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Posts tagged ‘IDH1 inhibitor’

ENA2014_Banner_400x250The annual Symposium on Molecular Targets and Cancer Therapeutics jointly run by the EORTC, NCI and AACR (aka “the Triple meeting”), starts tomorrow in Barcelona (Twitter hashtag #ENA2014).

This makes it a particularly busy week on the conference calendar as we segue from immunotherapy at SITC to Molecular Targets, not to mention the start of our previews on hematologic malignancies at the American Society of Hematology (ASH) coming up fast!

The Triple symposium alternates between the US and Europe. In case you missed it, here’s a link to our extensive coverage from last year’s Boston Molecular Targets Symposium that we attended.

This year in Barcelona, one of the highlights is the presentation of the latest clinical data for the phase 1 trial of AG-120 (Agios), an inhibitor of the IDH1 enzyme.

As the abstract that will be presented tomorrow by Daniel Pollyea, MD (University of Colorado, Denver) notes, “Cancer metabolism represents an emerging field of novel cancer target discovery.” Along with epigenetics, it’s an exciting area that we are actively following. For years metabolism has been promising to breakthrough with new ideas that move the needle in clinical research but few have lived up to the lofty expectations, with one exception.

We first wrote Agios back in 2012, when they showed that that mutations of the metabolic gene IDH1 were consistent with that of a cancer causing oncogene in glioblastoma.

Then at ASH 2013, we heard the preclinical data for AG-221 using IDH2 mutant acute myeloid leukemia (AML) xenografts and interviewed the Agios CEO, Dr David Schenkein. The story for AG-221 continued in a positive vein with early clinical data at AACR and ASCO earlier this year. You can read more in the related posts we’ve highlighted at  the end of this article.

Tomorrow at EORTC-NCI-AACR Molecular Targets in Barcelona we will hear about the preliminary results for the phase 1 trial of AG-120 in patients with advanced hematological malignancies including those with relapsed or refractory AML, myelodysplastic syndromes (MDS) and elderly untreated AML that harbor an IDH1 mutation.

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One of the challenges of the next decade in cancer research will be targeting cancer metabolism; imaging is likely to play a key role in drug development.

NMR-image-of-brain-gliomaThe cover of the January 11 online issue of Science Translational Medicine (STM) shows a brain tumor (glioma) in red, detected using non-invasive nuclear magnetic resonance imaging that highlights cancer metabolism.

In a paper published in STM, Andronesi and colleagues from Harvard & other Cambridge, MA institutions (including Agios Pharmaceuticals – more on them later), showed that excess production of the metabolite 2-hydroxyglutarate (2HG) could be used as a biomarker for a subset of glioma.

The subset this metabolic biomarker identified, were those patients with mutations of the isocitrate dehyrogenase gene (IDH1), present in 86% of the grade II & III gliomas and secondary glioblastomas.

Agios Pharmaceuticals founded by eminent cancer researchers, Lewis Cantley, Tak Mak and Craig Thompson is targeting the IDH1 and IDH2 metabolic pathways.

They have shown that mutations of the metabolic gene IDH1 are consistent with that of a cancer-causing oncogene.  Interestingly, Agios notes on their website that IDH1 and IDH2 mutations have also been seen in acute myeloid leukemia (AML).

What makes 2HG a functional biomarker for glioma is its correlation with survival.  2HG accumulates in the brains of patients with IDH1 mutations. These patients have a greater survival than those with wild-type IDH1 gliomas.

Developing a drug that targets cancer metabolism in the brain is not easy. NMR imaging of the 2HG in the brain will help researchers non-invasively follow the effects of inhibitors of mutated IDH1. This is particularly important given that, according to Andronesi et al,  “no report exists about increased D-2HG in the blood, cerebrospinal fluid, or urine of glioma patients with IDH1 mutations.”

The January 11 online issue of STM, also contains another paper on the detection of 2HG using NMR. Elkhaled and colleagues from UCSF report a technique of proton high-resolution magic angle spinning spectroscopy.  Their data confirms the potential of 2HG as a surrogate marker of patient survival.

Cancer metabolism as a drug development target is an area I expect we will see more of in the next ten years.  Key to success will be the ability to identify biomarkers with which to assess and monitor the success of drug candidates.

The identification of 2HG as a biomarker for IDH1 in glioma patients shows that cancer metabolism is an area of potential for drug development.

One cloud on the horizon for Agios Pharmaceuticals is, however, the filing of a lawsuit late last year by the Abramson Cancer Institute of the University of Pennsylvania. This alleges that Craig Thompson concealed the start-up of Agios while working for Penn, and in essence took the intellectual property of the University to the company. The merits of this claim have yet to be decided.


ResearchBlogging.orgAndronesi, O., Kim, G., Gerstner, E., Batchelor, T., Tzika, A., Fantin, V., Vander Heiden, M., & Sorensen, A. (2012). Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy Science Translational Medicine, 4 (116), 116-116 DOI: 10.1126/scitranslmed.3002693

Elkhaled, A., Jalbert, L., Phillips, J., Yoshihara, H., Parvataneni, R., Srinivasan, R., Bourne, G., Berger, M., Chang, S., Cha, S., & Nelson, S. (2012). Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas Science Translational Medicine, 4 (116), 116-116 DOI: 10.1126/scitranslmed.3002796

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