Nelfinavir (Viracept) as a pancreatic cancer therapeutic

 

Nelfinavir trade name Viracept (Pfizer) was approved by the FDA in 1997 as a human immunodeficiency virus (HIV) therapeutic. It’s anti-HIV mechanism of action is based upon inhibiting the virus’ aspartate protease [1]. HIV protease inhibitors including Nelfinavir have been demonstrated to inhibit the Akt pathway of cancer cell lines including pancreatic and sensitise mouse tumour xenografts to radiation therapy [2]. Nelfinavir inhibits in vivo tumor model growth and upregulates markers of ER stress, autophagy and apoptosis [3]. Cell death mediated by autophagy and ER stress (immunogenic cell death) is associated with immune responses against cancer [4].

 

Nelfinavir has entered a number of clinical trials for pancreatic cancer with, so far, promising but statistically low power results [5].

 

clinical-trials.png

 

Clinical Trials .gov links

NCT01068327, NCT01959672, NCT01086332, NCT02024009

 

EU Clinical Trials Register links

2008-006302-42

 

Refs

  1. Koltai T. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity. Version 2. F1000Res. 2015 Jan 12 [revised 2015 Jan 1];4:9. Doi: 10.12688/f1000research.5827.2. Review. PubMed PMID: 26097685.
  2. Gupta AK, Cerniglia GJ, Mick R, McKenna WG, Muschel RJ. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005 Sep 15;65(18):8256-65. PubMed PMID: 16166302.
  3. Gills JJ, Lopiccolo J, Dennis PA. Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 2008 Jan;4(1):107-9.  PubMed PMID: 18000394.
  4. Hou W, Zhang Q, Yan Z, Chen R, Zeh Iii HJ, Kang R, Lotze MT, Tang D. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 2013 Dec 12;4:e966. doi: 10.1038/cddis.2013.493. Review. PubMed PMID: 24336086.
  5. Wilson JM, Fokas E, Dutton SJ, Patel N, Hawkins MA, Eccles C, Chu KY, Durrant  L, Abraham AG, Partridge M, Woodward M, O’Neill E, Maughan T, McKenna WG, Mukherjee S, Brunner TB. ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer. Radiother Oncol. 2016 May;119(2):306-11. Doi: 10.1016/j.radonc.2016.03.021. PubMed PMID: 27117177.
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