Abstract C230: A platform for discovery of novel stem cell modulators and subsequent development of therapeutic targets.

Abstract

Abstract In recent years, there has been a significant and growing interest in specific pathways the human body utilizes in response to damage and their exploitation to induce cell proliferation, differentiation and apoptosis. Epistem's Novel Therapies division has created a discovery platform to allow identification of novel soluble regulators for development of therapeutic targets in oncology, regenerative medicine, and gastrointestinal diseases. Target discovery and identification starts with a known stem cell model and the creation of a disease system in vivo to identify potential stem cell markers. A damage response model of the gastrointestinal tract for stem cell proliferation and apoptosis post-irradiation describes the different phases of the cell recovery process. Post-irradiation, the stem cells, which are located at the base of the intestinal crypt, undergo apoptosis, followed by a rapid phase of regeneration, resulting in an ‘overshoot’ in crypt cell numbers, with homeostasis finally achieved by a ‘shut off’ phase with a decrease in proliferation to basal levels. Using high resolution gene expression profiling of dissected crypts (upper and lower), from small intestine and colon, isolated at various key time points post irradiation, we have identified many candidate novel stem cell regulators involved in damage response. Recombinant proteins have been produced; purified; and characterized, then tested using our proprietary in vitro model assays, looking for efficacy in cell proliferation, apoptosis and differentiation. Proteins that demonstrated robust and reproducible activities were then further evaluated using our industry standard in vivo intestinal stem cell function assays. Pharmocodynamic gene expression profiling was then applied to establish mechanism of action (MOA) linkages between in vitro and in vivo data. Having identified novel protein therapeutics, we are currently focused on pharmacotherapeutics that can modulate the identified pathways. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C230. Citation Format: Shaun Ainsworth, Sarah Hoyle, Aude-Marine Bonavita, Laura Kemp, Jo Read, Alan Murdoch, Lorna Woolford, Gino Miele, Cath Booth. A platform for discovery of novel stem cell modulators and subsequent development of therapeutic targets. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C230.