Targeting Metabolism for Cancer Therapy

In the paper

“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).”

What the sources say

• Disputed

  In “Nucleotide biosynthesis” (page unavailable), the review says glutamine-deprived cancer cells undergo cell-cycle arrest that cannot be rescued by TCA-cycle intermediates such as oxaloacetate; exogenous nucleotides can rescue it. Although the review describes glutamine entering the TCA cycle, it does not support the claimed rescue by the three listed metabolites or the conclusion that such rescue confirms anaplerosis as the explanation. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Altman et al., 2016 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that dimethyl α-ketoglutarate rescued colony growth when aminotransferase activity was inhibited, supporting a role for glutamine entry into the TCA cycle. They do not report rescue under glutamine starvation or show that added oxaloacetate or pyruvate rescues proliferation. The Results also state that α-ketoglutarate did not effectively rescue growth after glutaminase knockdown (page not specified in our copy). (LLM, conf=0.90)

  cites Weinberg et al., 2010 sourceExperimental — accuracy not yet measured
• Disputed

  In Results, under “Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle,” the paper says oxaloacetate and pyruvate prevented apoptosis but neither restored cell proliferation. It also reports depletion of Krebs-cycle intermediates, but that does not support the claim that supplying these metabolites rescued proliferation. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  cites Yuneva et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer.”

In the paper

“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).”

What the sources say

• Not checked yetcites Warburg, 1924 source

In the paper

“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.”

What the sources say

• Not checked yetcites Berti et al., 2014 source
• Not checked yetcites Cohade, 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Walling, 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Elion, 1989 source

In the paper

“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”

What the sources say

• Not checked yetcites Heidelberger et al., 1957 source
• Not checked yetcites Wagner et al., 2006 source

In the paper

“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”

What the sources say

• Not checked yetcites Quivoron et al., 2014 source
• Not checked yetcites Yen et al., 2017 source
• Not checked yetcites DiNardo et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dang et al., 2009 source
• Not checked yetcites Ward et al., 2010 source

In the paper

“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).”

What the sources say

• Not checked yetcites Tateishi et al., 2015 source
• Not checked yetcites Turcan et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Wick et al., 1957 source

In the paper

“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).”

What the sources say

• Not checked yetcites Rohle et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Landau et al., 1958

In the paper

“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).”

What the sources say

• Not checked yetcites Watanabe et al., 2009 source
• Not checked yetcites Johnson et al., 2014 source
• Not checked yetcites Wakimoto et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Raez et al., 2013 source
• Not checked yetcites Stein et al., 2010 source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites Hsu and Sabatini, 2008
• Not checked yetcites Lunt and Vander Heiden, 2011 source
• Not checked yetcites Pavlova and Thompson, 2016

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Chowdhury et al., 2011 source
• Not checked yetcites Janke et al., 2017 source
• Not checked yetcites Koivunen et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Parker, 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Locasale et al., 2011 source
• Not checked yetcites Possemato et al., 2011 source
• Not checked yetcites Zhang et al., 2017 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Mullarky et al., 2016 source
• Not checked yetcites Pacold et al., 2016 source
• Not checked yetcites Wang et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hosios et al., 2016 source
• Not checked yetcites DeBerardinis et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites Chen et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Fan et al., 2014 source
• Not checked yetcites Lewis et al., 2014 source
• Not checked yetcites Ye et al., 2014

In the paper

“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).”

What the sources say

• Not checked yetcites DeBerardinis and Cheng, 2010 source
• Not checked yetcites Eagle, 1955 source
• Not checked yetcites Jain et al., 2012 source

In the paper

“In certain contexts, MYC-transformed cancers become glutamine dependent and undergo apoptosis in the absence of glutamine (Yuneva et al., 2007).”

What the sources say

• Not checked yetcites Yuneva et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites Turcan et al., 2013 source
• Not checked yetcites Grassian et al., 2014 source
• Not checked yetcites Tateishi et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gao et al., 2009 source
• Not checked yetcites Wise et al., 2008 source
• Not checked yetcites Yuneva et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Molenaar et al., 2015 source

In the paper

“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”

What the sources say

• Not checked yetcites Livingston et al., 1970 source
• Not checked yetcites O’Dwyer et al., 1984

In the paper

“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”

What the sources say

• Not checked yetcites Beroukhim et al., 2010 source
• Not checked yetcites Locasale et al., 2011 source
• Not checked yetcites Possemato et al., 2011 source

In the paper

“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).”

What the sources say

• Not checked yetcites Furuya, 2008
• Not checked yetcites Yoshida et al., 2004 source

In the paper

“Increased activity of de novo serine synthesis enzymes in cancer has been observed for more than 30 years (Snell, 1984; Snell et al., 1988).”

What the sources say

• Not checked yetcites Snell, 1984 source
• Not checked yetcites Snell et al., 1988 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hewitson et al., 2007 source
• Not checked yetcites Pollard et al., 2005 source
• Not checked yetcites Selak et al., 2005 source

In the paper

“Removing serine from culture media limits incorporation of one-carbon units into nucleotides and impairs proliferation (Labuschagne et al., 2014).”

What the sources say

• Not checked yetcites Labuschagne et al., 2014 source

In the paper

“Loss of SDH also results in TCA cycle dysfunction, leading to the accumulation of succinate and depletion of aspartate, fumarate, citrate, and malate.”

In the paper

“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).”

What the sources say

• Not checked yetcites Batova et al., 1999
• Not checked yetcites Efferth et al., 2003 source
• Not checked yetcites Harasawa et al., 2002 source

In the paper

“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).”

What the sources say

• Not checked yetcites Kryukov et al., 2016 source
• Not checked yetcites Marjon et al., 2016 source
• Not checked yetcites Mavrakis et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Leonard et al., 2016 source
• Not checked yetcites Muller et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dey et al., 2017 source

In the paper

“In this context, aspartate cannot be synthesized from glutamine or other sources of αKG, and aspartate production is dependent on pyruvate carboxylase (PC) activity.”

In the paper

“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).”

In the paper

“Both epigenetic changes and aberrant HIF activation can contribute to tumor initiation and progression in these cancers.”

In the paper

“PC ablation impairs SDH-deficient cell proliferation and tumor formation, and thus targeting PC might be exploited to treat these types of cancers.”

In the paper

“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”

What the sources say

• Not checked yetcites Adam et al., 2013 source
• Not checked yetcites Zheng et al., 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gravel et al., 2014 source
• Not checked yetcites Maddocks et al., 2013 source
• Not checked yetcites Maddocks et al., 2017 source

In the paper

“Loss of FH activity or SDH activity results in disruption of the TCA cycle and accumulation of fumarate or succinate, respectively.”

In the paper

“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).”

What the sources say

• Not checked yetcites Hori et al., 1996

In the paper

“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).”

What the sources say

• Not checked yetcites Tan et al., 2015a

In the paper

“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).”

What the sources say

• Not checked yetcites Tateishi et al., 2016 source
• Not checked yetcites Bajrami et al., 2012 source
• Not checked yetcites Chan et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hosios and Vander Heiden, 2014

In the paper

“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).”

What the sources say

• Not checked yetcites Medes et al., 1953
• Not checked yetcites Ookhtens et al., 1984

In the paper

“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).”

What the sources say

• Not checked yetcites Harris, 1980 source
• Not checked yetcites Howell and Sager, 1979
• Not checked yetcites Kroll et al., 1983 source

In the paper

“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).”

What the sources say

• Not checked yetcites Comerford et al., 2014 source
• Not checked yetcites Schug et al., 2015 source

In the paper

“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).”

What the sources say

• Not checked yetcites Appleyard et al., 2012 source
• Not checked yetcites Schockel et al., 2015 source
• Not checked yetcites Viale et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Bridges et al., 2014 source
• Not checked yetcites El-Mir et al., 2000 source
• Not checked yetcites Owen et al., 2000 source

In the paper

“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).”

What the sources say

• Not checked yetcites Evans et al., 2005 source
• Not checked yetcites Franciosi et al., 2013 source
• Not checked yetcites Gandini et al., 2014 source

In the paper

“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).”

What the sources say

• Not checked yetcites Gui et al., 2016 source

In the paper

“Targeting FASN has been found to reduce palmitoylation of tubulin and disrupt microtubule organization, inhibiting tumor cell growth (Heuer et al., 2017).”

What the sources say

• Not checked yetcites Heuer et al., 2017 source

In the paper

“Higher NAD+/NADH ratios appear important for proliferation while lower ratios favor mitochondrial ATP production.”

In the paper

“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).”

What the sources say

• Not checked yetcites Brenner et al., 2017 source

In the paper

“Lung tumors support their nitrogen requirement by catabolizing free branched chain amino acids (BCAA), whereas pancreatic tumors expressing the same driver mutation do not.”

What the sources say

• Not checked yetcites Mayers et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Gaude and Frezza, 2016
• Not checked yetcites Hu et al., 2013

In the paper

“Targeting DHODH depletes uridine and downstream metabolites, and providing uridine is sufficient to maintain myeloid arrest, even in the presence of compounds targeting DHODH.”

What the sources say

• Not checked yetcites Sykes et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Ayton and Cleary, 2003
• Not checked yetcites Golub et al., 1999 source
• Not checked yetcites Kroon et al., 1998 source

In the paper

“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.”

What the sources say

• Not checked yetcites Duvel et al., 2010 source
• Not checked yetcites Ben-Sahra et al., 2013 source
• Not checked yetcites Ben-Sahra et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Chio et al., 2016 source
• Not checked yetcites DeNicola et al., 2011 source

In the paper

“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).”

What the sources say

• Not checked yetcites Harris et al., 2015 source
• Not checked yetcites Lien et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Graczyk-Jarzynka et al., 2017 source

In the paper

“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).”

What the sources say

• Not checked yetcites Mayers et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Juvekar et al., 2016 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Egler et al., 2016 source

In the paper

“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.”

In the paper

“The protein targets of methotrexate and 5-FU are present in almost all cancers, but the efficacy of these drugs varies dramatically across malignancies.”

In the paper

“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).”

What the sources say

• Not checked yetcites Svensson et al., 2016 source
• Not checked yetcites Jeon et al., 2012 source

In the paper

“Altering culture media conditions is sufficient to change cancer cell sensitivity to metformin, highlighting the importance of environment in modulating metabolic dependencies.”

What the sources say

• Not checked yetcites Gui et al., 2016 source

In the paper

“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.”

What the sources say

• Not checked yetcites Sykes et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Davidson et al., 2016 source
• Not checked yetcites Gui et al., 2016 source
• Not checked yetcites Marin-Valencia et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Hensley et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Locasale et al., 2011 source
• Not checked yetcites Mullarky et al., 2016 source
• Not checked yetcites Pacold et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Davidson et al., 2016 source
• Not checked yetcites Hensley et al., 2016 source
• Not checked yetcites Marin-Valencia et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Pinheiro et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Sousa et al., 2016 source

In the paper

“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).”

What the sources say

• Not checked yetcites Arteaga et al., 1989
• Not checked yetcites Noe et al., 1990
• Not checked yetcites Peters et al., 1990 source