Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy.

We have studied the role of protein kinase A (PKA) and its type I isoform (PKAI) in the transduction of mitogenic signaling, apoptosis, and angiogenesis. We have contributed to the development of selective inhibitors of PKAI, including a hybrid DNA/RNA mixed backbone oligonucleotide (AS-PKAI). We, and others, have demonstrated that AS-PKAI has a cooperative antitumor effect with a selected class of cytotoxic drugs and with radiotherapy in vitro and in vivo and that these effects can also be obtained following oral adinistration. Previously, we developed a series of therapeutic models based on the pleiotropic role played by PKAI in cell proliferation, apoptosis, and angiogenesis. On the basis of our former demonstration of functional and structural interactions of PKAI and the activated epidermal growth factor receptor (EGFR), we have shown that the combined blockade of both signaling molecules by AS-PKAI and either the monoclonal antibody C225 (erbitux) or the small molecule ZD1839 (gefitinib), results in a marked cooperative antitumor effect in a variety of human tumor models. A further cooperative antitumor effect can be obtained when AS-PKAI is used in combination with both EGFR inhibitors and either cytotoxic drugs or radiotherapy. The antitumor activity is associated with inhibition of growth factors and angiogenic factors production and to induction of apoptosis. In light of the recently demonstrated role of PKAI on the bcl-2-dependent apoptotic pathway, we have recently shown a synergistic antitumor, antiangiogenic, and proapoptotic effect of AS-PKAI in combination with antisense bcl-2 (oblimersen) or with a bispecific bcl-2/bcl-xL second generation antisense. A connection between COX-2, EGFR and PKAI was established, and we demonstrated that the combination of AS-PKAI with gefitinib and a COX-2 inhibitor, all adminstered orally, can result in a potent antitumor and antiangiogenic activity. These studies support the development of AS-PKAI as a novel anticancer agent and suggest its potentially relevant role when integrated with conventional treatments and/or other signaling inhibitors in novel therapeutic strategies.