The enzyme IDO1 (Indoleamine-pyrrole 2,3-dioxygenase) catalyzes the degradation of the amino acid L-tryptophan to N-formylkynurenine. The activity of IDO1 in cancer cells leads to suppression of the immune system. Catabolites of N-formylkynurenine are directly toxic to T-cells. Furthermore the activity of IDO1 in tumour cells leads to the depletion of L-tryptophan in the microenvironment. Depletion of L-tryptophan in T-cells and dendritic cells present in the tumour microenvironment leads to the build-up of uncharged tryptophan tRNA which triggers a stress response leading to their deactivation . IDO1 mRNA is highly expressed by 14% of the pancreatic cancer cell lines in the CCLE (figure 1) and is up-regulated in cancer tissue (GEO database).
|Figure 1: Comparison of IDO1 (purple) and for reference CDKN2A (blue) mRNA expression in 44 pancreatic cancer cell lines (data source CCLE). RMA = robust multiarray average (mRNA expression).|
Phase I/II metastatic pancreatic cancer clinical trials for IDO1 inhibitors in combination with chemotherapies such as gemcitabine and others are currently recruiting . IDO1 inhibitors are currently in clinical trial in combination with the mesothelin LADD vaccine (see here) in other cancers . In theory this combination should also be effective for pancreatic cancer. IDO1 inhibitors are also in trials in combination with immune checkpoint inhibitors such as PD-1 . IDO1 inhibitor combination with oncolytic viral vectors such as Imlygic (see here) should also be synergistic.
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- ‘Safety and Efficacy of CRS-207 With Epacadostat in Platinum Resistant Ovarian, Fallopian, or Peritoneal Cancer – Full Text View – ClinicalTrials.gov’. Accessed 22 February 2016. https://clinicaltrials.gov/ct2/show/NCT02575807?term=Epacadostat&rank=1.
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