Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

Peterse, Elisabeth F. P.; Niessen, Bertine; Addie, Ruben D.; Jong, Yvonne de; Cleven, Arjen H.G.; Kruisselbrink, Alwine B.; Akker, Brendy E.W.M. van den; Molenaar, Remco J.; Cleton‐Jansen, Anne‐Marie; Bovée, Judith V.M.G.

doi:10.1038/s41416-018-0050-9

Cited by 39 publications

(45 citation statements)

References 47 publications

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“…Likewise, the synthetic lethal interaction between temozolomide and IDH mutations described in gliomas was not observed in our study [35,36]. Our research group published that the reported synthetic lethal interaction between IDH mutations and Bcl-2, NAMPT, and glutaminase inhibition was absent in chondrosarcoma [11,[37][38][39]. Together, these findings indicate that therapeutic strategies in AML and glioma based on IDH mutation status cannot be directly translated to chondrosarcoma.…”

Section: Discussionsupporting

confidence: 42%

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Venneker

Kruisselbrink

Bruijn

et al. 2019

Cancers

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Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

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Section: Discussionsupporting

confidence: 42%

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Venneker

Kruisselbrink

Bruijn

et al. 2019

Cancers

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“…CB-839 (also known as telaglenastat) is a potent and noncompetitive allosteric GLS1 inhibitor. It exhibits significant anti-proliferative activity in several types of cancer cell lines and xenografts such as triple-negative breast cancer ( Gross et al, 2014 ), lung adenocarcinoma ( Galan-Cobo et al, 2019 ), chondrosarcoma ( Peterse et al, 2018 ), and lymphoma cancer ( Xiang et al, 2015 ). CB-839 is used increasingly in combination to treat cancer.…”

Section: Introductionmentioning

confidence: 99%

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Jin

Wang

Zaal

et al. 2020

eLife

129

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The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.

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“…Administration of 200 mg/kg of CB-839 significantly suppressed the volume of MPNST xenografts [52]. In chondrosarcoma cell lines, CB-839 activity correlated with the status of isocitrate dehydrogenase 1/2 (IDH1/2), as the cells carrying IDH1/2 mutation were more susceptible to this compound than the wild type cells [53]. In a very recent study, CB-839 administered twice daily at dose 200 mg/kg significantly reduced undifferentiated pleomorphic sarcoma (UPS) tumor growth and weight but did not alter animal weights [54].…”

Section: Inhibitors Of Glutaminase (Ga)mentioning

confidence: 99%

Thiadiazole derivatives as anticancer agents

Szeliga

2020

Pharmacol. Rep

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In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more effective anticancer therapeutics. Thiadiazole ring is a versatile scaffold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efficacy across the cancer models with an emphasis on targets of action. The influence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole-containing drugs in cancer patients are summarized.

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Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

Abstract: Targeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.

Cited by 39 publications

References 47 publications

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Thiadiazole derivatives as anticancer agents

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