Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Pharmacology
  4. Volume 17, Issue 1
  5. Article
Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
file format pdf download PDF
side by side viewer icon HTML

Abstract

Background:

This commentary explores the potential of Vorasidenib, also known as AG-881. This emerging small-molecule inhibitor has garnered substantial attention within the realm of oncology due to its unique mechanism of action and potential therapeutic applications.

Introduction:

Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.

Mechanism of Action:

Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion.

Preclinical Evidence:

Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.

Clinical Evidence:

Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable.

Challenges and Future Directions:

Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.

Conclusion:

Vorasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Loading

Article metrics loading...

/content/journals/cmp/10.2174/0118761429290327240222061812
2024-02-29
2024-11-23

  • From This Site

    /content/journals/cmp/10.2174/0118761429290327240222061812
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmp/17/1/e18761429290327.html?itemId=/content/journals/cmp/10.2174/0118761429290327240222061812&mimeType=html&fmt=ahah

References

  1. BucknerJ.C. ShawE.G. PughS.L. ChakravartiA. GilbertM.R. BargerG.R. CoonsS. RicciP. BullardD. BrownP.D. StelzerK. BrachmanD. SuhJ.H. SchultzC.J. BaharyJ.P. FisherB.J. KimH. MurthaA.D. BellE.H. WonM. MehtaM.P. CurranW.J.Jr Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma.N. Engl. J. Med.2016374141344135510.1056/NEJMoa150092527050206
     [Google Scholar]
  2. PoonanP. AgoniC. SolimanM.E.S. Dual‐knockout of mutant isocitrate dehydrogenase 1 and 2 subtypes towards glioma therapy: structural mechanistic insights on the role of vorasidenib.Chem. Biodivers.2021187e210011010.1002/cbdv.20210011033982420
     [Google Scholar]
  3. KonteatisZ. ArtinE. NicolayB. StraleyK. PadyanaA.K. JinL. ChenY. NarayaraswamyR. TongS. WangF. ZhouD. CuiD. CaiZ. LuoZ. FangC. TangH. LvX. NagarajaR. YangH. SuS.S.M. SuiZ. DangL. YenK. Popovici-MullerJ. CodegaP. CamposC. MellinghoffI.K. BillerS.A. Vorasidenib (AG-881): A first-in-class, brain-penetrant dual inhibitor of mutant idh1 and 2 for treatment of glioma.ACS Med. Chem. Lett.202011210110710.1021/acsmedchemlett.9b0050932071674
     [Google Scholar]
  4. ChuntovaP. YamamichiA. ChenT. NarayanaswamyR. RonseauxS. HudsonC. TronA.E. HyerM.L. MontoyaM. MendeA.L. NejoT. DowneyK.M. DieboldD. LuM. NicolayB. OkadaH. Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma.J. Immunother. Cancer2022105e00464410.1136/jitc‑2022‑00464435606087
     [Google Scholar]
  5. MellinghoffI.K. Penas-PradoM. PetersK.B. BurrisH.A.III MaherE.A. JankuF. CoteG.M. de la FuenteM.I. ClarkeJ.L. EllingsonB.M. ChunS. YoungR.J. LiuH. ChoeS. LuM. LeK. HassanI. SteelmanL. PandyaS.S. CloughesyT.F. WenP.Y. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase i trial.Clin. Cancer Res.202127164491449910.1158/1078‑0432.CCR‑21‑061134078652
     [Google Scholar]
  6. MellinghoffI.K. LuM. WenP.Y. TaylorJ.W. MaherE.A. Arrillaga-RomanyI. PetersK.B. EllingsonB.M. RosenblumM.K. ChunS. LeK. TassinariA. ChoeS. TouboutiY. SchoenfeldS. PandyaS.S. HassanI. SteelmanL. ClarkeJ.L. CloughesyT.F. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: A randomized, perioperative phase 1 trial.Nat. Med.202329361562210.1038/s41591‑022‑02141‑236823302
     [Google Scholar]
  7. MellinghoffI. K. INDIGO Trial Investigators. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.N Engl J Med.2023389758960110.1056/NEJMoa2304194
     [Google Scholar]
  8. BatsiosG. PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival.Scientific Reports20199115
     [Google Scholar]
  9. WallinJ.J. EdgarK.A. GuanJ. BerryM. PriorW.W. LeeL. LesnickJ.D. LewisC. NonomiyaJ. PangJ. SalphatiL. OliveroA.G. SutherlinD.P. O’BrienC. SpoerkeJ.M. PatelS. LensunL. KasseesR. RossL. LacknerM.R. SampathD. BelvinM. FriedmanL.S. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway.Mol. Cancer Ther.201110122426243610.1158/1535‑7163.MCT‑11‑044621998291
     [Google Scholar]
  10. MolloyA.R. NajacC. ViswanathP. LakhaniA. SubramaniE. BatsiosG. RadoulM. GillespieA.M. PieperR.O. RonenS.M. MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma.Theranostics202010198757877010.7150/thno.4731732754276
     [Google Scholar]
/content/journals/cmp/10.2174/0118761429290327240222061812
Loading

  • Article Type:     Editorial
Keyword(s): Brain tumors; Future challenges; Idh; Inhibitors; Low-grade gliomas; Vorasidenib

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test