citations
TL;DR: Current understanding of cancer metabolism is reviewed and how this might guide treatments targeting the metabolic requirements of tumor cells are discussed.
622 citations
TL;DR: The interdependencies of mTOR signalling and metabolism pathways in cancer and how metabolic reprogramming in response to changes in m TOR signalling and vice versa can sustain tumorigenicity are discussed.
Abstract: Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.
587 citations
TL;DR: Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models and may offer therapeutic antiangiogenic opportunities.
412 citations
Cites background from "A phase I dose-escalation trial of ..."
...Nonetheless, cancer patients receiving 2DG had a progressive disease and suffered adverse effects (Granchi and Minutolo, 2012; Raez et al., 2013)....
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...However, given that previous antiglycolytic, anticancer therapies were not always successful (Granchi and Minutolo, 2012; Raez et al., 2013), it was unknown if antiglycolytic strategies could inhibit pathological angiogenesis....
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TL;DR: 2-Deoxy-D-glucose (2DG), a glucose analog, targets glucose metabolism to deplete cancer cells of energy and can efficiently slow cell growth and potently facilitate apoptosis in specific cancer cells.
325 citations
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TL;DR: A model by which a combined assessment of all existing lesions, characterized by target lesions and nontarget lesions, is used to extrapolate an overall response to treatment is proposed, which is largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines.
Abstract: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
14,926 citations
10,654 citations
TL;DR: It is shown that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways, and Synthesis of Cytochrome c Oxidase 2 (SCO2) is identified as the downstream mediator of this effect.
Abstract: The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
1,629 citations
"A phase I dose-escalation trial of ..." refers background in this paper
...which is observed in nearly 50 % of all solid tumors, has recently been reported to reduce mitochondrial respiration via decreased production of SCO2, a component of complex IV [10]....
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TL;DR: Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy and renewed discussions about its exact role as cause, correlate, or facilitator of cancer.
Abstract: More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy.
1,204 citations
"A phase I dose-escalation trial of ..." refers background in this paper
...In addition to the toxicity of 2DG in hypoxic cells, it may also target tumor cells growing under normoxic conditions since many cancers often rely on glycolysis even under aerobic conditions, the so-called Warburg effect [6, 7]....
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