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Updated: May 2, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for
Jason H Gill1, Paul M Loadman, Steven D Shnyder
1Institute of Cancer Therapeutics, School of Life Sciences, University of Bradford , Bradford, Yorkshire BD7 1DP, United Kingdom.
Abstract:
Development of therapeutic strategies for tumor-selective delivery of therapeutics through exploitation of the proteolytic tumor phenotype has significant scope for improvement of cancer treatment. ICT2588 is a peptide-conjugated prodrug of the vascular disrupting agent (VDA) azademethylcolchicine developed to be selectively hydrolyzed by matrix metalloproteinase-14 (MMP-14) within the tumor. In this report, we extend our previous proof-of-concept studies and demonstrate the therapeutic potential of this agent against models of human colorectal, lung, breast, and prostate cancer. In all tumor types, ICT2588 was superior to azademethylcolchicine and was greater or comparable to standard clinically used agents for the respective tumor type. Prodrug activation in clinical human lung tumor homogenates relative to stability in human plasma and liver was observed, supporting clinical translation potential. A major limiting factor to the clinical value of VDAs is their inherent cardiovascular toxicity. No increase in plasma von Willebrand factor (vWF) levels, an indicator of systemic vascular dysfunction and acute cardiovascular toxicity, was detected with ICT2588, thereby supporting the tumor-selective activation and reduced potential of ICT2588 to cause cardiovascular toxicity. Our findings reinforce the improved therapeutic index and tumor-selective approach offered by ICT2588 and this nanotherapeutic approach.
Insights
ICT2588, a novel prodrug, shows significant promise for cancer treatment by selectively targeting tumors. This vascular disrupting agent (VDA) demonstrates superior efficacy and reduced cardiovascular toxicity compared to existing therapies.
Area of Science:
- Oncology
- Nanomedicine
- Drug Delivery
Background:
- Targeted cancer therapeutics can improve treatment efficacy and reduce side effects.
- Exploiting the tumor's proteolytic phenotype offers a strategy for selective drug delivery.
- Vascular disrupting agents (VDAs) face challenges with systemic toxicity.
Purpose of the Study:
- To evaluate the therapeutic potential of ICT2588, a matrix metalloproteinase-14 (MMP-14) activated prodrug of azademethylcolchicine.
- To assess ICT2588's efficacy across various cancer models, including colorectal, lung, breast, and prostate.
- To investigate ICT2588's safety profile, particularly regarding cardiovascular toxicity.
Main Methods:
- Development of ICT2588, a peptide-conjugated prodrug of azademethylcolchicine.
- In vitro and in vivo testing of ICT2588 in human cancer models.
- Assessment of prodrug activation in tumor homogenates versus stability in plasma and liver.
- Evaluation of cardiovascular toxicity markers, such as plasma von Willebrand factor (vWF).
Main Results:
- ICT2588 demonstrated superior or comparable efficacy to standard treatments in colorectal, lung, breast, and prostate cancer models.
- Selective activation of ICT2588 was observed in tumor homogenates, with stability in plasma and liver.
- ICT2588 did not increase plasma vWF levels, indicating reduced potential for cardiovascular toxicity.
Conclusions:
- ICT2588 exhibits significant therapeutic potential as a tumor-selective VDA.
- The prodrug approach enhances efficacy and mitigates the cardiovascular toxicity associated with VDAs.
- ICT2588 represents a promising nanotherapeutic strategy with an improved therapeutic index for cancer treatment.
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