IDH Mutations in Chondrosarcoma: Case Closed or Not?: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Sanne Venneker
,
Judith V. M. G. Bovée

Chondrosarcomas are malignant cartilage-producing tumours that frequently harbour isocitrate dehydrogenase 1 and -2 (IDH) gene mutations. Several studies have confirmed that these mutations are key players in the early stages of cartilage tumour development, but their role in later stages remains ambiguous. The prognostic value of the IDH mutation in chondrosarcoma seems controversial and (pre)clinical studies that have focused on the direct and indirect targeting of the IDH mutation have not yielded novel treatment strategies.

  • sarcoma
  • chondrosarcoma
  • isocitrate dehydrogenase mutation

1. Frequency and Prognostic Value of IDH1 and IDH2 Mutations

IDH mutations are also frequently observed in other tumour types, such as acute myeloid leukaemia (AML), glioma, and cholangiocarcinoma [1]. Interestingly, the most common variant differs between the above-stated tumour types. Cartilage tumours and cholangiocarcinoma mainly have IDH1 p.R132C variants (~60%), glioma predominantly harbours IDH1 p.R132H mutations (~90%), and AML often has IDH2 p.R140Q mutations (~40%) [2][3]. None of the variants are exclusively observed in one tumour type, suggesting that different point mutations can have a similar effect on tumourigenesis, although the level of the oncometabolite D-2-hydroxyglutarate (D-2-HG) produced by these variants differs [4][5][6]. The prognostic value of IDH mutations in these tumour types is also diverse, and only glioma patients have a clear favourable outcome when their tumour harbours an IDH mutation [7][8][9][10]. Studies that were performed to determine the prognostic value of IDH mutations in chondrosarcoma show contradictory results. While it was previously reported that IDH mutations do not predict outcomes [2], other studies showed either a worse [11] or better [12] prognosis for IDH mutant (IDHMUT) chondrosarcoma patients. The three patient cohorts were similar in size (n = 70 to 80) and median age (50 to 60 years), but the chondrosarcoma subtype inclusion (conventional versus addition of dedifferentiated and mesenchymal cases) and median follow-up time (4.3 versus ≥10 years) differed, which might explain the discrepancy in results. Another factor might be the type of technique used to assign patients to the IDHMUT subgroup. For instance, Sanger sequencing is not sensitive enough to detect mutations when present in less than <30% of the sequenced PCR product, leading to false-negative results in samples with a low IDHMUT variant allele frequency or tumour cell percentage and thereby the assignment of IDHMUT patients to the IDH wildtype (IDHWT) subgroup. Despite the lack of prognostic value, the high occurrence rate of IDH mutations in all of these tumour types suggests that they have an important role in driving tumourigenesis, already in the early stages of tumour development.

2. Oncogenic Activities of IDH Mutations

Both IDH enzymes function in the tricarboxylic acid (TCA) cycle, where they convert isocitrate into α-ketoglutarate (α-KG) and CO2. Mutated IDH enzymes acquire a neomorphic function, leading to the additional conversion of α-KG into the oncometabolite D-2-HG [13]. The IDH1 p.R132C variant is one of the most efficient D-2-HG producers, while both IDH1 p.R132H and IDH2 p.R140Q produce lower levels of the oncometabolite [4][5][6]. As certain variants are more frequently observed in specific tumour types [2][3], this could suggest that chondrosarcoma and cholangiocarcinoma rely on high D-2-HG levels, while glioma and AML depend on relatively lower levels of the oncometabolite.
Due to the high structural similarity between α-KG and its antagonist D-2-HG, the oncometabolite is able to competitively bind α-KG-dependent enzymes, leading to the overall inhibition of this class of enzymes [14][15]. The inhibition of α-KG-dependent enzymes leads to widespread changes in the epigenomes and metabolomes of cells and affects DNA repair and cellular growth signalling pathways [16][17]. For instance, the D-2-HG-mediated inhibition of α-KG-dependent DNA demethylases (family of TET enzymes, including TET1/2) and histone demethylases (family of Jumonji enzymes, including KDMA4A/B) leads to an overall DNA hypermethylation phenotype, as well as an aberrant histone methylation phenotype in IDH mutant tumours. IDHMUT enchondromas and chondrosarcomas are indeed characterised by a CpG island methylator phenotype (CIMP)-positive status, and DNA hypermethylation is present in primary IDHMUT chondrosarcomas [18][19][20]. The family of Jumonji enzymes is also involved in the regulation of the Mechanistic Target Of Rapamycin Kinase (mTOR) signalling pathway, as well as DNA repair via the homologous recombination pathway. Moreover, IDHMUT enzymes have a reduced ability to produce NADPH and consume high levels of NADPH to produce D-2-HG, resulting in severely reduced overall NADPH levels. This deficiency does not only cause metabolic stress but will also lead to an increase in reactive oxygen species (ROS), making IDHMUT tumours more vulnerable to DNA damage. Besides the induction of metabolic stress, IDHMUT tumours also undergo metabolic rewiring, including alterations in metabolites of the TCA cycle, a reduced dependency on glycolysis, and alterations in lipid metabolism. Additionally, D-2-HG-mediated inhibition of the prolyl hydroxylase domain proteins (EGLN1 and -2) leads to the upregulation of hypoxia-inducible factors (e.g., HIF1α), resulting in a metabolic switch to maintain oxygen homeostasis. D-2-HG also affects collagen maturation via the inhibition of proline and lysine hydroxylases (P4HA1-3 and PLOD1-3), leading to an impaired extracellular matrix structure. Thus, IDH mutations have a wide variety of downstream biological effects; therefore, these mutations are considered as the drivers in multiple tumour types.

3. Inhibition of the IDHMUT Protein

To counteract the oncogenic activity of the IDH mutations, several inhibitors targeting either IDH1 p.R132 variants (e.g., ivosidenib) or IDH2 p.R140 variants (e.g., enasidenib) have been developed over the past couple of years [21]. In vitro studies and clinical trials show that AML patients could benefit from IDHMUT protein inhibitors [22][23], although some patients develop resistance against these inhibitors over time. This acquired resistance is multi-factorial and can be caused by second-site mutations in IDHMUT genes to prevent the binding of IDHMUT protein inhibitors, IDHMUT isoform switching to circumvent the effect of IDHMUT protein inhibitors, or novel acquired mutations in genes encoding for receptor tyrosine kinases (RTKs) [24][25][26]. Direct inhibition of IDHMUT proteins seems less promising for other tumour types that frequently harbour an IDH mutation [27][28][29][30]. Especially in chondrosarcoma, the effect of IDHMUT protein inhibitors in in vitro assays seems controversial. While several studies have shown that IDH1MUT protein inhibition does not affect the tumourigenic properties of chondrosarcoma cell lines [27][31], other groups have shown that IDH1MUT protein inhibition causes a decreased proliferation rate in chondrosarcoma cell lines at higher doses or with a different compound [32][33]. Recent results from a phase I clinical trial with the IDH1MUT inhibitor ivosidenib showed that prolonged disease control (i.e., progression-free survival of ~6 months) could be achieved in a subset of patients with advanced chondrosarcoma, predominantly in patients with a minimal number of co-occurring mutations [34].

4. Synthetic Lethal Interactions with the IDH Mutation

As IDHMUT protein inhibitors showed limited efficacy in in vitro assays and clinical trials or acquired resistance was observed, a large number of in vitro studies were performed to determine whether directly targeting the downstream biological effects of IDH mutations would be more promising. Indeed, multiple synthetic lethal interactions with the IDH mutation were reported for AML and glioma, including radiotherapy, chemotherapy, and agents that target poly(ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) family members, Bromodomain and Extra-Terminal Motif (BET) proteins, DNA methyltransferases (DNMTs), mTOR, Nicotinamide Phosphoribosyltransferase (NAMPT), and glutaminase [27][28][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. However, chondrosarcoma cell lines are variably sensitive to a selection of these therapies, but the effect seems irrespective of the IDH mutation status, as IDHWT chondrosarcoma cell lines show similar treatment responses [49][50][51][52][53][54][55].
These contradictory findings on synthetic lethal interactions with the IDH mutation might be ascribed to different factors. First, the cell of origin and the tumour microenvironment (e.g., cartilaginous matrix formation and hypoxia in chondrosarcoma) of the distinct tumour types that frequently harbour an IDH mutation are highly different and could therefore influence the role that IDH mutations play in tumourigenesis. Second, the level of the D-2-HG oncometabolite may also influence the downstream biological effects of IDH mutations. The most common IDH variants in AML and glioma both produce relatively low D-2-HG levels, whilst the most common point mutation in both cholangiocarcinoma and chondrosarcoma produces relatively high levels of the oncometabolite [4][5][6]. It was recently shown that a lower level of DNA hypermethylation was observed for the IDH1 p.R132H variant compared to non-p.R132H variants, irrespective of tumour type [3]. Lastly, the type of in vitro model (endogenous vs. artificially created) might influence whether synthetic lethal interactions with the IDH mutation are present or not. The introduction of an IDH mutation in a glioma model leads to reduced glutamine and glutamate levels, but this change in TCA cycle metabolites is not present when endogenous IDHWT and IDHMUT glioma models are compared [56]. Most synthetic lethal interactions with the IDH mutation were indeed identified in generic cancer cell lines with an introduced IDHMUT. AML and glioma cell lines with an endogenous IDHMUT are scarce, but the utilised chondrosarcoma cell lines do harbour endogenous IDH mutations and this difference in model type could explain why synthetic lethal interactions with the IDH mutation are absent in the chondrosarcoma in vitro studies. As IDH mutations occur early during tumourigenesis, especially in chondrosarcoma, artificial models with an introduced IDH mutation may not be representative of the role that IDH mutations normally play in tumourigenesis. These studies also introduced the IDH mutation in generic cancer cell lines that are easy to transfect (e.g., HeLa, HCT116, and U2OS cells), and these cell lines do not represent the tumour types in which IDH mutations frequently occur. Moreover, most studies generated models that overexpressed the IDHMUT protein, whilst the balanced expression of IDHWT and IDHMUT is needed to retain efficient D-2-HG production [57].

5. Putting the IDH Mutation into Context to Define Underlying Vulnerabilities

In addition to these factors, it was recently shown that the (epi)genetic landscape in which IDHMUT and IDHWT are embedded is another important aspect to take into consideration when defining underlying vulnerabilities in tumour types that frequently harbour an IDH mutation. Studies on AML and glioma have shown that the genetic and epigenetic landscape in which IDHWT and IDHMUT function is highly heterogenous and thereby influences the therapy response and patient outcome [58][59][60][61][62][63][64][65][66][67][68][69]. For instance, mutations in TP53 and ATRX are the underlying denominator in defining which IDHWT and IDHMUT gliomas respond to radiotherapy [58]; the overexpression of BCAT1 in IDHWT AML leads to an IDHMUT-like DNA hypermethylation phenotype [59], and additional mutations in DNMT3A cause reduced levels of DNA hypermethylation in IDHMUT AML samples [62]. Furthermore, co-occurring (epi)genetic alterations such as CIMP status [66], 1p19q deletions [68], CDKN2A deletions [66][67], MET amplifications [66], PDGFRA amplifications [67], and TERT mutations [68] influence overall survival in IDHMUT glioma patients. Moreover, IDHMUT AML patients with a co-occurring NPM1 mutation show overall a better response to chemotherapy with or without venetoclax [69]. The influence of co-occurring (epi)genetic alterations may also explain why distinct IDHMUT tumour types differ in therapy sensitivity and underlines the need to use endogenous IDHMUT models, as generic cancer cell lines with an introduced IDH mutation do not represent the (epi)genetic landscape in which IDH mutations naturally exist. Thus, the IDH mutation status does not solely define the underlying vulnerabilities, which is in line with previous findings for chondrosarcoma [49][50][51][52][53][54][55], suggesting that a dichotomy between IDHWT and IDHMUT is too simplistic.
Besides IDH mutations, chondrosarcomas frequently harbour mutations in TP53, CDKN2A/B, COL2A1, YEATS2, NRAS, and TERT [70][71][72][73][74]. However, the rest of the previously observed co-occurring mutations seem to follow a more random pattern and are present in less than 10% of the chondrosarcomas [12][71][72][75], leading to a highly heterogeneous genetic landscape in which IDHWT and IDHMUT function in chondrosarcoma. Furthermore, IDHMUT chondrosarcomas are characterised by a global hypermethylation phenotype that changes with increasing histological grade [19][20], and, based on methylation profiles alone, several chondrosarcoma subgroups could be defined, even within IDHWT and IDHMUT tumours [76]. Moreover, using chondrosarcoma transcriptome and methylome data, it was previously shown that different molecular subtypes (i.e., high mitotic state, 14q32 miRNA cluster loss of expression, and IDHMUT-induced DNA hypermethylation) exist, and that these are associated with patient outcomes [77]. Moreover, (epi)genetic alterations in the TERT gene (i.e., hypermethylation and promotor mutations) affect the survival probability of IDH1MUT chondrosarcoma patients, whilst this association is absent in IDHWT and IDH2MUT patients [75].

This entry is adapted from the peer-reviewed paper 10.3390/cancers15143603

References

  1. Clark, O.; Yen, K.; Mellinghoff, I.K. Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer. Clin. Cancer Res. 2016, 22, 1837–1842.
  2. Cleven, A.H.G.; Suijker, J.; Agrogiannis, G.; Briaire-de Bruijn, I.H.; Frizzell, N.; Hoekstra, A.S.; Wijers-Koster, P.M.; Cleton-Jansen, A.-M.; Bovée, J.V.M.G. IDH1 or -2 Mutations Do Not Predict Outcome and Do Not Cause Loss of 5-Hydroxymethylcytosine or Altered Histone Modifications in Central Chondrosarcomas. Clin. Sarcoma Res. 2017, 7, 8.
  3. Tesileanu, C.M.S.; Vallentgoed, W.R.; Sanson, M.; Taal, W.; Clement, P.M.; Wick, W.; Brandes, A.A.; Baurain, J.F.; Chinot, O.L.; Wheeler, H.; et al. Non-IDH1-R132H IDH1/2 Mutations Are Associated with Increased DNA Methylation and Improved Survival in Astrocytomas, Compared to IDH1-R132H Mutations. Acta Neuropathol. 2021, 141, 945–957.
  4. Ward, P.S.; Lu, C.; Cross, J.R.; Abdel-Wahab, O.; Levine, R.L.; Schwartz, G.K.; Thompson, C.B. The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization. J. Biol. Chem. 2013, 288, 3804–3815.
  5. Pusch, S.; Schweizer, L.; Beck, A.C.; Lehmler, J.M.; Weissert, S.; Balss, J.; Miller, A.K.; von Deimling, A. D-2-Hydroxyglutarate Producing Neo-Enzymatic Activity Inversely Correlates with Frequency of the Type of Isocitrate Dehydrogenase 1 Mutations Found in Glioma. Acta Neuropathol. Commun. 2014, 2, 19.
  6. Molenaar, R.J.; Radivoyevitch, T.; Maciejewski, J.P.; van Noorden, C.J.F.; Bleeker, F.E. The Driver and Passenger Effects of Isocitrate Dehydrogenase 1 and 2 Mutations in Oncogenesis and Survival Prolongation. Biochim. Biophys. Acta 2014, 1846, 326–341.
  7. Jin, J.; Hu, C.; Yu, M.; Chen, F.; Ye, L.; Yin, X.; Zhuang, Z.; Tong, H. Prognostic Value of Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes: A Retrospective Cohort Study and Meta-Analysis. PLoS ONE 2014, 9, e100206.
  8. Dinardo, C.D.; Ravandi, F.; Agresta, S.; Konopleva, M.; Takahashi, K.; Kadia, T.; Routbort, M.; Patel, K.P.; Brandt, M.; Pierce, S.; et al. Characteristics, Clinical Outcome, and Prognostic Significance of IDH Mutations in AML. Am. J. Hematol. 2015, 90, 732–736.
  9. Xia, L.; Wu, B.; Fu, Z.; Feng, F.; Qiao, E.; Li, Q.; Sun, C.; Ge, M. Prognostic Role of IDH Mutations in Gliomas: A Meta-Analysis of 55 Observational Studies. Oncotarget 2015, 6, 17354–17365.
  10. Goyal, L.; Govindan, A.; Sheth, R.A.; Nardi, V.; Blaszkowsky, L.S.; Faris, J.E.; Clark, J.W.; Ryan, D.P.; Kwak, E.L.; Allen, J.N.; et al. Prognosis and Clinicopathologic Features of Patients with Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma. Oncologist 2015, 20, 1019–1027.
  11. Lugowska, I.; Teterycz, P.; Mikula, M.; Kulecka, M.; Kluska, A.; Balabas, A.; Piatkowska, M.; Wagrodzki, M.; Pienkowski, A.; Rutkowski, P.; et al. IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma. J. Cancer 2018, 9, 998–1005.
  12. Zhu, G.G.; Nafa, K.; Agaram, N.; Zehir, A.; Benayed, R.; Sadowska, J.; Borsu, L.; Kelly, C.; Tap, W.D.; Fabbri, N.; et al. Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma. Clin. Cancer Res. 2020, 26, 419–427.
  13. Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; et al. Cancer-Associated IDH1 Mutations Produce 2-Hydroxyglutarate. Nature 2009, 462, 739–744.
  14. Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S.H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.T.; et al. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 2011, 19, 17–30.
  15. Chowdhury, R.; Yeoh, K.K.; Tian, Y.M.; Hillringhaus, L.; Bagg, E.A.; Rose, N.R.; Leung, I.K.H.; Li, X.S.; Woon, E.C.Y.; Yang, M.; et al. The Oncometabolite 2-Hydroxyglutarate Inhibits Histone Lysine Demethylases. EMBO Rep. 2011, 12, 463–469.
  16. Gagné, L.M.; Boulay, K.; Topisirovic, I.; Huot, M.É.; Mallette, F.A. Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling. Trends Cell Biol. 2017, 27, 738–752.
  17. Hvinden, I.C.; Cadoux-Hudson, T.; Schofield, C.J.; McCullagh, J.S.O. Metabolic Adaptations in Cancers Expressing Isocitrate Dehydrogenase Mutations. Cell Rep. Med. 2021, 2, 100469.
  18. Pansuriya, T.C.; Van Eijk, R.; D’Adamo, P.; Van Ruler, M.A.J.H.; Kuijjer, M.L.; Oosting, J.; Cleton-Jansen, A.M.; Van Oosterwijk, J.G.; Verbeke, S.L.J.; Meijer, D.; et al. Somatic Mosaic IDH1 and IDH2 Mutations Are Associated with Enchondroma and Spindle Cell Hemangioma in Ollier Disease and Maffucci Syndrome. Nat. Genet. 2011, 43, 1256–1261.
  19. Venneker, S.; Kruisselbrink, A.B.; Baranski, Z.; Palubeckaite, I.; Briaire-de Bruijn, I.H.; Oosting, J.; French, P.J.; Danen, E.H.J.; Bovée, J.V.M.G. Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. Cancers 2020, 12, 3589.
  20. Guilhamon, P.; Eskandarpour, M.; Halai, D.; Wilson, G.A.; Feber, A.; Teschendorff, A.E.; Gomez, V.; Hergovich, A.; Tirabosco, R.; Fernanda Amary, M.; et al. Meta-Analysis of IDH-Mutant Cancers Identifies EBF1 as an Interaction Partner for TET2. Nat. Commun. 2013, 4, 2166.
  21. Liu, S.; Cadoux-Hudson, T.; Schofield, C.J. Isocitrate Dehydrogenase Variants in Cancer—Cellular Consequences and Therapeutic Opportunities. Curr. Opin. Chem. Biol. 2020, 57, 122–134.
  22. Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; et al. Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation. Science 2013, 340, 622–626.
  23. DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Swords, R.; Collins, R.H.; Mannis, G.N.; Pollyea, D.A.; et al. Durable Remissions with Ivosidenib in IDH1 -Mutated Relapsed or Refractory AML. N. Engl. J. Med. 2018, 378, 2386–2398.
  24. Intlekofer, A.M.; Shih, A.H.; Wang, B.; Nazir, A.; Rustenburg, A.S.; Albanese, S.K.; Patel, M.; Famulare, C.; Correa, F.M.; Takemoto, N.; et al. Acquired Resistance to IDH Inhibition through Trans or Cis Dimer-Interface Mutations. Nature 2018, 559, 125–129.
  25. Harding, J.J.; Lowery, M.A.; Shih, A.H.; Schvartzman, J.M.; Hou, S.; Famulare, C.; Patel, M.; Roshal, M.; Do, R.K.; Zehir, A.; et al. Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition. Cancer Discov. 2018, 8, 1540–1547.
  26. Choe, S.; Wang, H.; DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Watts, J.M.; Pollyea, D.A.; et al. Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in IDH1-Mutant Relapsed or Refractory AML. Blood Adv. 2020, 4, 1894–1905.
  27. Tateishi, K.; Wakimoto, H.; Iafrate, A.J.; Tanaka, S.; Loebel, F.; Lelic, N.; Wiederschain, D.; Bedel, O.; Deng, G.; Zhang, B.; et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell 2015, 28, 773–784.
  28. Fujiwara, H.; Tateishi, K.; Kato, H.; Nakatsuka, T.; Yamamoto, K.; Tanaka, Y.; Ijichi, H.; Takahara, N.; Mizuno, S.; Kogure, H.; et al. Isocitrate Dehydrogenase 1 Mutation Sensitizes Intrahepatic Cholangiocarcinoma to the BET Inhibitor JQ1. Cancer Sci. 2018, 109, 3602–3610.
  29. Mellinghoff, I.K.; Ellingson, B.M.; Touat, M.; Maher, E.; De La Fuente, M.I.; Holdhoff, M.; Cote, G.M.; Burris, H.; Janku, F.; Young, R.J.; et al. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma. J. Clin. Oncol. 2020, 38, 3398–3406.
  30. Abou-Alfa, G.K.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.; Borad, M.J.; Bridgewater, J.; et al. Ivosidenib in IDH1-Mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClarIDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study. Lancet Oncol. 2020, 21, 796–807.
  31. Suijker, J.; Oosting, J.; Koornneef, A.; Struys, E.A.; Salomons, G.S.; Schaap, F.G.; Waaijer, C.J.F.; Wijers-Koster, P.M.; Briaire-de Bruijn, I.H.; Haazen, L.; et al. Inhibition of Mutant IDH1 Decreases D-2-HG Levels without Affecting Tumorigenic Properties of Chondrosarcoma Cell Lines. Oncotarget 2015, 6, 12505–12519.
  32. Li, L.; Paz, A.C.; Wilky, B.A.; Johnson, B.; Galoian, K.; Rosenberg, A.; Hu, G.; Tinoco, G.; Bodamer, O.; Trent, J.C. Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLoS ONE 2015, 10, e0133813.
  33. Nakagawa, M.; Nakatani, F.; Matsunaga, H.; Seki, T.; Endo, M.; Ogawara, Y.; Machida, Y.; Katsumoto, T.; Yamagata, K.; Hattori, A.; et al. Selective Inhibition of Mutant IDH1 by DS-1001b Ameliorates Aberrant Histone Modifications and Impairs Tumor Activity in Chondrosarcoma. Oncogene 2019, 38, 6835–6849.
  34. Tap, W.D.; Villalobos, V.M.; Cote, G.M.; Burris, H.; Janku, F.; Mir, O.; Beeram, M.; Wagner, A.J.; Jiang, L.; Wu, B.; et al. Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients with Advanced Chondrosarcoma. J. Clin. Oncol. 2020, 38, 1693–1701.
  35. Molenaar, R.J.; Radivoyevitch, T.; Nagata, Y.; Khurshed, M.; Przychodzen, B.; Makishima, H.; Xu, M.; Bleeker, F.E.; Wilmink, J.W.; Carraway, H.E.; et al. Idh1/2 Mutations Sensitize Acute Myeloid Leukemia to Parp Inhibition and This Is Reversed by Idh1/2-Mutant Inhibitors. Clin. Cancer Res. 2018, 24, 1705–1715.
  36. Li, S.; Chou, A.P.; Chen, W.; Chen, R.; Deng, Y.; Phillips, H.S.; Selfridge, J.; Zurayk, M.; Lou, J.J.; Everson, R.G.; et al. Overexpression of Isocitrate Dehydrogenase Mutant Proteins Renders Glioma Cells More Sensitive to Radiation. Neuro. Oncol. 2013, 15, 57–68.
  37. Kessler, J.; Güttler, A.; Wichmann, H.; Rot, S.; Kappler, M.; Bache, M.; Vordermark, D. IDH1R132H Mutation Causes a Less Aggressive Phenotype and Radiosensitizes Human Malignant Glioma Cells Independent of the Oxygenation Status. Radiother. Oncol. 2015, 116, 381–387.
  38. Lu, Y.; Kwintkiewicz, J.; Liu, Y.; Tech, K.; Frady, L.N.; Su, Y.T.; Bautista, W.; Moon, S.I.; MacDonald, J.; Ewend, M.G.; et al. Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair. Cancer Res. 2017, 77, 1709–1718.
  39. Tateishi, K.; Higuchi, F.; Miller, J.J.; Koerner, M.V.A.; Lelic, N.; Shankar, G.M.; Tanaka, S.; Fisher, D.E.; Batchelor, T.T.; Iafrate, A.J.; et al. The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+depletion-Mediated Cytotoxicity. Cancer Res. 2017, 77, 4102–4115.
  40. Sulkowski, P.L.; Corso, C.D.; Robinson, N.D.; Scanlon, S.E.; Purshouse, K.R.; Bai, H.; Liu, Y.; Sundaram, R.K.; Hegan, D.C.; Fons, N.R.; et al. 2-Hydroxyglutarate Produced by Neomorphic IDH Mutations Suppresses Homologous Recombination and Induces PARP Inhibitor Sensitivity. Sci. Transl. Med. 2017, 9, eaal2463.
  41. Wang, Y.; Wild, A.T.; Turcan, S.; Wu, W.H.; Sigel, C.; Klimstra, D.S.; Ma, X.; Gong, Y.; Holland, E.C.; Huse, J.T.; et al. Targeting Therapeutic Vulnerabilities with PARP Inhibition and Radiation in IDH-Mutant Gliomas and Cholangiocarcinomas. Sci. Adv. 2020, 6, eaaz3221.
  42. Chan, S.M.; Thomas, D.; Corces-Zimmerman, M.R.; Xavy, S.; Rastogi, S.; Hong, W.J.; Zhao, F.; Medeiros, B.C.; Tyvoll, D.A.; Majeti, R. Isocitrate Dehydrogenase 1 and 2 Mutations Induce BCL-2 Dependence in Acute Myeloid Leukemia. Nat. Med. 2015, 21, 178–184.
  43. Karpel-Massler, G.; Ishida, C.T.; Bianchetti, E.; Zhang, Y.; Shu, C.; Tsujiuchi, T.; Banu, M.A.; Garcia, F.; Roth, K.A.; Bruce, J.N.; et al. Induction of Synthetic Lethality in IDH1-Mutated Gliomas through Inhibition of Bcl-XL. Nat. Commun. 2017, 8, 1067.
  44. Chen, C.; Liu, Y.; Lu, C.; Cross, J.R.; Morris IV, J.P.; Shroff, A.S.; Ward, P.S.; Bradner, J.E.; Thompson, C.; Lowe, S.W. Cancer-Associated IDH2 Mutants Drive an Acute Myeloid Leukemia That Is Susceptible to Brd4 Inhibition. Genes Dev. 2013, 27, 1974–1985.
  45. Turcan, S.; Fabius, A.W.; Borodovsky, A.; Pedraza, A.; Brennan, C.; Huse, J.; Viale, A.; Riggins, G.J.; Chan, T.A. Efficient Induction of Differentiation and Growth Inhibition in IDH1 Mutant Glioma Cells by the DNMT Inhibitor Decitabine. Oncotarget 2013, 4, 1729–1736.
  46. Batsios, G.; Viswanath, P.; Subramani, E.; Najac, C.; Gillespie, A.M.; Santos, R.D.; Molloy, A.R.; Pieper, R.O.; Ronen, S.M. PI3K/MTOR Inhibition of IDH1 Mutant Glioma Leads to Reduced 2HG Production That Is Associated with Increased Survival. Sci. Rep. 2019, 9, 10521.
  47. Emadi, A.; Jun, S.A.; Tsukamoto, T.; Fathi, A.T.; Minden, M.D.; Dang, C. V Inhibition of Glutaminase Selectively Suppresses the Growth of Primary Acute Myeloid Leukemia Cells with IDH Mutations. Exp. Hematol. 2014, 42, 247–251.
  48. Seltzer, M.J.; Bennett, B.D.; Joshi, A.D.; Gao, P.; Thomas, A.G.; Ferraris, D.V.; Tsukamoto, T.; Rojas, C.J.; Slusher, B.S.; Rabinowitz, J.D.; et al. Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1. Cancer Res. 2010, 70, 8981–8987.
  49. de Jong, Y.; Ingola, M.; Briaire-de Bruijn, I.H.; Kruisselbrink, A.B.; Venneker, S.; Palubeckaite, I.; Heijs, B.P.A.M.; Cleton-Jansen, A.-M.; Haas, R.L.M.; Bovée, J.V.M.G. Radiotherapy Resistance in Chondrosarcoma Cells; a Possible Correlation with Alterations in Cell Cycle Related Genes. Clin. Sarcoma Res. 2019, 9, 9.
  50. de Jong, Y.; Monderer, D.; Brandinelli, E.; Monchanin, M.; van den Akker, B.E.; van Oosterwijk, J.G.; Blay, J.Y.; Dutour, A.; Bovée, J.V.M.G. Bcl-Xl as the Most Promising Bcl-2 Family Member in Targeted Treatment of Chondrosarcoma. Oncogenesis 2018, 7, 74.
  51. Addie, R.D.; de Jong, Y.; Alberti, G.; Kruisselbrink, A.B.; Que, I.; Baelde, H.; Bovée, J.V.M.G. Exploration of the Chondrosarcoma Metabolome; the MTOR Pathway as an Important pro-Survival Pathway. J. Bone Oncol. 2019, 15, 100222.
  52. Peterse, E.F.P.; van den Akker, B.E.W.M.; Niessen, B.; Oosting, J.; Suijker, J.; de Jong, Y.; Danen, E.H.J.; Cleton-Jansen, A.-M.; Bovée, J.V.M.G. NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma. Mol. Cancer Res. 2017, 15, 1714–1721.
  53. Peterse, E.F.P.; Niessen, B.; Addie, R.D.; De Jong, Y.; Cleven, A.H.G.; Kruisselbrink, A.B.; Van Den Akker, B.E.W.M.; Molenaar, R.J.; Cleton-Jansen, A.M.; Bovée, J.V.M.G. Targeting Glutaminolysis in Chondrosarcoma in Context of the IDH1/2 Mutation. Br. J. Cancer 2018, 118, 1074–1083.
  54. Venneker, S.; Kruisselbrink, A.B.; Briaire-de Bruijn, I.H.; de Jong, Y.; van Wijnen, A.J.; Danen, E.H.J.; Bovée, J.V.M.G. Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status. Cancers 2019, 11, 1918.
  55. Palubeckaitė, I.; Venneker, S.; Van Den Akker, B.E.W.M.; Briaire-de Bruijn, I.H.; Bovée, J.V.M.G. Does PARP Inhibition Sensitize Chondrosarcoma Cell Lines to Chemotherapy or Radiotherapy? Results From a Three-Dimensional Spheroid Cell Model. Clin. Orthop. Relat. Res. 2022, 481, 608–619.
  56. Garrett, M.; Sperry, J.; Braas, D.; Yan, W.; Le, T.M.; Mottahedeh, J.; Ludwig, K.; Eskin, A.; Qin, Y.; Levy, R.; et al. Metabolic Characterization of Isocitrate Dehydrogenase (IDH) Mutant and IDH Wildtype Gliomaspheres Uncovers Cell Type-Specific Vulnerabilities. Cancer Metab. 2018, 6, 4.
  57. Jin, G.; Reitman, Z.J.; Duncan, C.G.; Spasojevic, I.; Gooden, D.M.; Rasheed, B.A.; Yang, R.; Lopez, G.Y.; He, Y.; McLendon, R.E.; et al. Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas. Cancer Res. 2013, 73, 496–501.
  58. Núñez, F.J.; Mendez, F.M.; Kadiyala, P.; Alghamri, M.S.; Savelieff, M.G.; Garcia-Fabiani, M.B.; Haase, S.; Koschmann, C.; Calinescu, A.-A.; Kamran, N.; et al. IDH1-R132H Acts as a Tumor Suppressor in Glioma via Epigenetic up-Regulation of the DNA Damage Response. Sci. Transl. Med. 2019, 11, eaaq1427.
  59. Raffel, S.; Falcone, M.; Kneisel, N.; Hansson, J.; Wang, W.; Lutz, C.; Bullinger, L.; Poschet, G.; Nonnenmacher, Y.; Barnert, A.; et al. BCAT1 Restricts AkG Levels in AML Stem Cells Leading to IDHmut-like DNA Hypermethylation. Nature 2017, 551, 384–388.
  60. Yang, Z.; Hu, N.; Wang, W.; Hu, W.; Zhou, S.; Shi, J.; Li, M.; Jing, Z.; Chen, C.; Zhang, X.; et al. Loss of FBXW7 Correlates with Increased IDH1 Expression in Glioma and Enhances IDH1-Mutant Cancer Cell Sensitivity to Radiation. Cancer Res. 2022, 82, 497–509.
  61. Hu, C.; Wang, K.; Damon, C.; Fu, Y.; Ma, T.; Kratz, L.; Lal, B.; Ying, M.; Xia, S.; Cahill, D.P.; et al. ATRX Loss Promotes Immunosuppressive Mechanisms in IDH1 Mutant Glioma. Neuro. Oncol. 2021, noab292.
  62. Wilson, E.R.; Helton, N.M.; Heath, S.E.; Fulton, R.S.; Payton, J.E.; Welch, J.S.; Walter, M.J.; Westervelt, P.; DiPersio, J.F.; Link, D.C.; et al. Focal Disruption of DNA Methylation Dynamics at Enhancers in IDH-Mutant AML Cells. Leukemia 2022, 36, 935–945.
  63. Lee, S.D.; Song, J.; LeBlanc, V.G.; Marra, M.A. Integrative Multi-Omic Analysis Reveals Neurodevelopmental Gene Dysregulation in CIC-Knockout and IDH1-Mutant Cells. J. Pathol. 2022, 256, 297–309.
  64. Middeke, J.M.; Metzeler, K.H.; Röllig, C.; Krämer, M.; Eckardt, J.-N.; Stasik, S.; Greif, P.A.; Spiekermann, K.; Rothenberg-Thurley, M.; Krug, U.; et al. Differential Impact of IDH1/2 Mutational Subclasses on Outcome in Adult AML: Results from a Large Multicenter Study. Blood Adv. 2022, 6, 1394–1405.
  65. Duchmann, M.; Micol, J.B.; Duployez, N.; Raffoux, E.; Thomas, X.; Marolleau, J.P.; Braun, T.; Adès, L.; Chantepie, S.; Lemasle, E.; et al. Prognostic Significance of Concurrent Gene Mutations in Intensively Treated Patients with IDH-Mutated AML: An ALFA Study. Blood 2021, 137, 2827–2837.
  66. Li, K.K.-W.; Shi, Z.-F.; Malta, T.M.; Chan, A.K.-Y.; Cheng, S.; Kwan, J.S.H.; Yang, R.R.; Poon, W.S.; Mao, Y.; Noushmehr, H.; et al. Identification of Subsets of IDH-Mutant Glioblastomas with Distinct Epigenetic and Copy Number Alterations and Stratified Clinical Risks. Neuro-Oncol. Adv. 2019, 1, vdz015.
  67. Yang, R.R.; Shi, Z.F.; Zhang, Z.; Chan, A.K.Y.; Aibaidula, A.; Wang, W.-W.; Kwan, J.S.H.; Poon, W.S.; Chen, H.; Li, W.-C.; et al. IDH Mutant Lower Grade (WHO Grades II/III) Astrocytomas Can Be Stratified for Risk by CDKN2A, CDK4 and PDGFRA Copy Number Alterations. Brain Pathol. 2020, 30, 541–553.
  68. Chan, A.K.Y.; Shi, Z.F.; Li, K.K.W.; Wang, W.W.; Chen, H.; Chung, N.Y.F.; Chan, D.T.M.; Poon, W.S.; Loong, H.H.F.; Liu, X.Z.; et al. Combinations of Single-Gene Biomarkers Can Precisely Stratify 1,028 Adult Gliomas for Prognostication. Front. Oncol. 2022, 12, 839302.
  69. Lachowiez, C.A.; Reville, P.K.; Kantarjian, H.; Jabbour, E.; Borthakur, G.; Daver, N.; Issa, G.; Furudate, K.; Tanaka, T.; Pierce, S.; et al. Contemporary Outcomes in IDH-mutated AML: The Impact of Co-occurring NPM1 Mutations and Venetoclax-based Treatment. Am. J. Hematol. 2022, 97, 1443–1452.
  70. Schrage, Y.M.; Lam, S.; Jochemsen, A.G.; Cleton-Jansen, A.M.; Taminiau, A.H.M.; Hogendoorn, P.C.W.; Bovée, J.V.M.G. Central Chondrosarcoma Progression Is Associated with PRb Pathway Alterations: CDK4 down-Regulation and P16 Overexpression Inhibit Cell Growth in Vitro. J. Cell Mol. Med. 2009, 13, 2843–2852.
  71. Tarpey, P.S.; Behjati, S.; Cooke, S.L.; Van Loo, P.; Wedge, D.C.; Pillay, N.; Marshall, J.; Meara, S.O.; Davies, H.; Zainal, S.N.; et al. Frequent Mutation of the Major Cartilage Collagen Gene COL2A1 in Chondrosarcoma. Nat. Genet. 2013, 45, 923–926.
  72. Totoki, Y.; Yoshida, A.; Hosoda, F.; Nakamura, H.; Hama, N.; Ogura, K.; Yoshida, A.; Fujiwara, T.; Arai, Y.; Toguchida, J.; et al. Unique Mutation Portraits and Frequent COL2A1 Gene Alteration in Chondrosarcoma. Genome Res. 2014, 24, 1411–1420.
  73. Zhang, Y.X.; Van Oosterwijk, J.G.; Sicinska, E.; Moss, S.; Remillard, S.P.; Van Wezel, T.; Bühnemann, C.; Hassan, A.B.; Demetri, G.D.; Bovée, J.V.M.G.; et al. Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy. Clin. Cancer Res. 2013, 19, 3796–3807.
  74. Zhang, Y.; Chen, Y.; Yang, C.; Seger, N.; Hesla, A.C.; Tsagkozis, P.; Larsson, O.; Lin, Y.; Haglund, F. TERT Promoter Mutation Is an Objective Clinical Marker for Disease Progression in Chondrosarcoma. Mod. Pathol. 2021, 34, 2020–2027.
  75. Cross, W.; Lyskjær, I.; Lesluyes, T.; Hargreaves, S.; Strobl, A.-C.; Davies, C.; Waise, S.; Hames-Fathi, S.; Oukrif, D.; Ye, H.; et al. A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome. Genome Med. 2022, 14, 99.
  76. Koelsche, C.; Schrimpf, D.; Stichel, D.; Sill, M.; Sahm, F.; Reuss, D.E.; Blattner, M.; Worst, B.; Heilig, C.E.; Beck, K.; et al. Sarcoma Classification by DNA Methylation Profiling. Nat. Commun. 2021, 12, 498.
  77. Nicolle, R.; Ayadi, M.; Gomez-Brouchet, A.; Armenoult, L.; Banneau, G.; Elarouci, N.; Tallegas, M.; Decouvelaere, A.V.; Aubert, S.; Rédini, F.; et al. Integrated Molecular Characterization of Chondrosarcoma Reveals Critical Determinants of Disease Progression. Nat. Commun. 2019, 10, 4622.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback