Agios oncogene discovery casts spotlight on cancer metabolism

A discovery announced by Agios Pharmaceuticals in the journal Nature this week cast a spotlight on cancer metabolism, an emerging field in oncology that has been getting researchers excited and attracting an increasing amount of R&D dollars in the last few years.

The company, which was set up only last year by three leading scientists in the field, published a paper identifying a new oncogene and associated metabolic enzyme, both of which are implicated in the development of some brain cancers. Although it is well known that cancer cell metabolism is different to the metabolism seen in normal cells, this is one of the first reported instances where a metabolic enzyme has been shown to play a role in tumour formation. This discovery would appear to reinforce the pathway that many companies, including Agios, are taking as they try to develop potent and targeted new cancer drugs.

Bad mutations

The gene Agios was working with is IDH1, the mutated form of which has already been linked to cancer; it is exhibited by approximately 70% of gliomas and a significant proportion of acute myeloid leukemias, for example.

Previously the gene was thought to act as a tumour suppressor, with the mutation responsible for shutting down this function. However, Agios discovered that the gene mutation makes the IDH1 enzyme produce the metabolite 2-hydroxyglutarate (2HG). This metabolite has been found in very high concentrations in tumour samples from patients with the IDH1 mutation, and has been linked to the formation and progression of glioma.

Agios, therefore, believes it has established that the mutated IDH1 gene is an oncogene, a gene directly responsible for causing cancer. This certainly makes it a viable target for drug research. Additionally, with 2HG as a potential biomarker, able to predict which patients might benefit from any IDH1 targeted therapy, the potential in Agios' discovery is clear.

Fatal rewiring

The field of cancer metabolism is thought to hold great potential for therapeutic agents. Because the metabolic pathways in cancer cells are essentially rewired to support a tumour’s aggressive proliferation and survival, targeting these pathways represents a different route to attack the disease.

Many of the cancer cell's metabolic pathways are triggered by growth signals from mutant oncogenes, therapies like Avastin and Herceptin work by interfering with this process. However, this has no impact on the metabolic processes within the cells. Agios believes combining these approaches should produce a much broader and more profound impact on cancer.

To this end, Agios is developing a metabolic research platform designed to decipher these pathways, and help select drug targets. It is trying to identify which metabolic enzymes might lend themselves to further research, the optimal time to administer any therapeutic, and combination potential.

The company’s lead programme, which is not IDH1, could potentially be in the clinic in 2010, Duncan Higgons, chief operating officer at Agios, told EP Vantage today. However, the IDH1 programme is being prioritized and could enter the clinic in the next two to three years, he said.

Broad interest

Of course, Agios is not alone in its work in this field. 

Threshold Pharmaceuticals has a phase I/II candidate, TH-302, in trials for advanced soft tissue sarcoma and advanced solid tumours, which works by targeting tumour hypoxia or low oxygen concentrations, a metabolic condition common in cancer cells.

Cornerstone Pharmaceuticals, meanwhile, has developed what it calls an altered energy metabolism directed technology platform, which exploits biochemical alterations in the conversion of glucose to energy seen in many cancer cells. A compound called CPI-613 entered a phase I/II study earlier this year in pancreatic cancer, in combination with gemcitabine.

Big pharma is also interested; GlaxoSmithKline for example has created a dedicated cancer metabolism drug discovery group within its R&D operations.

Mr Higgons said he expects Agios to secure collaborations with oncology players interested in this space in the future. The group, which only employs around 40 people, raised $33m in a Series A funding round in July last year and recently announced the appointment of Dr David Schenkein, Genentech’s former senior vice president of clinical hematology/oncology, as chief executive, an appointment that certainly points to grand ambitions.

The field might still be at an early stage, but considering the potential to create novel targeted therapeutics, it certainly represents a sweet spot for the industry, and Agios should have no trouble attracting interested parties.

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