Synerglstic antltumor effect by novel modified oligonucleotides targeting PKAI combined with cytotoxic drugs or monoclonal antibodies.

Introduction: Protein klnase A type I (PKAI) plays a key role in neoplasbc transformation and conveys mitogenic signals of different growth factors and oncogenes. Moreover, PKAI Is overexpressed in cancer cells with an active TGFo-epidermal growth factor receptor (EGFR) autocrine pathway and shows a structural and functional interaction with EGFR. Inhibition of PKAI, or its regulatory subunit Rio, results in cancer growth inhibition In vitro and In vivo. Methods: A novel class of mixed backbone oligonucleotides (MBOs) targeting PKAI (ASRIo), with Improved phannacokinetic and bioavallability, and a humanized monoclonal antibody which blocks activation of EGFR, MAb C225, have been tested In vitro and In vivo on several human cancer cells. Results: A dose-dependent inhibition of soft agar growth was obtained in all cancer types tested with the AS Rlor MBOs, as compared to mismatched control ollgos. Non-lnhlbltory doses of each MBO resulted In a synergistic growth Inhibition and Increased apoptosis, when combined with taxanes, platinum-derivatives and topo ll-selectlve drugs. When the MBOs administered either I.p. or p.o. were added to paclitaxel, a cooperative effect was also obtained in vivo, causing tumor growth Inhibition and increase of survival In nude mice bearing human cancer xenografts Finally, combined treatment of human breast and renal cancer cells, which overexpress PKAI and EGFR, with the ASRIo MBO and MAb C225, caused a cooperative antitumor effect in vitro and In vivo. Conclusions: Since both the AS Rio MBOs and the MAb C225 are currently studied In clinical trials, the combination between them or with selected cytotoxic drugs may represent a feasible novel therapeutic strategy