Targeting amino acid metabolism as a therapeutic strategy for pancreatic cancer

 

Amino acid metabolism plays an important role in pancreatic cancer. Targeting of amino acid metabolism in both the tumour and the microenvironment can trigger cancer cell death and relieve immunosuppression which is important for effective immunotherapy.

 

The activity of the enzyme Indoleamine-pyrrole 2,3-dioxygenase (IDO1) in tumours leads to suppression of the immune system [1]. IDO1 catalyzes the degradation of the amino acid L-tryptophan to N-formylkynurenine which impairs CD4+ T cell receptor activation and leads to CD8+ T cell suppression/anergy. Furthermore the activity of IDO1 in tumour cells and TAMs leads to the depletion of L-tryptophan in the microenvironment which in turn triggers a stress response in dendritic cells leading to their deactivation [2]. The activity of dendritic cells is crucial to an immune response against cancer. IDO1 inhibitors are in clinical development (see here).

 

Arginine depletion via the enzyme arginase 1 (ARG1) by tumour associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) inhibits the activity of CD4+ T cells in the tumour microenvironment. ARG1 and 2 inhibitors have been developed for treatment of myocardial reperfusion injury [3], however they could also be applied to pancreatic cancer. These compounds are available from the authors upon request [3].

 

By analysing the publically available pancreatic cancer microarray datasets available in the GEO database the authors of a recent paper identified the amino acid transporter SLC6A14 as consistently upregulated in pancreatic cancer [4]. Using LC3 as a marker of autophagy the authors demonstrated that pharmacologic inhibition of SLC6A14 induced autophagy in BxPC3 pancreatic cancer cells. Furthermore pharmacologic inhibition of SLC6A14 significantly reduced tumour volumes in pancreatic cancer mouse xenograft models. It should be noted that, although significant, shRNA mediated ablation of SLC6A14 was not as effective in the xenograft models which could indicate that the pharmacologic inhibition is broader than expected assuming shRNA ablation of SLC6A14 in mouse xenograft is stable [4].

 

Thus targeting amino acid metabolism in pancreatic cancer can potentially induce cancer cell death and relieve immunosuppression, important aspects for the successful completion of the cancer immunity cycle [5].

 

Refs

 

  1. Adams JL, Smothers J, Srinivasan R, Hoos A. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015 Sep;14(9):603-22. doi: 10.1038/nrd4596. Epub 2015 Jul 31. Review. PubMed PMID: 26228631.
  2. Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer J. 2010 Jul-Aug;16(4):354-9. Doi:10.1097/PPO.0b013e3181eb3343. Review. PubMed PMID: 20693847.
  3. Van Zandt MC, Whitehouse DL, Golebiowski A, Ji MK, Zhang M, Beckett RP, Jagdmann GE, Ryder TR, Sheeler R, Andreoli M, Conway B, Mahboubi K, D’Angelo G, Mitschler A, Cousido-Siah A, Ruiz FX, Howard EI, Podjarny AD, Schroeter H. Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury. J Med Chem. 2013 Mar 28;56(6):2568-80. Doi: 10.1021/jm400014c. PubMed PMID: 23472952.
  4. Coothankandaswamy V, Cao S, Xu Y, Prasad PD, Singh PK, Reynolds CP, Yang S, Ogura J, Ganapathy V, Bhutia YD. Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. Br J Pharmacol. 2016 Oct 17. Doi: 10.1111/bph.13616. PubMed PMID: 27747870.
  5. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012. Review. PubMed PMID: 23890059.
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