Abstract 1779: CYP2W1 as a novel therapeutic target in colon cancer

Abstract

Abstract Colorectal cancer is the third most frequently diagnosed malignancy in both men and women and a leading cause of cancer-related deaths in the Western world. Advances in neoadjuvant/adjuvant chemotherapy (including 5-fluorouracil, irinotecan, and oxaliplatin) as well as radiation therapy have improved the clinical outcome, however, the overall impact of these amended treatment regiments has been relatively modest, leaving metastasised or recurrent disease largely incurable by conventional approaches and requiring the development of better therapeutics. Targeted chemotherapy aimed towards more effective advanced colon cancer treatment could be achieved by the use of agents that are systemically inactive but selectively converted to potent cytotoxins locoregionally. We have shown cytochrome P450 2W1 (CYP2W1) to be overexpressed in colorectal cancer, and recently shown this enzyme to be a druggable target in a proof-of-concept study using CYP2W1-transfected colon cancer cells [selected references below]. At this meeting we will present an update on our progress on re-engineering the duocarmycin family of compounds for CYP2W1-targeting. New findings reveal that subtle changes in the duocarmycin pharmacophore can lead to dramatic changes (> 100-fold) in the anti-cancer activity. This drop in anticancer activity of small molecules such as ICT2726 means these can be used as biomarker to detect CYP2W1 functional activity, which can be used alongside immunological methods to characterise malignant colorectal tissue. Similarly, interrogation of R and S-enantiomers of duocarmycin bioprecursors also reveal significant differential anticancer activity in vitro. Studies are currently underway to understand if this differential activity is also observed in CYP2W1-expressing colon cancer xenografts and the results will be presented at the AACR meeting. Our findings reveal the opportunities in targeting CYP2W1 as a novel therapeutic approach in colon cancer chemotherapy. [1] Travica S. et al. Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins. Clin. Cancer Res. 2013, 19(11), 2952-61. [2] Sheldrake et al. Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity. J Med Chem. 2013, 56 (15), 6273-7. [3] Stenstedt, K. et al. Cytochrome P450 2W1 polymorphism: functional aspects and relation to risk for colorectal cancer. Pharmacogenomics. 2013, 14(13), 1615-1622. [4] Sutherland M. et al. Anti-tumor Activity of a Duocarmycin Analogue Rationalised to be Metabolically Activated By Cytochrome P450 1A1 in Human Bladder Cancer. Mol Cancer Ther. 2013, 12 (1), 27-37. [5] Pors K. et al. Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity. Chem. Commun., 2011, 47, 12062-4. [6] Stenstedt K et al. The expression of CYP2W1: a prognostic marker in colon cancer. Anticancer Res. 2012, 32, 3869-74. Citation Format: Klaus Pors, Paul M. Loadman, Sandra Travica, Steven D. Shnyder, Mark Sutherland, Helen Sheldrake, Mark Searcey, Inger Johansson, Souren Mkrtchian, Magnus Ingelman-Sundberg, Laurence H. Patterson. CYP2W1 as a novel therapeutic target in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1779. doi:10.1158/1538-7445.AM2014-1779