Targeting Metabolism for Cancer Therapy
Open accessAbstract
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
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- Interpretationreasoning
New insights into differential metabolic dependencies of tumors have provided novel therapeutic strategies, some of which are being evaluated in preclinical models or clinical trials.
“New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in pre-clinical models or clinical trials.”
Quote in the paperSubstantial claim - Premisecitation
The proliferation rates of normal cells are often greater than those of cancer cells.
“Furthermore, the proliferation rates of normal cells are often greater than those of cancer cells (Vander Heiden and DeBerardinis, 2017), and prominent side effects of antimetabolite chemotherapy are caused by the destruction of normal rapidly proliferating cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vander Heiden and DeBerardinis, 2017
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- Interpretationreasoning
The clinical effectiveness of antimetabolite chemotherapies suggests that a metabolic therapeutic window exists beyond proliferation rate and response to DNA damage.
“Nevertheless, the fact that antimetabolite chemotherapies are clinically effective suggests that a metabolic therapeutic window exists beyond proliferation rate and response to DNA damage.”
Quote in the paperSubstantial claim - Premisenone given
The clinical success of antimetabolites is attributed to the increased metabolic demand of neoplastic cells for nucleotide biosynthesis and DNA replication.
“The clinical success of antimetabolites for treating cancer is attributed to the increased metabolic demand of neoplastic cells for nucleotide biosynthesis and DNA replication.”
Quote in the paperSubstantial claim - Premisecitation
Activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings.
“Indeed, activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings (Anastasiou et al., 2012; Kung et al., 2012; Walsh et al., 2010), but because pyruvate kinase expression is dispensable for the growth of some tumors (Cortes-Cros et al., 2013; Israelsen et al., 2013), whether pyruvate kinase activation will lead to durable responses remains an area of”
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- Premisecitation
Aminopterin caused disease remission in children with acute lymphoblastic leukemia.
“In 1947, Sidney Farber, one of the pioneers of modern chemotherapy, discovered that aminopterin could cause disease remission in children with acute lymphoblastic leukemia (Dayton et al., 2016; Farber and Diamond, 1948).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dayton et al., 2016 source
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- cites Farber and Diamond, 1948
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- Premisereasoning
D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA.
“As a result, D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA (Figueroa et al., 2010; Lu et al., 2012; Turcan et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Alterations in the basal enzymatic activity of a given reaction present potential vulnerabilities that might be targeted for cancer therapy.
“Regardless of the underlying mechanism, alterations in basal enzymatic activity of a given reaction present potential vulnerabilities that might be targeted for cancer therapy.”
Quote in the paperSubstantial claim - Premisenone given
The expression of metabolic genes is frequently altered in cancer through gene amplification or deletion, downstream growth signaling, epigenetic changes, or mutations in the genes encoding metabolic enzymes.
“The expression of metabolic genes is frequently altered in cancer. Some changes in metabolic enzyme expression result from gene amplification or deletion, while others are downstream of growth signaling pathways or are the consequences of epigenetic changes. The activity of metabolic enzymes can also be affected by mutations in the genes encoding these enzymes.”
Quote in the paperSubstantial claim - Premisereasoning
Aerobic glycolysis represents a striking metabolic difference between cancer and most normal tissues.
“This phenomenon is now referred to as aerobic glycolysis, or the Warburg effect, and represents a striking metabolic difference between cancer and most normal tissues.”
Quote in the paperSubstantial claim - Interpretationreasoning
Doses of 2-DG that inhibit glycolysis enough to limit cancer growth may not be tolerated due to similar effects in normal tissues that also rely on glucose metabolism.
“Doses of 2-DG that inhibit glycolysis enough to limit cancer growth may not be tolerated due to similar effects in normal tissues that also rely on glucose metabolism.”
Quote in the paperSubstantial claim - Interpretationreasoning
Targeting general proliferative metabolism may not offer an adequate therapeutic window because many non-malignant cells are rapidly proliferating.
“Targeting general proliferative metabolism may not offer an adequate therapeutic window since many non-malignant cells, including those in bone marrow, intestinal crypts, and hair follicles, are rapidly proliferating.”
Quote in the paperSubstantial claim - Premisecitation
Recurrent somatic point mutations in IDH1 and IDH2 are found in a wide variety of cancers, including glioblastoma multiforme and acute myeloid leukemia.
“Recurrent somatic point mutations in the genes coding for isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) are found in a wide variety of cancers, including glioblastoma multiforme (GBM) (Yan et al., 2009) and acute myeloid leukemia (AML) (Dang et al., 2016; Mardis et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Oncogenic mutations that reduce the DNA damage response are one explanation for why a therapeutic window exists for antimetabolite compounds.
“Inducing DNA damage with the use of genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis (Brown et al., 2017; Peters et al., 2000), suggesting that oncogenic mutations that reduce the DNA damage response is one explanation for why a therapeutic window exists for antimetabolite compounds.”
Quote in the paperNot a substantial claim - Premisecitation
Inducing DNA damage with genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis.
“Inducing DNA damage with the use of genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis (Brown et al., 2017; Peters et al., 2000), suggesting that oncogenic mutations that reduce the DNA damage response is one explanation for why a therapeutic window exists for antimetabolite compounds.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Numerous preclinical studies have demonstrated anti-proliferative effects of 2-DG.
“Numerous preclinical studies have demonstrated anti-proliferative effects of 2-DG (Zhang et al., 2014a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang et al., 2014a
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- Premisecitation
Glucose uptake by cancer cells has been successfully exploited via FDG-PET imaging to stage cancers and assess response to therapy.
“Despite challenges associated with targeting glucose metabolism directly, glucose uptake by cancer cells has been successfully exploited in patients through the use of the fluoro-deoxyglucose positron-emission-tomography (FDG-PET) imaging to stage cancers and assess response to therapy (d’Amico, 2015; Farwell et al., 2014; Zhu et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Decreased pyruvate kinase activity is associated with increased aerobic glycolysis.
“Paradoxically, decreased pyruvate kinase activity is associated with increased aerobic glycolysis, suggesting the activation of pyruvate kinase activity might be a way to target cancer (Christofk et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Christofk et al., 2008 source
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- Interpretationreasoning
Most other attempts to directly target aerobic glycolysis have shown limited clinical success at tolerable doses.
“The relative lack of 2-DG clinical efficacy at tolerable doses has been echoed by most other attempts to directly target aerobic glycolysis.”
Quote in the paperSubstantial claim - Premisecitation
Pyruvate kinase expression is dispensable for the growth of some tumors.
“but because pyruvate kinase expression is dispensable for the growth of some tumors (Cortes-Cros et al., 2013; Israelsen et al., 2013), whether pyruvate kinase activation will lead to durable responses remains an area of active study”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Cancers expressing mutant IDH represent a unique case in which a metabolic enzyme can act as an oncogene and contribute to tumor development.
“Cancers expressing mutant IDH represent a unique case in which a metabolic enzyme can act as an oncogene and contribute to tumor development.”
Quote in the paperSubstantial claim - Premisecitation
Targeting glutaminase with chemical inhibitors decreases cancer cell proliferation in both in vitro and in vivo models.
“Mammals have two glutaminase genes, GLS and GLS2, and targeting the enzymes encoded by these genes with chemical inhibitors has been found to decrease cancer cell proliferation in both in vitro and in vivo models (Gross et al., 2014; Jacque et al., 2015; Le et al., 2012; Xiang et al., 2015; Yuneva et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Emerging work suggests that increased serine synthesis may be particularly important for maintaining redox homeostasis during metastasis.
“Emerging work suggests that increased serine synthesis may be particularly important for maintaining redox homeostasis during metastasis (Piskounova et al., 2015).”
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- Premisecitation
PHGDH expression and increased serine biosynthesis are important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings.
“Serine is present in plasma and can be taken up by cells via amino acid transporters, yet PHGDH expression and increased serine biosynthesis have been shown to be important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings (Locasale et al., 2011; Possemato et al., 2011).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Glutamine metabolism is upregulated by various oncogenic signaling pathways.
“Glutamine metabolism is upregulated by various oncogenic signaling pathways (Altman et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Altman et al., 2016 source
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- Premisecitation
GLS2 activity can be tumor suppressive.
“There is also data that GLS2 activity can be tumor suppressive (Hu et al., 2010), underscoring the importance of defining the patient population likely to benefit from glutaminase inhibition.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hu et al., 2010
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Glutamine carbon contributes to aspartate, glutamate, and tricarboxylic acid cycle metabolites via glutaminolysis.
“Glutamine carbon has been found to contribute to aspartate, glutamate and tricarboxylic acid (TCA) cycle metabolites via glutaminolysis (Figure 5) (Altman et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Altman et al., 2016 source
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- Premisecitation
Certain tumors are dependent on uptake of environmental serine.
“Certain tumors are dependent on uptake of environmental serine (Jain et al., 2012; Maddocks et al., 2013; Maddocks et al., 2017), and limiting plasma serine availability can be beneficial for patients with these cancers.”
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Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux.
“Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux (Locasale et al., 2011; Mattaini et al., 2015; Possemato et al., 2011; Zhang et al., 2017), and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Inhibiting glutamine entry into the TCA cycle can blunt tumor progression in a MYC-driven liver cancer model and a MYC-inducible Burkitt lymphoma model.
“Importantly, inhibiting glutamine entry into the TCA cycle can blunt tumor progression in a MYC-driven cancer model of liver cancer (Xiang et al., 2015; Yuneva et al., 2012) and a MYC-inducible Burkitt lymphoma model (Le et al., 2012; Xiang et al., 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Serine is the primary carbon donor to the tetrahydrofolate cycle, which is required for both purine and pyrimidine nucleotide biosynthesis.
“With respect to proliferating cells such as cancer, serine is the primary carbon donor to the tetrahydrofolate (THF) cycle, which is required for both purine and pyrimidine nucleotide biosynthesis (Figure 6)(Snell et al., 1987).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Snell et al., 1987 source
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- Interpretationreasoning
Therapies that deplete exogenous arginine may be effective in treating malignancies where FH is lost.
“and therapies that deplete exogenous arginine (Table 1) may be effective in treating malignancies where FH is lost (Phillips et al., 2013).”
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- Premisereasoning
Loss of metabolic enzyme expression can occur as a passenger event when genomic deletions remove tumor suppressor genes and adjacent non-essential metabolic genes.
“Loss of metabolic enzyme expression can also occur as a passenger event. For example, genomic deletions leading to loss of tumor suppressor genes can also lead to loss of adjacent non-essential metabolic genes.”
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ENO1 loss results in extreme sensitivity to the pan-enolase inhibitor phosphonoacetohydroxamate and SF2312.
“Furthermore, ENO1 loss results in extreme sensitivity to the pan-enolase inhibitor phosphonoacetohydroxamate (PHAH) and SF2312 (Leonard et al., 2016; Muller et al., 2012).”
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Recombinant pegylated arginine deiminase (ADI-PEG20) has been tested in clinical trials for melanoma and hepatocellular carcinoma with some therapeutic benefit.
“Recombinant pegylated arginine deiminase (ADI-PEG20) has been tested in clinical trials to treat melanoma and hepatocellular carcinoma with some therapeutic benefit (Ascierto et al., 2005; Izzo et al., 2004; Ott et al., 2013; Szlosarek et al., 2013; Yang et al., 2010).”
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SDH-defective cells upregulate pyruvate carboxylase protein expression in culture and in tumors to synthesize aspartate from glucose.
“To cope with TCA cycle truncation and still produce aspartate, SDH defective cells upregulate PC protein expression in culture and in tumors to synthesize aspartate from glucose (Cardaci et al., 2015; Lussey-Lepoutre et al., 2015).”
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Combining serine restriction with other drugs may potentiate antitumor responses.
“Combining serine restriction with other drugs may also potentiate antitumor responses (Gravel et al., 2014; Maddocks et al., 2013; Maddocks et al., 2017).”
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MTAP-null cancer cells are more sensitive to PRMT5 depletion than isogenic cancer cells that express MTAP.
“MTAP loss results in reduced PRMT5 activity and renders MTAP-null cancer cell more sensitive to PRMT5 depletion than isogenic counterparts that express MTAP (Kryukov et al., 2016; Marjon et al., 2016; Mavrakis et al., 2016).”
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The use of arginine-catabolizing enzymes may not be an effective therapeutic strategy for all ASS1-deficient cancers, as some ADI-treated tumors have been found to re-express ASS1.
“However, the use of arginine-catabolizing enzymes may not be an effective therapeutic strategy for all ASS1-deficient cancers, as some ADI-treated tumors have been found to re-express ASS1 (Feun et al., 2012; Long et al., 2013; Shen et al., 2003).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisereasoning
FH deletion renders mouse and human cells more sensitive to genetic and pharmacological inhibition of heme oxygenase 1.
“Consequently, FH deletion renders mouse and human cells more sensitive to genetic and pharmacological inhibition of heme oxygenase 1 (Hmox1), an enzyme involved in heme degradation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Frezza et al., 2011 source
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- Premisecitation
Ablating MAT2A reduces PRMT5-dependent methylation and proliferation in MTAP-deleted cancer cells.
“Additionally, ablation of methionine adenosyltransferase II alpha (MAT2A), the enzyme that produces the canonical and high-affinity PRMT5 substrate, S-adenosylmethionine (SAM), also reduces PRMT5-dependent methylation and proliferation in MTAP-deleted cancer cells (Marjon et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Marjon et al., 2016 source
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Genetic or epigenetic silencing of ASS1 provides an advantage to tumor cells by allowing them to preserve cellular aspartate, a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation.
“Genetic or epigenetic silencing of ASS1 expression provides an advantage to tumor cells by allowing them to preserve cellular aspartate (Rabinovich et al., 2015), a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation (Birsoy et al., 2015; Sullivan et al., 2015).”
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Co-administration of MTA with toxic adenosine analogues is selectively lethal to MTAP-deficient cancer cells because MTAP-expressing normal tissues can convert MTA to adenine to competitively inhibit the effects of the analogues.
“Co-administration of MTA with toxic adenosine analogues has been shown to be selectively lethal to MTAP deficient cancer cells, since MTAP-expressing normal tissues are able to convert MTA to adenine to competitively inhibit the effects of the analogues (Lubin and Lubin, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lubin and Lubin, 2009
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Fumarate and succinate accumulation can inhibit some alpha-ketoglutarate-dependent dioxygenases, resulting in hypermethylation of DNA and histones in tumors with FH or SDH loss.
“Like D-2HG, fumarate and succinate accumulation can inhibit some αKG-dependent dioxygenases, resulting in hypermethylation of DNA and histones in tumors exhibiting loss of FH or SDH (Hoekstra et al., 2015; Letouze et al., 2013; Xiao et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Because cells often exhibit redundancy in essential pathways, passenger loss of metabolic genes can introduce a therapeutic opportunity termed collateral lethality.
“Because cells often exhibit redundancy in essential pathways, this phenomenon can introduce a therapeutic opportunity to target cancer cells that has been termed collateral lethality (Muller et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Muller et al., 2015 source
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- Premisecitation
Some melanoma, lymphoma, glioma, and prostate cancers reduce or lose expression of the urea cycle enzyme argininosuccinate synthase 1.
“For example, some melanoma, lymphoma, glioma, and prostate cancers reduce or lose the expression of the urea cycle enzyme argininosuccinate synthase 1 (ASS1) (Delage et al., 2010).”
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Familial cancer syndromes caused by fumarate hydratase or succinate dehydrogenase deletion suggest that these TCA enzymes can behave as classical tumor suppressors.
“Familial cancer syndromes caused by fumarate hydratase (FH) or succinate dehydrogenase (SDH) deletion suggest that these TCA enzymes can behave as classical tumor suppressors.”
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L-alanosine was clinically ineffective in patients with advanced MTAP-deficient tumors in a Phase II trial.
“but was found to be clinically ineffective in patients with advanced MTAP-deficient tumors in a Phase II trial (Kindler et al., 2009).”
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Deletion of CDKN2A results in concomitant deletion of MTAP in many cancers, including 53% of glioblastomas and 26% of pancreatic cancers.
“Deletion of the tumor suppressor CDKN2A results in concomitant deletion of the methionine salvage pathway enzyme methylthioadenosine phosphorylase (MTAP) in many cancers, including 53% of glioblastomas and 26% of pancreatic cancers (Mavrakis et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mavrakis et al., 2016 source
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- Premisenone given
Pharmacokinetic analyses confirming successful purine biosynthesis inhibition by the doses of L-alanosine used in the study were not reported.
“Pharmacokinetic analyses confirming successful purine biosynthesis inhibition by doses of L-alanosine used in the study were not reported, so further exploration of why this approach failed may yield insight into how best to exploit MTAP deficiency.”
Quote in the paperSubstantial claim - Premisecitation
Mitochondrial ATP production appears dispensable for many proliferating cells.
“However, mitochondrial ATP production appears dispensable for many proliferating cells (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Targeting de novo fatty acid synthesis might be effective in treating some cancers.
“Several lines of evidence suggest that targeting de novo fatty acid synthesis might be effective in the treatment of some cancers.”
Quote in the paperSubstantial claim - Premisecitation
Except for liver, adipose tissue, and lactating breast, adult tissues do not synthesize fatty acids de novo under normal physiological conditions.
“With the exception of liver, adipose tissue, and lactating breast, adult tissues do not synthesize fatty acids de novo under normal physiological conditions (Menendez and Lupu, 2006), so inhibition of de novo fatty acid synthesis might have an adequate therapeutic window.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Menendez and Lupu, 2006
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- Premisecitation
Respiration is needed for tumor initiation, as tumor cells with impaired oxidative phosphorylation due to mtDNA depletion show increased tumor latency after subcutaneous transplantation.
“Respiration is also needed for tumor initiation, as tumor cells with impaired oxidative phosphorylation due to depletion of mitochondrial DNA (mtDNA) exhibit increased tumor latency upon subcutaneous transplantation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tan et al., 2015a
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The ACC allosteric inhibitor ND-646 has antitumor efficacy in autochthonous mouse lung tumor models.
“Genetic knockdown of ACC induces apoptosis in cancer cell lines (Brusselmans et al., 2005; Chajes et al., 2006), and an allosteric inhibitor of ACC, ND-646, has shown antitumor efficacy in autochthonous mouse lung tumor models (Svensson et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Svensson et al., 2016 source
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Small-molecule NAMPT inhibitors can be effective anti-tumor agents in vitro and in xenograft cancer models.
“Small-molecules targeting NAMPT can be effective anti-tumor agents in vitro and in xenograft cancer models (Nahimana et al., 2009; Tan et al., 2015b; Watson et al., 2009).”
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Respiration serves an anabolic role for proliferating cells by regenerating NAD+ from NADH.
“Instead, respiration serves an alternative anabolic role for proliferating cells by regenerating the oxidized form of nicotinamide adenine dinucleotide (NAD+) from the reduced form (NADH) (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016).”
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Targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation.
“ACLY activity is elevated in cancers (Migita et al., 2008), and targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation (Adam et al., 2013; Bauer et al., 2005; Hatzivassiliou et al., 2005; Migita et al., 2008).”
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ACLY activity is elevated in cancers.
“ACLY activity is elevated in cancers (Migita et al., 2008), and targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation (Adam et al., 2013; Bauer et al., 2005; Hatzivassiliou et al., 2005; Migita et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Migita et al., 2008 source
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Despite engaging in aerobic glycolysis, cancer cells consume oxygen at levels comparable to normal tissue.
“However, subsequent work determined that despite engaging in aerobic glycolysis, cancer cells consume oxygen at levels comparable to normal tissue (Weinhouse, 1956; Zu and Guppy, 2004).”
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- cites Zu and Guppy, 2004
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In clinical trials, NAMPT inhibitors used as single agents have not caused tumor remission.
“In clinical trials, use of these inhibitors as single agents has not caused tumor remission (von Heideman et al., 2010), but additional studies may uncover how best to safely use these drugs for patient benefit.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites von Heideman et al., 2010 source
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- Premisecitation
Recent work shows that the anti-tumorigenic effect of metformin can be at least partially accounted for by direct mitochondrial complex I inhibition in tumors.
“Although the precise mechanism of metformin action remains controversial (Luengo et al., 2014), recent work has shown that the anti-tumorigenic effect of metformin can at least be partially accounted for by direct mitochondrial complex I inhibition in tumors (Gui et al., 2016; Wheaton et al., 2014).”
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De novo fatty acid biosynthesis is a key metabolic requirement for some cancers.
“Since then, numerous studies have identified de novo fatty acid biosynthesis as a key metabolic requirement for some cancers, and it has been dubbed by some as a distinct metabolic “hallmark of the transformed phenotype” (Kuhajda et al., 1994; Menendez and Lupu, 2006; Rohrig and Schulze, 2016).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Inhibiting de novo fatty acid synthesis might have an adequate therapeutic window.
“With the exception of liver, adipose tissue, and lactating breast, adult tissues do not synthesize fatty acids de novo under normal physiological conditions (Menendez and Lupu, 2006), so inhibition of de novo fatty acid synthesis might have an adequate therapeutic window.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Menendez and Lupu, 2006
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- Premisecitation
Cancer cells can generate acetyl-CoA from cytosolic acetate.
“Cancer cells are also able to generate acetyl-CoA from cytosolic acetate (Comerford et al., 2014; Gao et al., 2016; Kamphorst et al., 2014; Mashimo et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
PRMT5 inhibitors currently in clinical trials may be ineffective in MTAP-null cancers because the high MTA levels in these cells compete with the inhibitors for binding to PRMT5.
“However, PRMT5 inhibitors in current clinical trials may not be effective in MTAP null cancers, in part because the high levels of MTA in these cells compete for binding of the inhibitors to the enzyme.”
Quote in the paperSubstantial claim - Premisecitation
Genetic knockdown of ACC induces apoptosis in cancer cell lines.
“Genetic knockdown of ACC induces apoptosis in cancer cell lines (Brusselmans et al., 2005; Chajes et al., 2006), and an allosteric inhibitor of ACC, ND-646, has shown antitumor efficacy in autochthonous mouse lung tumor models (Svensson et al., 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Metformin has been found to cooperate with neo-adjuvant chemotherapy to result in complete tumor regression in some breast cancer patients.
“Metformin has also been found to cooperate with neo-adjuvant chemotherapy to result in complete tumor regression in some breast cancer patients (Jiralerspong et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jiralerspong et al., 2009 source
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- Premisecitation
Eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impair purine biosynthesis.
“For example, eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impairs purine biosynthesis (Ducker et al., 2016; Labuschagne et al., 2014; Sullivan et al., 2015).”
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Circulating nucleotide concentrations are likely too low for many tumors to satisfy their nucleotide demand through salvage alone.
“Though nucleotide salvage pathways can support tumor cell proliferation in certain contexts (Tabata et al., 2017), concentrations of circulating nucleotides are likely too low for many tumors to satisfy their nucleotides demand via salvage alone (Traut, 1994).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Traut, 1994 source
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KRAS/LKB1-null lung cancer cells are more reliant on CPS1 for pyrimidine biosynthesis, independent of mTOR signaling.
“KRAS/LKB1-null lung cancer cells are more reliant on the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1) for pyrimidine biosynthesis, although this dependency is independent of mTOR signaling (Kim et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kim et al., 2017 source
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Inhibitors of mutant IDH1 or IDH2 induce differentiation in AML cells harboring mutant IDH.
“Inhibitors of mutant IDH1 or IDH2 have been shown to induce differentiation in AML cells harboring mutant IDH (Okoye-Okafor et al., 2015; Wang et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Tissue-of-origin can influence metabolic requirements and vulnerabilities.
“Together, these observations suggest that tissue-of-origin can influence metabolic requirements and vulnerabilities.”
Quote in the paperSubstantial claim - Premisecitation
Acute lymphoblastic leukemia and related lymphomas are auxotrophic for asparagine.
“Acute lymphoblastic leukemia (ALL) and related lymphomas, however, are auxotrophic for asparagine (Neuman and McCoy, 1956).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Neuman and McCoy, 1956
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- Interpretationreasoning
Asparagine auxotrophy in ALL may be lineage dependent.
“The absence of a genetic driver for asparagine auxotrophy, combined with the fact that L-asparaginase has little known clinical utility outside of the context of ALL, suggests that this metabolic vulnerability may be lineage dependent.”
Quote in the paperSubstantial claim - Interpretationcitation
Targeting nucleotide metabolism may be more effective in tumor contexts with mTOR hyperactivation.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Administering 5hmdC and 5fdC may selectively target tumors that overexpress CDA.
“Thus, administering 5hmdC and 5fdC may selectively target tumors overexpressing CDA.”
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Genome-wide analysis has shown that no consistent gene expression pattern dictates sensitivity to L-asparaginase.
“In fact, genome-wide analysis has shown that there is no consistent gene expression pattern that dictates sensitivity to L-asparaginase (Fine et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fine et al., 2005 source
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Mouse lung and pancreatic tumors exhibit differences in amino acid metabolism even when they harbor the same genetic lesion.
“Recently, it has been determined that mouse lung and pancreatic tumors exhibit differences in amino acid metabolism, even when harboring the same genetic lesion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mayers et al., 2016 source
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- Premisecitation
Inhibition of DHODH can induce differentiation in a myeloid cell screen involving HoxA9-enforced differentiation arrest.
“Recently, a myeloid cell screen involving HoxA9-enforced differentiation arrest found that inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the pyrimidine biosynthesis pathway (Figure 1b), can induce differentiation (Sykes et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sykes et al., 2016 source
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- Premisecitation
Tumors retain many features that correspond to their parental normal tissue.
“In fact, tumors retain many features that correspond to their parental normal tissue (Gaude and Frezza, 2016; Hu et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gaude and Frezza, 2016
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- cites Hu et al., 2013
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- Premisecitation
Clinical response to L-asparaginase treatment is independent of asparagine synthase expression.
“Though the mechanism of asparagine auxotrophy in ALL cells was assumed to be genetically defined, studies have shown that clinical response to L-asparaginase treatment is independent of asparagine synthase (ASNS) expression, the enzyme that converts aspartate to asparagine (Figure 7) (Appel et al., 2006; Stams et al., 2003).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Nucleotide salvage pathways can support tumor cell proliferation in certain contexts.
“Though nucleotide salvage pathways can support tumor cell proliferation in certain contexts (Tabata et al., 2017), concentrations of circulating nucleotides are likely too low for many tumors to satisfy their nucleotides demand via salvage alone (Traut, 1994).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tabata et al., 2017 source
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- Premisecitation
Cancer cells generally have increased levels of reactive metabolites.
“Cancer cells generally have increased levels of reactive metabolites (DeBerardinis and Chandel, 2016; Sullivan et al., 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites DeBerardinis and Chandel, 2016
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- cites Sullivan et al., 2016 source
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- Premisecitation
Tumors of other lineages, including some glioblastomas and blast crisis chronic myeloid leukemia, are also dependent on BCAA transaminases.
“Tumors of other lineages are also dependent on BCAA transaminases, including some glioblastomas and blast crisis chronic myeloid leukemia (Hattori et al., 2017; Tonjes et al., 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Inhibitors of the cystine/glutamate transporter xCT deplete intracellular glutathione in cancer cells, resulting in iron-dependent ROS accumulation and ferroptosis.
“Inhibitors of this transporter have been found to deplete intracellular glutathione in cancer cells, resulting in iron-dependent accumulation of ROS and a form of cell death termed ferroptosis (Dixon et al., 2012; Dixon et al., 2014; Yang et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Therapeutic interventions that decrease intracellular glutathione, such as dehydroascorbate, can result in cancer cell death and impaired tumor progression.
“Therapeutic interventions that decrease intracellular glutathione levels, such as administration of the oxidized form of vitamin C, dehydroascorbate (DHA), can result in cancer cell death and impaired tumor progression (Yun et al., 2015)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yun et al., 2015 source
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- Premisecitation
Elevation of reactive metabolites can support oncogenesis in some contexts.
“While elevation of reactive metabolites can support oncogenesis in some contexts (Arnold et al., 2001; Irani et al., 1997; Suh et al., 1999; Weinberg et al., 2010), at high levels reactive metabolites become toxic and kill cells due to the resulting damage to the proteome and genome (Karisch et al., 2011; Rabbani and Thornalley, 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
PTEN-deficient cells, which have active mTOR signaling, are more sensitive to DHODH inhibition by brequinar and leflunomide.
“PTEN-deficient cells, which have active mTOR signaling, are more sensitive to inhibition of DHODH by brequinar and leflunomide (Mathur et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mathur et al., 2017 source
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- Premisecitation
At high levels, reactive metabolites become toxic and kill cells through damage to the proteome and genome.
“While elevation of reactive metabolites can support oncogenesis in some contexts (Arnold et al., 2001; Irani et al., 1997; Suh et al., 1999; Weinberg et al., 2010), at high levels reactive metabolites become toxic and kill cells due to the resulting damage to the proteome and genome (Karisch et al., 2011; Rabbani and Thornalley, 2014).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Lactate produced by cancer-associated fibroblasts can enter the TCA cycle of cancer cells.
“It has been reported that lactate produced by cancer-associated fibroblasts can enter the TCA cycle of cancer cells (Bonuccelli et al., 2014; Witkiewicz et al., 2012), and lactate produced in hypoxic regions of a tumor can fuel respiration in well-oxygenated tumor cells (Kennedy et al., 2013; Sonveaux et al., 2008).”
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Lactate produced in hypoxic regions of a tumor can fuel respiration in well-oxygenated tumor cells.
“It has been reported that lactate produced by cancer-associated fibroblasts can enter the TCA cycle of cancer cells (Bonuccelli et al., 2014; Witkiewicz et al., 2012), and lactate produced in hypoxic regions of a tumor can fuel respiration in well-oxygenated tumor cells (Kennedy et al., 2013; Sonveaux et al., 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kennedy et al., 2013 source
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- cites Sonveaux et al., 2008
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Cell lines derived from resistant lung tumors become sensitive to glutaminase inhibition in vitro, highlighting that environment can contribute to glutaminase sensitivity.
“Importantly, cell lines derived from resistant lung tumors become sensitive to glutaminase inhibition in vitro, highlighting that environment can be a contributor to glutaminase sensitivity (Davidson et al., 2016).”
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- Interpretationreasoning
Metabolic dependencies in cancer are influenced by tissue environment, cancer lineage, and genetic events.
“There is growing evidence that metabolic dependencies in cancer are influenced by tissue environment, cancer lineage, as well as genetic events.”
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Sensitivity to mutant IDH inhibitors appears to differ between leukemia and solid tumor models.
“Even among cancers where mutant IDH is an oncogenic driver, sensitivity to mutant IDH inhibitors appears to differ between leukemia and solid tumor models (Tateishi et al., 2015; Turcan et al., 2013).”
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- Classified as probably not a substantial claim. 3
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InterpretationreasoningChemotherapies targeting metabolism have been effective cancer treatments for decades, demonstrating that a therapeutic window exists to target malignant metabolism.
“Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism.”
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Interpretationnone givenMetabolic reprogramming contributes to tumor development and creates exploitable metabolic liabilities for cancer treatment.
“Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer.”
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PremisecitationCancer cells consume large amounts of glucose and metabolize most of it to lactate even in the presence of oxygen (the Warburg effect).
“More than thirty years preceding Farber’s work on antifolates, Otto Warburg reported that cancer cells consume tremendous amounts of glucose and metabolize the majority of the glucose into lactate, even in the presence of oxygen (Warburg, 1924).”
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InterpretationcitationMany noncancerous tissues, including the brain, are FDG-PET avid, showing that high glucose uptake is not unique to tumors.
“Notably, many noncancerous tissues, including the brain, are FDG-PET avid (Berti et al., 2014; Cohade, 2010), illustrating that high glucose uptake is not a unique feature of tumors and offering a potential explanation for the relative lack of success in directly targeting glucose metabolism for cancer treatment.”
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PremisecitationAminopterin is the precursor of methotrexate and pemetrexed, folate analogues that inhibit one-carbon transfer reactions required for de novo nucleotide synthesis.
“Aminopterin is the precursor of the currently used drugs methotrexate and pemetrexed, both of which are folate analogues that inhibit one-carbon transfer reactions required for de novo nucleotide synthesis (Figure 1, Figure 2a)(Walling, 2006).”
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Premisecitation6-MP and 6-TG inhibit PRPP amidotransferase, the first enzyme in de novo purine biosynthesis, and have been successful in treating many cancers including childhood leukemia.
“Notable examples include the purine analogues 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), which inhibit 5-phosphoribosyl-1-pyrophosphatase (PRPP) amidotransferase, the first enzyme in de novo purine biosynthesis (Figure 1a, Figure 2b). 6-MP and 6-TG have been successful in treating many cancers including childhood leukemia (Elion, 1989).”
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Premisecitation5-FU inhibits thymidylate synthase, limiting thymidine nucleotides for DNA synthesis, and 5-FU and capecitabine remain widely used and important for gastrointestinal cancers.
“The pyrimidine analogue 5-fluorouracil (5-FU) is a synthetic analogue of uracil that inhibits thymidylate synthase, limiting the availability of thymidine nucleotides for DNA synthesis (Figure 1b, Figure 2c). 5-FU and the related 5-FU-prodrug capecitabine remain widely used chemotherapies today and are an important treatment for gastrointestinal cancers (Heidelberger et al., 1957; Wagner et al., 2”
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PremisecitationAG-221 (enasidenib) inhibits mutant IDH2 and confers survival benefit in a mouse model of IDH2-mutant AML; early results in IDH2-mutant AML patients suggest it can provide clinical benefit.
“A specific inhibitor of mutant IDH2, AG-221 (enasidenib) confers survival benefit in a mouse model of IDH2-mutant AML (Quivoron et al., 2014; Yen et al., 2017) and became the first compound targeting mutant IDH to enter clinical trials in 2014. Early results in IDH2-mutant AML patients have suggested enasidenib can provide clinical benefit (DiNardo et al., 2015; Stein et al., 2014), and this drug”
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PremisecitationWild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate and CO2; cancer-associated mutations eliminate this function and confer a neomorphic activity generating D-2-hydroxyglutarate via reduction of alpha-ketoglutarate.
“Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (αKG) and CO2 (Figure 4a). Cancer associated mutations in IDH1 and IDH2 eliminate this function and confer a neomorphic activity to the enzyme, generating D-2-hydroxyglutarate (D-2HG) via the reduction of αKG (Figure 4b)(Dang et al., 2009; Ward et al., 2010).”
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InterpretationcitationMutant IDH inhibitors may not be effective in all IDH-mutant cancers; in many IDH-mutant glioma models they fail to reverse epigenetic changes or inhibit tumor proliferation despite lowering 2-HG.
“Despite success in some preclinical models and patients with AML, mutant IDH inhibitors may not be effective in all IDH-mutant cancers. For example, these drugs are unable to reverse epigenetic changes or inhibit tumor proliferation in many models of IDH mutant glioma, despite a robust ability to lower 2-HG in cells and tumors (Tateishi et al., 2015; Turcan et al., 2013).”
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Premisecitation2-DG is phosphorylated by hexokinase to 2-deoxyglucose-6-phosphate, which cannot be further metabolized, accumulates intracellularly, and competitively inhibits hexokinase to slow glucose uptake.
“2-DG is phosphorylated by hexokinase to produce 2-deoxyglucose-6-phosphate, which cannot be further metabolized by cells. It therefore accumulates intracellularly and competitively inhibits hexokinase to slow glucose uptake (Figure 3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wick et al., 1957 source
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PremisecitationAGI-5198 targets mutant IDH1, reduces intratumoral D-2HG levels, induces expression of genes involved in glial cell differentiation, and suppresses growth of IDH1-mutant human glioma cells in a xenograft model.
“One of the first compounds reported was AGI-5198, which targets mutant IDH1. AGI-5198 reduces intratumoral D-2HG levels, induces expression of genes involved in glial cell differentiation, and suppresses growth of IDH1-mutant human glioma cells in a xenograft model (Rohle et al., 2013).”
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PremisecitationEarly clinical testing of 2-DG yielded responses in some patients but was limited by toxicity associated with hypoglycemia symptoms.
“Although early clinical testing yielded responses in some patients, the use of this drug was limited by toxicity associated with hypoglycemia symptoms (Landau et al., 1958).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Landau et al., 1958
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InterpretationcitationIDH1 mutations are early events in glial cancer development, raising the possibility that additional oncogenic mutations render GBM tumors less dependent on mutant IDH for proliferation and progression.
“IDH1 mutations are early events in the development of glial cancer (Watanabe et al., 2009), raising the possibility that IDH mutations are important for tumor initiation, but accumulation of additional oncogenic mutations renders GBM tumors less dependent on constitutive expression of mutant IDH for tumor proliferation and progression (Johnson et al., 2014; Wakimoto et al., 2014).”
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PremisecitationRecent clinical trials revisited 2-DG at lower doses, but these doses are insufficient to inhibit disease progression.
“Recent clinical trials have revisited use of 2-DG at lower doses, but these doses are insufficient to inhibit disease progression (Raez et al., 2013; Stein et al., 2010).”
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Premisenone givenAntimetabolite drugs are only effective against a subset of cancer types; many resistant cancers have the same mutational spectrum as sensitive cancers, and defining genetic predictors of response has been difficult.
“However, antimetabolite drugs are only effective against a subset of cancer types. Many resistant cancers have the same mutational spectrum as sensitive cancers, and defining genetic predictors of chemotherapy response for most malignancies has been difficult.”
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PremisecitationProliferating cells have different metabolic requirements from non-proliferating cells and engage a metabolic program distinct from that of the normal tissue from which they arose.
“Proliferating cells have different metabolic requirements from non-proliferating cells (Hsu and Sabatini, 2008; Lunt and Vander Heiden, 2011; Pavlova and Thompson, 2016). While non-proliferating cells have primarily catabolic demands, proliferating cells must balance the divergent catabolic and anabolic requirements of sustaining cellular homeostasis while duplicating cell mass, and thus engage in”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Hsu and Sabatini, 2008
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- cites Lunt and Vander Heiden, 2011 source
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- cites Pavlova and Thompson, 2016
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PremisereasoningProminent side effects of antimetabolite chemotherapy are caused by destruction of normal rapidly proliferating cells, and myeloid suppression or gastrointestinal toxicity are often dose-limiting.
“Furthermore, the proliferation rates of normal cells are often greater than those of cancer cells (Vander Heiden and DeBerardinis, 2017), and prominent side effects of antimetabolite chemotherapy are caused by the destruction of normal rapidly proliferating cells. Myeloid suppression or gastrointestinal toxicity are often dose-limiting toxicities for these drugs.”
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PremisecitationD-2HG can accumulate to millimolar levels in cancer cells expressing mutant IDH and at these concentrations inhibits alpha-ketoglutarate-dependent dioxygenases, including enzymes involved in histone and DNA demethylation.
“Though it is found at low levels in normal cells, D-2HG can accumulate to millimolar levels in cancer cells expressing mutant IDH. At these high concentrations, D-2HG can inhibit αKG-dependent dioxygenases, including enzymes involved in histone and DNA demethylation (Chowdhury et al., 2011; Janke et al., 2017; Koivunen et al., 2012; Xu et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGemcitabine and cytarabine are incorporated into DNA, inhibit DNA polymerases, and are commonly used to treat select cancers.
“Other antimetabolite nucleoside analogues, such as gemcitabine and cytarabine, are incorporated into DNA, resulting in inhibition of DNA polymerases, and are commonly used to treat select cancers (Parker, 2009).”
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PremisecitationIncreased PHGDH expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma.
“Increased PHGDH gene expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma (Locasale et al., 2011; Possemato et al., 2011; Zhang et al., 2017).”
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Premisenone givenCB-839 is a potent glutaminase inhibitor currently being evaluated in cancer trials.
“One potent glutaminase inhibitor, CB-839, is currently being evaluated in cancer trials in patients (Table 1), although the exact disease context where glutaminase inhibition will be most effective remains an area of active investigation.”
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PremisecitationSmall-molecule inhibitors targeting PHGDH inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models.
“and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang et al., 2017).”
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PremisecitationProviding alpha-ketoglutarate, oxaloacetate, or pyruvate rescues cancer cell proliferation under glutamine starvation, confirming that glutamine supports proliferation by replenishing depleted TCA cycle intermediates (anaplerosis).
“Providing cells with αKG, oxaloacetate, or pyruvate is sufficient to rescue cancer cell proliferation in conditions of glutamine starvation, confirming that glutamine supports proliferation by replenishing depleted TCA cycle intermediates, a process termed anaplerosis (Altman et al., 2016; Weinberg et al., 2010; Yuneva et al., 2007).”
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PremisecitationGlutamine is an important nitrogen donor for amino acids and nucleotides, but glutamine uptake can exceed the nitrogen requirement of some cancer cells.
“Glutamine is an important nitrogen donor for amino acids and nucleotides (Hosios et al., 2016), but glutamine uptake can exceed the nitrogen requirement of some cancer cells (DeBerardinis et al., 2007).”
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PremisecitationPHGDH activity may not be required for proliferation in all PHGDH-amplified cancers; expression has been shown to be dispensable in a breast cancer xenograft model.
“However, PHGDH activity may not be a requirement for proliferation for all PHGDH-amplified cancers, as expression has been shown to be dispensable in a breast cancer xenograft model (Chen et al., 2013).”
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PremisecitationSerine can contribute to NADPH production via the folate cycle, which maintains redox homeostasis and supports anabolic reactions.
“Serine can also contribute to NADPH production via the folate cycle, which serves to maintain redox homeostasis and support anabolic reactions (Fan et al., 2014; Lewis et al., 2014; Ye et al., 2014).”
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PremisecitationCancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival.
“Glutamine is a non-essential amino acid, and yet cancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival (DeBerardinis and Cheng, 2010; Eagle, 1955; Jain et al., 2012).”
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PremisecitationIn certain contexts, MYC-transformed cancers become glutamine dependent and undergo apoptosis in the absence of glutamine.
“In certain contexts, MYC-transformed cancers become glutamine dependent and undergo apoptosis in the absence of glutamine (Yuneva et al., 2007).”
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PremisecitationTumors harboring an IDH mutation have increased sensitivity to hypomethylating agents, electron transport chain inhibitors, depletion of NAD+, and chemoradiotherapy.
“For example, tumors harboring an IDH mutation have increased sensitivity to hypomethylating agents (Turcan et al., 2013), electron transport chain inhibitors (Grassian et al., 2014), depletion of the coenzyme NAD+ (Tateishi et al., 2015) and chemoradiotherapy (Cairncross et al., 2014).”
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PremisecitationMYC increases mRNA and protein levels of glutamine transporters and expression of the enzyme glutaminase.
“MYC has been found to increase mRNA and protein levels of glutamine transporters as well as expression of the enzyme glutaminase, which catalyzes the first step in glutaminolysis (Gao et al., 2009; Wise et al., 2008; Yuneva et al., 2012).”
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PremisecitationInhibitors targeting mutant IDH1 can antagonize the effects of radiation therapy in glioma, suggesting that inhibiting mutant IDH could confer resistance to some therapies.
“However, some evidence suggests that inhibiting mutant IDH could confer resistance to some therapies, as inhibitors targeting mutant IDH1 can antagonize the effects of radiation therapy in glioma (Molenaar et al., 2015).”
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InterpretationcitationClinical trials using glutamine analogues were abandoned due to lack of efficacy and/or severe toxicity, likely because the drugs were relatively non-specific and affected many glutamine-utilizing enzymes.
“Clinical trials using glutamine analogues to treat cancers were initiated decades ago, but these trials were abandoned due to lack of efficacy and/or severe patient toxicity (Livingston et al., 1970; O’Dwyer et al., 1984). The absence of a therapeutic window for these studies can likely be attributed to fact that these drugs were relatively non-specific and a panoply of glutamine utilizing enzymes”
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- cites O’Dwyer et al., 1984
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PremisecitationIncreased PHGDH expression in some cancers can result from copy number gain of a region on chromosome 1p or from oncogenic signaling including NRF2 and ATF4 signaling or hypoxia responses.
“More recently, it was found that increased expression of the serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH) in some cancers can result from copy number gain of a region on chromosome 1p (Beroukhim et al., 2010; Locasale et al., 2011; Possemato et al., 2011) or a consequence of oncogenic signaling, including NRF2 and ATF4 signaling (DeNicola et al., 2015), or hypoxia responses (Sam”
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InterpretationcitationInhibitors of PHGDH might have a limited therapeutic index because de novo serine synthesis has an important physiological role in the central nervous system and PHGDH-deficient mice exhibit severe brain morphogenesis defects.
“However, inhibitors of PHGDH might have a limited therapeutic index, as de novo serine synthesis has an important physiological role in the central nervous system (Furuya, 2008) and PHGDH-deficient mice exhibit severe brain morphogenesis defects (Yoshida et al., 2004).”
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- cites Yoshida et al., 2004 source
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PremisecitationIncreased activity of de novo serine synthesis enzymes in cancer has been observed for more than 30 years.
“Increased activity of de novo serine synthesis enzymes in cancer has been observed for more than 30 years (Snell, 1984; Snell et al., 1988).”
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PremisecitationSuccinate and fumarate inhibit prolyl hydroxylase domain-containing enzymes that regulate hypoxia-inducible factor stability, so FH- and SDH-deficient cancers activate the hypoxic gene expression program even under normoxic conditions.
“Additionally, succinate and fumarate inhibit the prolyl hydroxylase domain-containing (PHD) enzymes that regulate stability of hypoxia-inducible factors (HIFs), such that FH and SDH deficient cancers activate the hypoxic gene expression program even under normoxic conditions (Hewitson et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
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PremisecitationRemoving serine from culture media limits incorporation of one-carbon units into nucleotides and impairs proliferation.
“Removing serine from culture media limits incorporation of one-carbon units into nucleotides and impairs proliferation (Labuschagne et al., 2014).”
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Premisenone givenLoss of SDH results in TCA cycle dysfunction, leading to accumulation of succinate and depletion of aspartate, fumarate, citrate, and malate.
“Loss of SDH also results in TCA cycle dysfunction, leading to the accumulation of succinate and depletion of aspartate, fumarate, citrate, and malate.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationL-alanosine inhibits conversion of inosine monophosphate to AMP and shows selective toxicity towards MTAP-null cancer cells.
“L-alanosine inhibits conversion of inosine monophosphate (IMP) to AMP, and shows selective toxicity towards MTAP-null cancer cells (Batova et al., 1999; Efferth et al., 2003; Harasawa et al., 2002), but was found to be clinically ineffective in patients with advanced MTAP-deficient tumors in a Phase II trial (Kindler et al., 2009).”
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PremisecitationLoss of MTAP causes MTA to accumulate, and this MTA can inhibit PRMT5, creating a vulnerability in cancer cells.
“Loss of MTAP expression can result in another vulnerability for cancer cells because the MTA that accumulates following MTAP loss can act as a potent inhibitor of the enzyme arginine methyltransferase 5 (PRMT5).”
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PremisecitationENO1 undergoes homozygous deletion in 1-5% of GBM cancers; knockdown of ENO2 in ENO1-null GBM cells inhibits proliferation and intracranial tumorigenesis, whereas ENO1-expressing cancer cells are insensitive to ENO2 ablation.
“Similarly, the gene encoding enolase 1 (ENO1) is on the tumor-suppressor locus 1p36, and undergoes homozygous deletion in 1–5% of GBM cancers. Knockdown of enolase 2 (ENO2) in ENO1-null GBM cells resulted in significant inhibition of proliferation and intracranial tumorigenesis, whereas ENO1 expressing cancer cells were insensitive to ENO2 ablation.”
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PremisecitationPDAC cells with homozygous deletion of SMAD4 often lose ME2 due to chromosomal proximity; targeting ME3 impairs tumor proliferation of PDAC xenografts lacking ME2 but has no effect on tumors with intact ME2.
“Pancreatic ductal adenocarcinoma (PDAC) cells exhibiting homozygous deletion of the tumor suppressor SMAD4 often lose malic enzyme 2 (ME2) expression due to the chromosomal proximity of the two genes. Targeting the malic enzyme 3 (ME3) isoform was found to impair tumor proliferation of PDAC xenografts lacking ME2 expression, but had no effect on tumors with intact ME2 (Dey et al., 2017).”
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PremisereasoningIn SDH-deficient cells, aspartate cannot be synthesized from glutamine or other sources of alpha-ketoglutarate, and aspartate production depends on pyruvate carboxylase activity.
“In this context, aspartate cannot be synthesized from glutamine or other sources of αKG, and aspartate production is dependent on pyruvate carboxylase (PC) activity.”
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InterpretationreasoningASS1-deficient cancers are unable to synthesize arginine de novo, making them reliant on exogenous arginine for proliferation and survival and potentially sensitive to therapies that lower arginine availability.
“A potential liability of ASS1 deficient cancers is that, like FH null cancers, they are unable to synthesize arginine de novo. As functional arginine auxotrophs, these cells are reliant on exogenous arginine for proliferation and survival and may be sensitive to therapies that lower arginine availability (Table 1).”
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InterpretationreasoningBoth epigenetic changes and aberrant HIF activation can contribute to tumor initiation and progression in FH- or SDH-deficient cancers.
“Both epigenetic changes and aberrant HIF activation can contribute to tumor initiation and progression in these cancers.”
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InterpretationreasoningPC ablation impairs SDH-deficient cell proliferation and tumor formation, so targeting PC might be exploited to treat these types of cancers.
“PC ablation impairs SDH-deficient cell proliferation and tumor formation, and thus targeting PC might be exploited to treat these types of cancers.”
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PremisecitationHigh levels of fumarate resulting from FH deficiency drive argininosuccinate lyase and argininosuccinate synthase in a direction that consumes arginine, depleting intracellular arginine and making these cells arginine auxotrophs.
“The high levels of fumarate resulting from FH deficiency drives argininosuccinate lyase (ASL) and argininosuccinate synthase (ASS1) in a direction that consumes arginine (Figure 7). Depletion of intracellular arginine causes these cells to become arginine auxotrophs (Adam et al., 2013; Zheng et al., 2013), and therapies that deplete exogenous arginine (Table 1) may be effective in treating malign”
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PremisecitationSerine deprivation by dietary restriction is sufficient to slow growth of both xenograft and autochthonous cancer models, although efficacy is influenced by the oncogenic driver mutation and tissue context.
“Additionally, serine deprivation by dietary restriction is sufficient to slow growth of both xenograft (Gravel et al., 2014; Maddocks et al., 2013) and autochthonous cancer models, although efficacy of serine deprivation appears to be influenced by both the oncogenic driver mutation and tissue context (Maddocks et al., 2017).”
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Premisenone givenLoss of FH or SDH activity results in disruption of the TCA cycle and accumulation of fumarate or succinate, respectively.
“Loss of FH activity or SDH activity results in disruption of the TCA cycle and accumulation of fumarate or succinate, respectively.”
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PremisecitationMTAP-deficient cells are more reliant on de novo purine synthesis to generate AMP because they cannot cleave MTA to salvage adenine, making them more susceptible to inhibitors of purine biosynthesis and to methionine depletion.
“MTAP deficient cells are more reliant on de novo purine synthesis to generate AMP, since they are unable to cleave MTA to salvage adenine, and thus MTAP loss makes cells more susceptible to inhibitors of purine biosynthesis as well as to methionine depletion (Hori et al., 1996).”
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PremisecitationCells derived from mtDNA-depleted tumors acquire host mtDNA to regain respiration, providing evidence that respiration is required and selected for in tumorigenesis.
“In fact, cells derived from these tumors acquire host mtDNA to regain the ability to do respiration, providing compelling evidence that respiration is required and selected for in tumorigenesis (Tan et al., 2015a).”
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InterpretationcitationNAMPT inhibitors may be more effective in MYC-amplified glioblastoma or when combined with other drugs that deplete NAD+ pools.
“For example, NAMPT inhibitors may be more effective in contexts of MYC-amplified glioblastoma (Tateishi et al., 2016) or when used in combination with other drugs known to deplete NAD+ pools (Bajrami et al., 2012; Chan et al., 2014).”
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PremisecitationAcetate is not always abundant in blood and is not the predominant source of acetyl-CoA for fatty acid synthesis in some cells.
“However, acetate is not always abundant in blood and is not the predominate source of acetyl-CoA used for fatty acid synthesis in some cells (Hosios and Vander Heiden, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hosios and Vander Heiden, 2014
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PremisecitationTumors can synthesize lipids, and most lipids in tumor cells are synthesized de novo rather than obtained from exogenous sources.
“It was first discovered in the 1950s that tumors are able to synthesize lipids, and a subsequent study determined that the large majority of lipids in tumors cells are synthesized de novo, rather being consumed from exogenous sources (Medes et al., 1953; Ookhtens et al., 1984).”
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- cites Ookhtens et al., 1984
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PremisecitationInhibitors of cellular respiration block proliferation, suggesting that most cancer cells require respiration to proliferate.
“Moreover, inhibitors of cellular respiration block proliferation, suggesting that most cancer cells require respiration in order to proliferate (Harris, 1980; Howell and Sager, 1979; Kroll et al., 1983; Loffer and Schneider, 1982; Zhang et al., 2014b).”
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PremisecitationSome cancers depend on ACSS2 expression, making ACSS2 a potential therapeutic target.
“Some cancers are nevertheless dependent on expression of acetyl-CoA synthetase 2 (ACSS2), the cytosolic enzyme that allows cells to synthesize acetyl-CoA from acetate, making this represents a potential therapeutic target (Comerford et al., 2014; Schug et al., 2015).”
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PremisecitationOther complex I inhibitors have shown efficacy as anti-tumor agents and may show selective toxicity against oncogene-ablation resistant cells and cancer stem cells.
“Consistent with this notion, other complex I inhibitors have shown efficacy as anti-tumor agents (Appleyard et al., 2012; Schockel et al., 2015) and may show selective toxicity against oncogene-ablation resistant cells (Viale et al., 2014) and cancer stem cells (Sancho et al., 2015).”
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PremisecitationMetformin is safe despite acting as a mitochondrial complex I inhibitor that impairs respiration.
“However, metformin, one of the commonly prescribed drugs for treating type II diabetes, is safe despite acting as a mitochondrial complex I inhibitor that impairs respiration (Bridges et al., 2014; El-Mir et al., 2000; Owen et al., 2000; Wheaton et al., 2014).”
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PremisecitationRetrospective clinical studies have found that metformin use is associated with improved cancer outcomes, reductions in cancer incidence, and decreased cancer mortality.
“Furthermore, retrospective clinical studies have found that metformin use is associated with improved cancer outcomes, reductions in cancer incidence, and decreased cancer mortality (Evans et al., 2005; Franciosi et al., 2013; Gandini et al., 2014; Lee et al., 2012; Noto et al., 2012).”
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PremisecitationProliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate.
“Proliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate (Gui et al., 2016).”
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PremisecitationTargeting FASN reduces tubulin palmitoylation, disrupts microtubule organization, and inhibits tumor cell growth.
“Targeting FASN has been found to reduce palmitoylation of tubulin and disrupt microtubule organization, inhibiting tumor cell growth (Heuer et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heuer et al., 2017 source
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PremisereasoningHigher NAD+/NADH ratios appear important for proliferation, while lower ratios favor mitochondrial ATP production.
“Higher NAD+/NADH ratios appear important for proliferation while lower ratios favor mitochondrial ATP production.”
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PremisecitationTVB-2640 is the first FASN-targeting compound to enter clinical trials, and when combined with paclitaxel it can cause partial responses or prolonged stable disease.
“The compound TVB-2640 is the first compound targeting FASN to enter clinical trials (Table 1), and when combined with paclitaxel, can cause partial responses or prolonged stable disease (Brenner et al., 2017).”
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PremisecitationLung tumors support their nitrogen requirement by catabolizing free branched chain amino acids, whereas pancreatic tumors expressing the same driver mutation do not.
“Lung tumors support their nitrogen requirement by catabolizing free branched chain amino acids (BCAA), whereas pancreatic tumors expressing the same driver mutation do not.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mayers et al., 2016 source
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PremisecitationMetabolic enzyme expression is heterogeneous across tumors, and there is no universal metabolic transformation common to all cancers.
“Analysis of gene expression across different cancer types has determined that metabolic enzyme expression is heterogeneous across tumors, and there is no universal metabolic transformation common to all cancers.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gaude and Frezza, 2016
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- cites Hu et al., 2013
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PremisecitationTargeting DHODH depletes uridine and downstream metabolites, and providing uridine is sufficient to maintain myeloid arrest even in the presence of DHODH-targeting compounds.
“Targeting DHODH depletes uridine and downstream metabolites, and providing uridine is sufficient to maintain myeloid arrest, even in the presence of compounds targeting DHODH.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sykes et al., 2016 source
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PremisecitationHoxA9 is overexpressed in 70% of AML cases, and overexpression of this transcription factor alone is sufficient to immortalize murine bone marrow derived myeloid cells.
“The transcription factor HoxA9 is overexpressed in 70% of AML cases, and overexpression of this transcription factor alone is sufficient to immortalize murine bone marrow derived myeloid cells (Ayton and Cleary, 2003; Golub et al., 1999; Kroon et al., 1998).”
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PremisecitationActivation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway and enhance flux through pyrimidine and purine synthesis pathways.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
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PremisecitationNrf2 mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation.
“For example, the transcription factor Nrf2, which mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation (Chio et al., 2016; DeNicola et al., 2011).”
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PremisecitationGenetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation.
“Several screens for small-molecules that selectively kill transformed cells have identified compounds that reduce glutathione levels (Dolma et al., 2003; Raj et al., 2011; Trachootham et al., 2006), and genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation (Harris et al., 2015; Lien et al., 2016).”
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PremisecitationMany cancer cells are auxotrophic for cysteine, and lowering whole-body cysteine levels with bacterial cysteineases is a potential cancer treatment being evaluated in clinical trials.
“Many cancer cells are auxotrophic for this amino acid, and lowering whole body cysteine levels with bacterial cysteineases is a potential cancer treatment being evaluated in clinical trials (Graczyk-Jarzynka et al., 2017).”
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PremisecitationTargeting BCAA transaminases inhibits lung tumor formation better than pancreatic tumor formation, suggesting that dependence on BCAA catabolism is determined by cell lineage rather than tumor site.
“Targeting BCAA transaminases inhibits lung tumor formation better than pancreatic tumor formation, suggesting that dependence on branched chain amino acid catabolism is determined by cell lineage rather than tumor site (Mayers et al., 2016).”
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PremisecitationInhibiting oncogenic signaling with PI3K inhibitors depletes DNA nucleotides, decreases DNA synthesis, and causes DNA damage.
“Conversely, inhibiting oncogenic signaling using PI3K inhibitors, has been found to deplete DNA nucleotides, decrease DNA synthesis, and cause DNA damage (Juvekar et al., 2016).”
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InterpretationreasoningDisruption of detoxification pathways is predicted to harm cancer cells more than normal cells, making such pathways a potential targetable metabolic liability.
“Disruption of this and other detoxification pathways is predicted to have a more deleterious effect on cancer cells than normal cells, and thus serves as a potential targetable metabolic liability.”
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PremisecitationL-asparaginase is effective in treating ALL and is included in standard chemotherapy regimens for the disease.
“L-asparaginase has been found to be effective in the treatment of ALL and is included in standard chemotherapy regimens for this disease (Table 1)(Egler et al., 2016).”
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InterpretationreasoningMetabolic vulnerabilities may not be universal across all cancers and may be modulated by environment or defined by tumor lineage.
“However, these analyses suggest that metabolic vulnerabilities may not be universal across all cancers and highlight the possibility that some metabolic dependencies of cancer may be modulated by environment or defined by tumor lineage.”
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Premisenone givenThe protein targets of methotrexate and 5-FU are present in almost all cancers, but the efficacy of these drugs varies dramatically across malignancies.
“The protein targets of methotrexate and 5-FU are present in almost all cancers, but the efficacy of these drugs varies dramatically across malignancies.”
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PremisecitationTargeting ACC to limit fatty acid synthesis can suppress lung tumor progression in some models, but loss of ACC activity can accelerate tumor growth in other cancer models.
“For example, while targeting ACC to limit fatty synthesis can suppress lung tumor progression in some models (Svensson et al., 2016), loss of ACC activity can accelerate tumor growth in other cancer models (Jeon et al., 2012).”
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PremisecitationAltering culture media conditions is sufficient to change cancer cell sensitivity to metformin, highlighting the importance of environment in modulating metabolic dependencies.
“Altering culture media conditions is sufficient to change cancer cell sensitivity to metformin, highlighting the importance of environment in modulating metabolic dependencies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gui et al., 2016 source
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PremisecitationBrequinar sodium, a DHODH inhibitor approved for autoimmune disease, overcomes myeloid differentiation blockade and reduces leukemic cell burden in patient-derived xenografts and syngeneic mouse AML models of diverse genetic subtypes.
“Treatment with brequinar sodium (BRQ), an inhibitor of DHODH that is approved to treat autoimmune disease, is able to overcome myeloid differentiation blockade and reduces leukemic cell burden in patient-derived xenografts and syngeneic mouse AML models of diverse genetic subtypes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sykes et al., 2016 source
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PremisecitationCancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase.
“Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can also influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase (Davidson et al., 2016; Gui et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Sykes et al., 2016; Tardito et al., 2015).”
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PremisecitationIn non-small cell lung cancer patients, intraoperative isotopically labeled glucose infusions showed a higher contribution of glucose carbon to TCA intermediates than to glycolytic intermediates, leading the authors to conclude that lactate could serve as an anaplerotic substrate.
“Intraoperative isotopically-labeled glucose infusions performed on non-small cell lung cancer patients revealed higher contribution of glucose carbon to TCA intermediates than glycolytic intermediates in tumors, leading the authors to conclude that lactate could serve as an anaplerotic substrate in this context as well (Hensley et al., 2016).”
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PremisecitationMany PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of PHGDH, but for some tumor models PHGDH expression is dispensable for growth.
“Similarly, many PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of the enzyme (Locasale et al., 2011; Mullarky et al., 2016; Pacold et al., 2016; Possemato et al., 2011; Wang et al., 2017; Zhang et al., 2017), but for some tumor models PHGDH expression can be dispensable for growth (Chen et al., 2013).”
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PremisecitationGlutamine tracing studies have demonstrated that in some tumor tissues glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition.
“Glutamine tracing studies have demonstrated that in some tumor tissues, glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition (Davidson et al., 2016; Hensley et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Tardito et al., 2015).”
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PremisecitationLactate utilization by tumors depends on monocarboxylate transporters, which are highly expressed in a variety of tumors.
“Lactate utilization by tumors is dependent on monocarboxylate transporters (MCTs) (Figure 3), which are highly expressed in a variety of tumors (Pinheiro et al., 2012).”
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PremisecitationPancreatic ductal adenocarcinoma cells can consume alanine produced by pancreatic stellate cells in vitro, and the secreted alanine appears to help promote tumor cell proliferation and survival under nutrient-limited conditions.
“Pancreatic ductal adenocarcinoma cells can consume alanine produced by pancreatic stellate cells in vitro, and the secreted alanine appears to help promote tumor cell proliferation and survival under nutrient-limited conditions (Sousa et al., 2016).”
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PremisecitationBrequinar sodium was previously evaluated to treat advanced solid tumors but was not shown to be effective in clinical trials.
“BRQ was previously evaluated to treat advanced solid tumors but was not shown to be effective in clinical trials (Arteaga et al., 1989; Noe et al., 1990; Peters et al., 1990).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Arteaga et al., 1989
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- cites Noe et al., 1990
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pro-fibrotic macrophages commonly coordinate scar formation via interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis.
“pro-fibrotic macrophages commonly coordinate scar formation via a range of interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis18,27,74–78.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [75]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Warburg-to-Farber interval is 23 years, not over 30
MinorThe introduction dates Farber's discovery to 1947 and Warburg's report to 1924. The interval is 23 years, not more than thirty.
Reported 30 · recomputed 23
“More than thirty years preceding Farber’s work on antifolates, Otto Warburg reported that cancer cells consume tremendous amounts of glucose and metabolize the majority of the glucose into lactate, even in the presence of oxygen (Warburg, 1924).”
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Modulating T Cell Responses by Targeting CD3
Menon, A. P., Moreno, B., Meraviglia-Crivelli, D., Nonatelli, F., Villanueva, H., Barainka, M., Zheleva, A., van Santen, H. M., & Pastor, F. (2023) · Cancers · doi:10.3390/cancers15041189 · Cited by 95 · see citing works
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p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas
Hsieh, M.-H., Choe, J. H., Gadhvi, J. G., Kim, Y. J., Arguez, M. A., Palmer, M., Gerold, H., Nowak, C. M., Do, H., Mazambani, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.027 · Cited by 92 · see citing works
Dysbiosis of skin microbiome and gut microbiome in melanoma progression
Mekadim, C., Skalníková, H. K., Čížková, J., Cizkova, V., Palanová, A., Horák, V., & Mrázek, J. (2022) · BMC Microbiology · doi:10.1186/s12866-022-02458-5 · Cited by 94 · see citing works
- Authors
- Luengo, A., Gui, D. Y., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 24
- Issue
- 9
- Pages
- 1161-1180
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5744685
- OpenAlex
- W2758067903
- Cited by
- 971
- References
- 292
- Citations by year
- 2026: 46 · 2025: 81 · 2024: 111 · 2023: 130 · 2022: 194 · 2021: 161 · 2020: 141 · 2019: 80 · 2018: 24 · 2017: 2
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lustgarten Foundation
- SU2C
- Ludwig Center
- NCI
- HHMI
- Ludwig Center for Molecular Oncology
- NSF (GRFP DGE-1122374)
- NIH (T32 GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cancer metabolism, metabolic reprogramming, metabolic cancer therapy, metabolic liability
- MeSH terms
- Antimetabolites, Argininosuccinate Synthase, Fatty Acids, Glutamine, Glycolysis, Humans, Isocitrate Dehydrogenase, NAD, Neoplasms, Carbohydrate Metabolism, Metabolic Engineering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
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