Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

Mathupala, Saroj P.

doi:10.2174/157489211793980114

Cited by 15 publications

(7 citation statements)

References 39 publications

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“…Possible future applications of the presented model are simulations of the effect of these spatio‐temporal fluctuations on the tumor energy metabolism, the viable rim and oxygen consumption or the in silico evaluation of the metabolic effects of inhibitors of GLY or OXP [48, 49]. Metabolic zonation not only plays an important role in cancer, but also in normal tissue function, for instance in the liver [1, 2].…”

Section: Discussionmentioning

confidence: 99%

Metabolic gradients as key regulators in zonation of tumor energy metabolism: A tissue‐scale model‐based study

König

Holzhütter

Berndt

2013

Biotechnology Journal

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Characteristics of many tumor types are the reprogramming of metabolism and the occurrence of regional hypoxia. In this work, we investigated the hypothesis that metabolic reprogramming in combination with metabolic zonation of cellular energy metabolism are important factors in promotion of the growth capacity of solid tumors. A tissue-scale model of the two main ATP delivering pathways, glycolysis (GLY) and oxidative phosphorylation (OXP), was used to simulate the energy metabolism within solid tumors under various metabolic strategies. Remarkably, despite the high diversity in the usage of glucose, lactate and oxygen in various spatial regions, the tumor as a whole clearly displays the hallmark of the so-called Warburg effect, i.e. a high rate of glucose consumption and lactate production in the presence of sufficiently high levels of oxygen. Our simulations suggest that an increase in GLY capacity and concomitant decrease in OXP capacity from the periphery towards the center of the tumor improves the availability of oxygen to pericentral tumor cells. The found relationship between the regional oxygen level and the relative share of GLY and OXP capacities supports the view that metabolite availability functions as key regulator of tumor energy metabolism.

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Section: Discussionmentioning

confidence: 99%

Metabolic gradients as key regulators in zonation of tumor energy metabolism: A tissue‐scale model‐based study

König

Holzhütter

Berndt

2013

Biotechnology Journal

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“…With the explosion of cancer metabolism studies in recent decades, clinically accessible inhibitors of energy metabolism in cancer cells are increasingly emerging, and some have already received promising data from clinical Cancers 2020, 12, 686 5 of 21 trials [33]. There are two main categories: (1) small molecules against fundamental enzymes in different metabolic pathways, such as glucose transporters (GLUTs) in glucose uptake, hexokinase 2 in glycolysis, and citrate dehydrogenase in the TCA cycle [34][35][36] and (2) competitive molecules of essential metabolites such as 2-deoxy-D-glucose [37]. Studies focused on metabolic alterations are rare in EC, let alone USC.…”

Section: Metabolic Profile Alterationsmentioning

confidence: 99%

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

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“…The amino acid metabolism pathway is frequently altered in tumors due to altered mitochondrial function [55]. The KEGG database has listed 13 major processes that are important in amino acid metabolism (Table 1).…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

Metabolic isoenzyme shifts in cancer as potential novel therapeutic targets

Ononye

Shi

Wali

et al. 2014

Breast Cancer Res Treat

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The functional redundancy of metabolic enzyme expression may present a new strategy for developing targeted therapies in cancer. To satisfy the increased metabolic demand required during neoplastic transformations and proliferation, cancer cells may rely on additional isoforms of a metabolic enzyme to satisfy the increased demand for metabolic precursors, which could subsequently render cancer cells more vulnerable to isoform-specific inhibitors. In this review, we provide a survey of common isoenzyme shifts that have been reported to be important in cancer metabolism and link those to metabolic pathways that currently have drugs in various stages of development. This phenomenon suggests a potentially new therapeutic strategy for the treatment of cancer by identifying shifts in the expression of metabolic isoenzymes between cancer and normal cells. We also delineate other putative metabolic isoenzymes that could be targets for novel targeted therapies for cancer. Changes in isoenzyme expression that occur during neoplastic transformations or in response to environmental pressure in cancer cells may result in isoenzyme diversity that may subsequently render cancer cells more vulnerable to isoform-specific inhibitors due to reliance on a single isoform to perform a vital enzymatic function.

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Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

Cited by 15 publications

References 39 publications

Metabolic gradients as key regulators in zonation of tumor energy metabolism: A tissue‐scale model‐based study

Metabolic gradients as key regulators in zonation of tumor energy metabolism: A tissue‐scale model‐based study

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Metabolic isoenzyme shifts in cancer as potential novel therapeutic targets

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