The Pak family of serine/threonine kinases are important signaling proteins implicated in many cellular functions including cell proliferation, migration and cytoskeletal organization.Pak function is increased in many human cancers and is in general positively correlated with advanced grade and decreased survival. Due to Paks roles in cancer, several small molecule inhibitors are being developed to inhibit the PAKs, and there is interest in investigating their efficacy as treatments for cancer.
Summary of the Invention
Researchers at Fox Chase Cancer Center have developed unique transgenic mice line with transgene of iBox peptide inhibitor of group B p21-activated kinases designed to enable conditional expression of thepeptide inhibitor of Group B Paks (Pak 4, Pak 5, and Pak 6) in any cell, tissue, or organ of interest. In these transgenic mice, iBox is inactive due to the iBox sequence preceded by a stop cassette flanked by LoxP sites that are the binding sites of the recombinase Cre. When crossed with mice carrying a Cre transgene, the resulting Cre/iBox mice express iBox peptide, which leads to inactivation of all group B Pak isoforms. As there are many Cre-recombinase mice available, including drug inducible Cre mouse strains and mice with Cre-recombinase expression limited to particular tissues, it is possible to have tissue-specific expression of the iBox peptide. Thus, the iBox transgenic mouse allows the evaluation of the role of group B Paks in preclinical cancer models.
Applications of the Invention
In the iBox peptide inhibitor of group B p21-activated kinases mouse model the PAKs proteins are still expressed, but the kinase activity is inhibited. This feature is superior to previous knockout models as it allows Paks to be conditionally inhibited in any elected tissue, and it is thus a more reliable testing system for small molecule inhibitors. The iBox peptide inhibitor of group B p21-activated kinasesmouse model can be further used to identify novel functions of group B Paks during embryodevelopment as well as to differentiate group B PAKs role in various tissues and different cancer models.
Patent Status: Published application# US20180055020A1
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Inna Khartchenko, MSc, MBA
Director, Technology Transfer
E-mail: [email protected]