Article
Medicine, General & Internal
Ingo K. Mellinghoff, Martin J. van den Bent, Deborah T. Blumenthal, Mehdi Touat, Katherine B. Peters, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Liam Welsh, Warren P. Mason, Francois Ducray, Yoshie Umemura, Burt Nabors, Matthias Holdhoff, Andreas F. Hottinger, Yoshiki Arakawa, Juan M. Sepulveda, Wolfgang Wick, Riccardo Soffietti, James R. Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth A. Maher, Steven Schoenfeld, Dan Zhao, Shuchi S. Pandya, Lori Steelman, Islam Hassan, Patrick Y. Wen, Timothy F. Cloughesy
Summary: In a phase 3 trial, vorasidenib showed significant improvement in progression-free survival and delay in the time to the next intervention for patients with grade 2 IDH-mutant glioma.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Oncology
Rana Gbyli, Yuanbin Song, Wei Liu, Yimeng Gao, Giulia Biancon, Namrata S. Chandhok, Xiaman Wang, Xiaoying Fu, Amisha Patel, Ranjini Sundaram, Toma Tebaldi, Padmavathi Mamillapalli, Amer M. Zeidan, Richard A. Flavell, Thomas Prebet, Ranjit S. Bindra, Stephanie Halene
Summary: Treatment options for relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients are limited. Our study demonstrates the effectiveness of the PARP inhibitor olaparib in IDH1/2-mutant AML/MDS patients, particularly those who are resistant to IDH(m)i treatment or have relapsed.
Article
Cell Biology
Emily Gruber, Joan So, Alexander C. Lewis, Rheana Franich, Rachel Cole, Luciano G. Martelotto, Amy J. Rogers, Eva Vidacs, Peter Fraser, Kym Stanley, Lisa Jones, Anna Trigos, Niko Thio, Jason Li, Brandon Nicolay, Scott Daigle, Adriana E. Tron, Marc L. Hyer, Jake Shortt, Ricky W. Johnstone, Lev M. Kats
Summary: A study found that the efficacy of the IDH1 inhibitor AG-120 in AML patients depends on the cell type. Although AG-120 as a single agent cannot completely eradicate the disease, it can increase the proliferation of leukemia stem cells and enhance sensitivity to azacitidine. Therefore, the combination therapy of AG-120 and azacitidine shows improved efficacy in patients.
Article
Cell Biology
Xiaomin Wang, Ziqi Chen, Jun Xu, Shuai Tang, Nan An, Lei Jiang, Yixiang Zhang, Shaoying Zhang, Qingli Zhang, Yanyan Shen, Shijie Chen, Xiaojing Lan, Ting Wang, Linhui Zhai, Siyuwei Cao, Siqi Guo, Yingluo Liu, Aiwei Bi, Yuehong Chen, Xiameng Gai, Yichen Duan, Ying Zheng, Yixian Fu, Yize Li, Liang Yuan, Linjiang Tong, Kun Mo, Mingcheng Wang, Shu-Hai Lin, Minjia Tan, Cheng Luo, Yi Chen, Jia Liu, Qiansen Zhang, Leping Li, Min Huang
Summary: The mutant form of isocitrate dehydrogenase 1 (mIDH1) drives tumor development by producing oncometabolite R-2-hydroxyglutarate (R-2-HG) in various types of tumors. However, mIDH1 inhibitors have been found to only be effective in hematological tumors and their therapeutic impact in solid tumors is still unclear due to the complex tumor microenvironment. This study reveals that R-2-HG produced by IDH1-mutant tumor cells is preferentially taken up by vascular endothelial cells and alters mitochondrial respiration to promote tumor angiogenesis. This highlights the potential therapeutic vulnerability of IDH1-mutant solid tumors and suggests that disrupting R-2-HG-promoted tumor angiogenesis could be a promising strategy for treatment.
Article
Biochemistry & Molecular Biology
Ingo K. Mellinghoff, Min Lu, Patrick Y. Wen, Jennie W. Taylor, Elizabeth A. Maher, Isabel Arrillaga-Romany, Katherine B. Peters, Benjamin M. Ellingson, Marc K. Rosenblum, Saewon Chun, Kha Le, Ania Tassinari, Sung Choe, Youssef Toubouti, Steven Schoenfeld, Shuchi S. Pandya, Islam Hassan, Lori Steelman, Jennifer L. Clarke, Timothy F. Cloughesy
Summary: In a pilot perioperative randomized clinical trial, the dual IDH1/IDH2 inhibitor vorasidenib was found to have better brain permeability and target engagement than ivosidenib in patients with IDH1-mutant glioma. Both agents showed significant reduction in tumor 2-HG concentrations, with vorasidenib demonstrating more consistent suppression. Exploratory analyses revealed additional positive effects of 2-HG reduction. Vorasidenib was selected for further testing in phase 3 trials. This study was funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC.
Article
Hematology
Anuhar Chaturvedi, Charu Gupta, Razif Gabdoulline, Nora M. Borchert, Ramya Goparaju, Stefan Kaulfuss, Kerstin Goerlich, Renate Schottmann, Basem Othman, Julia Welzenbach, Olaf Panknin, Markus Wagner, Robert Geffers, Arnold Ganser, Felicitas Thol, Andrea Haegebarth, Michael Jeffers, Michael Heuser
Summary: The study demonstrates that the combination treatment of mIDH1 inhibitors and azacitidine has significant efficacy in AML patients, reducing leukemia stem cell numbers through different mechanisms and signaling pathways. The strong synergy between the two treatments is mediated through inhibition of MAPK/ERK and Rb/E2F signaling, suggesting an improved outcome for IDH1 mutated AML patients.
Article
Oncology
Ingo K. Mellinghoff, Marta Penas-Prado, Katherine B. Peters, Howard A. Burris, Elizabeth A. Maher, Filip Janku, Gregory M. Cote, Macarena de la Fuente, Jennifer L. Clarke, Benjamin M. Ellingson, Saewon Chun, Robert J. Young, Hua Liu, Sung Choe, Min Lu, Kha Le, Islam Hassan, Lori Steelman, Shuchi S. Pandya, Timothy F. Cloughesy, Patrick Y. Wen
Summary: Vorasidenib demonstrated favorable safety profile and preliminary antitumor activity in patients with non-enhancing mIDH LGG, with a median progression-free survival of 36.8 months.
CLINICAL CANCER RESEARCH
(2021)
Article
Medicine, Research & Experimental
Padma Kadiyala, Stephen Carney, Jessica C. Gauss, Maria B. Garcia-Fabiani, Santiago Haase, Mahmoud S. Alghamri, Felipe J. Nunez, Yayuan Liu, Minzhi Yu, Ayman Taher, Fernando M. Nunez, Dan Li, Marta B. Edwards, Celina G. Kleer, Henry Appelman, Yilun Sun, Lili Zhao, James J. Moon, Anna Schwendeman, Pedro R. Lowenstein, Maria G. Castro
Summary: The study focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. In a mouse model, inhibition of D-2HG in combination with radiation and temozolomide (IR/TMZ) led to increased survival and anti-glioma immunological memory, which was enhanced by anti-PDL1 immune checkpoint blockade resulting in complete tumor regression in 60% of mice. This combination strategy reduced T cell exhaustion and favored memory CD8(+) T cell generation.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Michael Platten, Lukas Bunse, Antje Wick, Theresa Bunse, Lucian Le Cornet, Inga Harting, Felix Sahm, Khwab Sanghvi, Chin Leng Tan, Isabel Poschke, Edward Green, Sune Justesen, Geoffrey A. Behrens, Michael O. Breckwoldt, Angelika Freitag, Lisa-Marie Rother, Anita Schmitt, Oliver Schnell, Joerg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Joachim P. Steinbach, Martin Bendszus, Andreas von Deimling, Michael Schmitt, Wolfgang Wick
Summary: Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours.
Review
Oncology
Gabrielle W. Johnson, Rowland H. Han, Matthew D. Smyth, Eric C. Leuthardt, Albert H. Kim
Summary: LITT is an effective treatment option for patients with IDH1/2 mutant glioma, as suggested by the outcomes of this study.
Article
Multidisciplinary Sciences
Mahmoud S. Alghamri, Brandon L. McClellan, Ruthvik P. Avvari, Rohit Thalla, Stephen Carney, Margaret S. Hartlage, Santiago Haase, Maria Ventosa, Ayman Taher, Neha Kamran, Li Zhang, Syed Mohd Faisal, Felipe J. Nunez, Maria Belen Garcia-Fabiani, Wajd N. Al-Holou, Daniel Orringer, Shawn Hervey-Jumper, Jason Heth, Parag G. Patil, Karen Eddy, Sofia D. Merajver, Peter J. Ulintz, Joshua Welch, Chao Gao, Jialin Liu, Gabriel Nunez, Dolores Hambardzumyan, Pedro R. Lowenstein, Maria G. Castro
Summary: The efficacy of immune-stimulatory gene therapy is enhanced in mIDH1 gliomas due to the reprogramming of infiltrating myeloid cells, mainly non-suppressive neutrophils and pre-neutrophils, in the tumor microenvironment. This reprogramming is triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells, leading to non-inhibitory myeloid cells within the tumor microenvironment and enhancing the therapy's effectiveness.
Review
Pharmacology & Pharmacy
Wangqi Tian, Weitong Zhang, Yifan Wang, Ruyi Jin, Yuwei Wang, Hui Guo, Yuping Tang, Xiaojun Yao
Summary: IDH is a key metabolic enzyme that is mutated in various tumors, with IDH1 mutations being more frequent than IDH2 mutations. IDH1 mutations lead to accumulation of 2-HG, which impairs cell differentiation. Small molecule inhibitors targeting mutant IDH1 have emerged as a promising therapeutic approach.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
M. Saikiran Reddy, Debanjan Bhattacharjee, Nishant Jain
Summary: The study reveals that the mitotic kinase Plk1 regulates the function of mutant IDH1 and IDH2 in mitosis. Plk1 phosphorylates mutant IDH1 and IDH2, thereby controlling their enzyme activity and ubiquitination. These findings suggest that Plk1 could be a potential therapeutic target in mutant IDH-linked tumors.
CELLULAR SIGNALLING
(2022)
Review
Medicine, General & Internal
Vikram Sumbly, Ian Landry, Vincent Rizzo
Summary: This article briefly reviews the genomics and prognosis of cholangiocarcinoma, with a special focus on ivosidenib and its effectiveness in patients with IDH1 mutated cholangiocarcinoma.
CUREUS JOURNAL OF MEDICAL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Connor Yanchus, Kristen L. Drucker, Thomas M. Kollmeyer, Ricky Tsai, Warren Winick-Ng, Minggao Liang, Ahmad Malik, Judy Pawling, Silvana B. De Lorenzo, Asma Ali, Paul A. Decker, Matt L. Kosel, Arijit Panda, Khalid N. Al-Zahrani, Lingyan Jiang, Jared W. L. Browning, Chris Lowden, Michael Geuenich, J. Javier Hernandez, Jessica T. Gosio, Musaddeque Ahmed Section, Sampath Kumar Loganathan Paragraph, Jacob Berman, Daniel Trcka, Kulandaimanuvel Antony Michealraj, Jerome Fortin, Brittany Carson, Ethan W. Hollingsworth, Sandra Jacinto, Parisa Mazrooei, Lily Zhou, Andrew Elia, Mathieu Lupien, Housheng Hansen He, Daniel J. Murphy, Liguo Wang, Alexej Abyzov, James W. Dennis, Philipp G. Maass, Kieran Campbell, Michael D. Wilson, Daniel H. Lachance, Margaret Wrensch, John Wiencke, Tak Mak, Len A. Pennacchio, Diane E. Dickel Section Section, Axel Visel, Jeffrey Wrana, Michael D. Taylor, Gelareh Zadeh, Peter Dirks, Jeanette E. Eckel-Passow, Liliana Attisano, Ana Pombo, Cristiane M. Ida, Evgeny Z. Kvon, Robert B. Jenkins, Daniel Schramek
Summary: This study reveals the causal relationship between the single-nucleotide polymorphism rs55705857 and the increased risk of low-grade glioma (LGG). The research also identifies the molecular pathways associated with this polymorphism. The risk allele disrupts the binding of OCT2/4 and increases the expression of Myc. In a mouse model, mutating the rs55705857 locus accelerates tumor development and increases disease penetrance.
