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 | 
Oct 27, 2011
 |  BC Innovations  |  Cover Story

Much ado about TDO

While companies are pursuing indolamine 2,3-dioxygenase inhibitors for cancer, German academics have identified an alternate tryptophan metabolism pathway mediated by an enzyme called tryptophan 2,3-dioxygenase that tumors exploit to grow and evade the immune system.1 The study suggests the need to monitor tumors for activation in both pathways.

Indolamine 2,3-dioxygenase (IDO)-mediated tryptophan catabolism generates kynurenine, a metabolite that inhibits the antitumor immune response.2

At least two companies have inhibitors of IDO in Phase I testing for solid tumors. NewLink Genetics Corp. is developing 1-methyl-d-tryptophan, a selective inhibitor of IDO. Incyte Corp. is developing INCB24360.

Incyte previously ran high throughput screening and in vitro assays to identify compounds that inhibited IDO with little or no activity against tryptophan 2,3-dioxygenase (TDO2; TDO) to help decrease potential side effects.3-5 The company's desire to avoid TDO activity made sense, as the enzyme had not been previously linked to cancer and is expressed in healthy liver cells and neurons.

Meanwhile, Michael Platten began to suspect a role for TDO in cancer following his German team's studies on the immunoregulatory role of tryptophan metabolism in human diseases.

"Our past work in animal models has suggested that tryptophan metabolism suppresses the autoimmune response and could be significant for treating diseases like multiple sclerosis," said Platten, who is a professor in the Department of Neurooncology at Heidelberg University Hospital and head of the Experimental Neuroimmunology Unit at...

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