PracticeUpdate: Haematology & Oncology

CNS/BRAIN

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2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility in patients with glioma Written by Patrick Y. Wen MD T he majority of grade II and III gliomas and up to 10% of glioblastomas harbor mutations management of IDH-mutated gliomas. However, there remain important technical challenges and issues of standardization that will have to be addressed.

EXPERT OPINION PATRICK Y. WEN Advances in glioma treatment Interview by Farzanna S Haffizulla MD, FACP, FAMWA Dr Haffizulla: What about some of the major advances in low-grade gliomas over the last year? Dr Wen: The past year has really seen two tremendous advances in low- grade gliomas, which was an area where nothing much had happened for many years. The first was the publication of three papers from looking at the genomics of these tumours and now we can clearly classify low-grade gliomas into three groups based on IDH mutation in 1p/19q co-deletion. So, those lower-grade gliomas that do not have IDH mutation have the molecular alterations of glioblastoma and behave like glioblastoma even though they are diagnosed histologically as low-grade tumours, and then the IDH-mutated tumours can be divided into two groups based on 1p/19q co-deletion. Those who have the co-deletion, oligodendrogliomas, and have a very good prognosis and those who have intact 1p/19q are astrocytomas and have an intermediate prognosis, so the ability to separate out these tumours into more clear subgroups is really important and this has been taken into account by the newWHO classification that just came out. The second area for low-grade gliomas that’s made a real difference is a report of a trial from the NIG group where they treated grade II gliomas at high risk in those patients over the age of 40 with subtotal resection and they compared radiation to radiation with PCV chemotherapy. The addition of the PCV chemotherapy is significant in the increased survival and the benefit was mainly for oligodendrogliomas and oligoastrocytomas, so that I think will change the standard of practice significantly. Dr Haffizulla: Are there any other treatments currently in development that are likely to have a significant clinical impact in the near future or anything else you’d like to highlight? Dr Wen: So the other area where there’s a lot of interest is targeting IDH; 70–80% of these tumours have IDH mutations so there are many trials of IDH inhibitors that are ongoing. One called AG120 has completed the phase 1 and dose expansion and by the end of this year we will have some idea of efficacy, and there are vaccines also being developed that target tumours with IDH mutation, so both of those approaches are very exciting. Dr Haffizulla: That sounds exciting, and you know we mentioned already the Cancer MoonShot Program and looking at sort of epitope-driven therapies, and we also have ASCO’s first clinical trial, the TAPUR, which is Targeted Agents and Profiling Utilization Registry, which will allow patients who typically are not allowed to get certain drugs because they’re not FDA approved for those particular cancer subgroups, they certainly can get and then these particular patient populations and it’s all driven by genomic profiling. Dr Wen: I think those are really important developments and hopefully the Cancer MoonShot will make a significant difference. Dr Haffizulla: Absolutely. Dr Wen: Vice President Biden has a personal interest in brain tumours. Hopefully this will help that field. Dr Haffizulla: And Dr Patrick Soon-Shiong has done a phenomenal job as well, kind of putting this initiative together. And I think that there’s absolutely a push to improve that collaborative spirit to make sure we have a unified platform, not only where we can share information, but allow our patients to be enrolled in appropriate clinical trials, in a sense, and to be able to share the information as best as possible to improve our science and clinical research so we can have the best patient outcomes. The past year has really seen two tremendous advances in low-grade gliomas, which was an area where nothing much had happened for many years.

>1 mM could be reliably detected and varied by <1mMwhile the disease was relatively stable, but increased sharply with tumor progression. Furthermore, 2HG concentration was positively correlated with tumour cellularity and higher-grade gliomas. Following cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q co-deleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. This study showed that 2HG concentration, as measured by MRS, was reproducible and reliably reflected the disease state, suggesting that 2HG MRS may have a role in the clinical

in the gene coding for isocitrate dehy- drogenase (IDH), which results in the conversion of alpha-ketoglutarate to 2-hydroxyglutarate (2HG). In the tumour, 2HG accumulates in high concentrations and can be detected by proton magnetic resonance spec- troscopy (MRS). In this study, serial quantitative assessment of 2HG by MRS was performed in 136 patients to determine whether it can serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. This study revealed that 2HG concentrations of

Dr Wen is Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of Cancer Neurology, Department

of Neurology, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School, Boston, Massachusetts.

Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma Journal of Clinical Oncology Take-home message • This study looked at whether quantitative assessment of 2-hydroxyglutarate (2HG) by proton magnetic resonance spectroscopy (MRS) could serve as a noninvasive clinical imaging biomarker in the context of gliomas characterized by mutation in the IDH gene. The 2HG concentration was positively correlated with tumor progression and tumor cellularity, and the concentration of 2HG significantly differed between high- and low-grade gliomas. • The study results showed that measuring 2HG concentration by MRS is reproducible and that measuring 2HG concentra- tion reliably reports on glioma disease state. Abstract

concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively corre- latedwith tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendro- gliomas and with a slower time course in astrocytomas andmixed gliomas. The magnitude and time course of the decrease in 2HG concentration andmagnitude of the decrease in tumor volume did not differ between oligodendrogliomas treatedwith temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. CONCLUSION 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas. J Clin Oncol 2016 Oct 03;[Epub ahead of print], Choi C, Raisanen JM, Ganji SK, et al.

PURPOSE Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase (IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. PATIENTS AND METHODS 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. RESULTS Quantitative 2HG MRS was technically and biologically reproducible. 2HGconcentration > 1 mMcould be reliably detected with high confidence. During the period of indolent disease, 2HG

JOURNAL SCAN IDHmutation leads to PI3K/AKT-independent mTOR activation Journal of Clinical Oncology Take-home message

• The intracellular oncometabolite 2-hydroxyglutarate (2-HG) is produced at high concentrations in gliomas containing mutations in the IDH1 or IDH2 genes. To further investigate the role of 2-HG in tumor formation, the authors used a cell culture model to examine the activity of the mTOR pathway, which has been previously reported to exhibit aberrant activity in glioma. The authors performed a screen using short hairpin RNA to deplete alpha-ketoglutarate–dependent enzymes and noted that knock-down of KDMA4 led to abnormal activation of mTOR, as determined by elevated levels of phosphorylation of S6, the downstream effector. • Overall, these data are suggestive of a mechanism in which the IDH mutation leads to PI3K/AKT-independent mTOR activation and provide a rationale to explore mTOR inhibition in this specific population of gliomas.

Dr Wen is Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and Director of the Division of Cancer Neurology in the Department of Neurology at Brigham and Women’s Hospital.

the DEP domain-containing mTOR-interacting protein (DEP- TOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway. Prospective longitudinal analysis of 2-hydroxyglutarate mag- netic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma J Clin Oncol 2016 Oct 03;[Epub ahead of print], Choi C, Raisanen MH, Ganji SK, et al

ABSTRACT The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydro- genases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isoci- trate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with

He is Professor of Neurology at Harvard Medical School.

Dr Haffizulla practices general internal medicine in Davie, Florida, within her own internal medicine concierge practice.

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PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY