Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘IDH1 mutation’

For the final postcard in our 2020 summer mini-series on the potential of immunometabolism in oncology R&D, we’re taking an in-depth look at the ways in which metabolic programming can overcome immunosuppression in the tumour microenvironment (TME), as well as looking at additional novel ways in which the fitness of T cells can be impacted.

We’ve already covered glutaminase, arginine, p38 and others, yet there are other metabolic effects to consider too, as we discover in our latest expert interview.  In the penultimate postcard, we looked at mitochondrial phenotypes and how they can impact both mitochondrial and T cell fitness, which are important aspects in making adoptive cell therapy (ACT) based approaches such as TILs and CAR-T cell therapies more effective.

Deep thoughts on immunometabolism and how it can impact antitumour response

These themes show up yet again, but in a rather different context because T cell fitness can also impact immune checkpoint blockade, oncogenic targeting, as well as transcriptional and epigenetic approaches.

As much as we have been slowing building up the evidence during this series, in the finale it’s now time to kick up things up a notch or two and draw some unifying ideas together.

We accomplish this feat with a rising young star in this particular niche, Dr Ping-Chih Ho, who is at the University of Lausanne.

He kindly spoke to BSB about his pioneering and prolific research, some of the critical questions he has sought to answer, plus what he sees are important future directions to consider in metabolism research.

To learn more from our oncology analysis and get a heads up on insights and commentary emerging on immunometabolism, subscribers can log-in or you can click to gain access to BSB Premium Content.

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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.

References

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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