Biotech Strategy Blog

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

Posts tagged ‘Glioblastoma’

Long time attendees at the annual meeting of the American Association for Cancer Research (AACR) know that there are usually interesting posters and sessions buried on the last day of the meeting.

This year was no exception, with a major symposium on CAR T Cell Cancer Immunotherapy chaired by Michael Jensen MD (pictured right).

BSB readers will recall we interviewed him at the 2016 BMT Tandem meeting in Honolulu (See post: Optimizing CD19 CAR T cell therapy).  Excerpts from this interview also featured in Episode 14 – Cell Therapy Pioneers of the Novel Targets Podcast.

The CAR T symposium on the last day of AACR was one of my highlights of the meeting. The three speakers were:

  • Michael Jensen, MD (Seattle Children’s) Engineering Next Generation CAR T cells using Synthetic Biology-Inspired Technologies
  • Terry J. Fry, MD (National Cancer Institute) Defining and overcoming limitations of CD19 CAR immunotherapy in pediatric ALL
  • Christine E. Brown, PhD (City of Hope) Progress and Challenge in CAR T Cell Therapy for Brain Tumors

Each of these presentations would merit a full blog post in their own right, but in this particular post we’re focusing on CAR T cell therapy targeting glioblastoma multiforme (GBM).

GBM is the most common primary malignant brain tumor, and one with a dismal prognosis – the 5-year survival rate is only around 5%, so there is also a high unmet medical need for new effective treatment options. This devastating disease has proven to be a miserable graveyard for Pharma over the last decade, with many agents unfortunately ending up in dog drug heaven.

After her AACR17 presentation, Dr Brown kindly spoke to BSB.

This post is part of our series of thouight leader interviews from AACR17. It also continues our ongoing posts on the adoptive cellular therapy landscape, and in particular, CAR modified T cells.

Subscribers with an interest in the CAR T cell competitive landscape can login to read more

Lindt Gold BunnyWhat questions are BSB readers sending in to us this month?

I wanted to take a moment out of AACR Previews and catch up on some recent news that is intriguing or perplexing subscribers. All questions are anonymous and in many cases, the same questions were actually sent in by multiple people, a testament to what’s top of mind in oncology lately.

Today, we cover a Q&A on a variety of topics on Kite Pharma (the Genentech collaboration and their TCR in solid tumours), a discussion about EGVRvIII in glioblastoma, and Gilead’s woes with idelalisib and an IO pipeline.

So let’s get started – subscribers can sign-in…

Biotech IPOs were a pretty hot topic in 2013, with some of the young stars in oncology seeing very good uptake and prices. Two companies that come to mind are Foundation Medicine and Agios Pharmaceuticals.  Last week, we covered Foundation Medicine (FMI) and their progress with genomic testing, which is used by a number of Pharma companies including Novartis, in their clinical trial program. Interestingly, another company using their platform is Agios (AGIO), a start up biotechnology company focusing on metabolism and its errant mechanisms in cancer related areas. Both Foundation Medicine and Agios are based in Cambridge, MA.

Agios have an impressive Founder list in Lew Cantley, Tak Mak, Craig Thompson, all strong scientists with an interest in biochemistry and metabolism. The Scientific Advisory Board is equally impressive and includes Charles Sawyers, Jeff Engelman, Pier Paolo Pandolfi and David Sabatini, to name a few luminaries. The last two are well known metabolism researchers who have published extensively on the PI3K pathway, as has Lew Cantley. Craig Thompson has published significant research on IDH metabolism and his lectures on the topic are always fascinating and educational.

You can imagine that board meetings at Agios could well be rather different from the average biotech if the founders or the advisory board decided to brainstorm or riff on the science… Whoa, who wouldn’t want to be a fly on the wall and learn from the experts?  For a CEO, though, it might be akin to herding cats!  That said, I’m impressed that the company has such a clear, focused approach.

The company have a number of industry partnerships, including a recent extension last month to their existing agreement with Celgene.

With my background in biochemistry, I’m naturally drawn to follow metabolism-based approaches including the PI3K-AKT-mTOR pathway and anything that involves the TCA cycle.  It’s a highly complex area, not least because most cancers have a high demand for metabolic inputs such as glucose and glutamine in order to constantly drive tumour proliferation and survival.

David SchenkeinAt the recent ASH meeting, they presented interesting preclinical data for AG-221 using IDH2 mutant AML xenografts. While in New Orleans,  I had the opportunity to sit down with the Agios CEO, Dr David Schenkein, and discuss their approach, challenges and direction in some detail. He is also presenting at the JP Morgan Healthcare Conference today and giving a business update on the company’s progress.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

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

1 Comment
error: Content is protected !!