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Insulin receptor substrate 1 (IRS1); phosphatidylinositol 3-kinase catalytic subunit a-polypeptide (PIK3CA; p110a); phosphoinositide 3-kinase-a (PI3Ka)

Cell culture and mouse studies suggest disrupting the interaction between IRS1 and mutant p110a could help treat cancer. p110a is the catalytic subunit of PI3Ka. In a human colorectal cancer cell line, E545K mutant p110a interacted with IRS1, whereas wild-type p110a did not. In a mouse xenograft model for human colorectal cancer that expressed the E545K mutant p110a, injection of a stapled peptide that disrupts the IRS1-mutant p110a interaction decreased tumor growth compared with injection of a control peptide or vehicle. Next steps include developing peptidomimetics with improved pharmacokinetics and potency and developing an assay to screen for small molecules that could disrupt the IRS1-mutant p110a interaction.
Gene Signal International S.A.'s aganirsen, an antisense oligonucleotide that targets IRS1 mRNA, is in preclinical development to treat bladder cancer.
At least four companies have PI3Ka-specific inhibitors in Phase I or Phase II testing for cancer.

SciBX 6(19); doi:10.1038/scibx.2013.464
Published online May 16, 2013

Patent application filed; available for licensing from the Case Western Reserve University Technology Transfer Office

Hao, Y. et al. Cancer Cell; published online May 13, 2013;
Contact: Zhenghe Wang,
Case Western Reserve University, Cleveland, Ohio
Contact: Weiping Zheng,
Jiangsu University School of Pharmacy, Zhenjiang, China