Immunosuppressive enzyme IDO1 – an inhibitor target for pancreatic cancer

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 [1]. 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).

IDO1
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 [2]. IDO1 inhibitors are currently in clinical trial in combination with the mesothelin LADD vaccine (see here) in other cancers [3]. 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 [4]. IDO1 inhibitor combination with oncolytic viral vectors such as Imlygic (see here) should also be synergistic.

Refs

  1. Soliman, Hatem, Melanie Mediavilla-Varela, and Scott Antonia. ‘Indoleamine 2,3-Dioxygenase’. Cancer Journal (Sudbury, Mass.) 16, no. 4 (2010). doi:10.1097/PPO.0b013e3181eb3343.
  2. ‘Study of IDO Inhibitor in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer – Full Text View – ClinicalTrials.gov’. Accessed 22 February 2016. https://clinicaltrials.gov/ct2/show/NCT02077881.
  3. ‘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.
  4. Gangadhar, Tara C, Omid Hamid, David C Smith, Todd M Bauer, Jeffrey S Wasser, Jason J Luke, Ani S Balmanoukian, et al. ‘Preliminary Results from a Phase I/II Study of Epacadostat (incb024360) in Combination with Pembrolizumab in Patients with Selected Advanced Cancers’. Journal for ImmunoTherapy of Cancer 3, no. Suppl 2 (2015): O7. doi:10.1186/2051-1426-3-S2-O7.
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