Biotech Strategy Blog

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

Posts from the ‘Metabolism’ category

The past year has seen hype and hope over targeting KRAS mutant cancers and many challenges still remain to be addressed. We’ve seen the emergence of selective G12C inhibitors, as well as others targeting SOS1:RAS upstream and even related pathways to address cross-talk such as SHP2 and ULK1, for example. The oncology R&D ecosystem is beginning to motor again as new competitors start entering the niche.

Riding the KRAS wave

To put things into broader perspective, however, despite all the positive news in lung cancer, consider the colorectal carcinoma data was less impressive than lung because of more complex, heterogeneous disease.

Meanwhile, Lilly recently announced the discontinuation of their selective G12C inhibitor, LY3499446, due to adverse toxicity, so clearly it is not all going to be plain sailing in this landscape!

Let’s also not forget the G12C mutation is not the only viable target in this context. People with advanced lung cancer can also present with one or more of several co-occurring mutations such as the serine/threonine kinase 11 gene (STK11) and kelch like ECH associated protein 1 gene (KEAP1), for example.

Unfortunately those presenting with both STK11 and KEAP1 mutations – independent of KRAS status – often have a poorer prognosis and there remains an unmet medical need for effective new treatments.

In this fourth postcard in our summer mini-series on the potential of immunometabolism for cancer immunotherapy, we’re taking a look at a novel way to target KRAS mutant lung cancer and, in particular, those with an STK11 and KEAP1 mutation who tend to do poorly on current therapies.

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What do T cells want?

In the third post in our summer mini-series on immunometabolism, we’re continuing our journey by taking a look at glutamine as a target, and in particular, the potential of glutaminase inhibitors.

Cancer cells compete with immune cells for glucose and glutamine in the tumor microenvironment, and if the cancer cell wins then immuno-surveillance and anti-tumour immune response can be diminished. Of interest, glutamine addiction is commonly seen in cultured cancer cells.

This begs a critical question – can we target glutamine therapeutically in patients, and if so, what happens?

In this article we highlight an expert interview with Dr Jeffrey Rathmell, who is Professor of Pathology, Microbiology and Immunology at Vanderbilt, where he directs the Vanderbilt Center for Immunobiology.

Dr Rathmell is at the forefront of research into T cell fuels such as glutamine and has published preclinical work on early compounds in this niche, including Calithera’s glutaminase inhibitor, CB-839, for example.

He kindly spoke to BSB after the AACR20 virtual annual meeting where he chaired a session on Metabolism and the Tumor Microenvironment.

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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.

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