Protein kinase A as target for novel integrated strategies of cancer therapy.

We have studied the role of protein kinase A (PKA) in neoplastic transformation, apoptosis, and angiogenesis and its relationship with other signaling molecules, as a basis for developing novel therapeutic strategies. We demonstrated the involvement of PKA type I (PKA-I) in the transduction of mitogenic signals from different sources and demonstrated functional and structural interactions between PKA-I and the activated epidermal growth factor receptor (EGFR). We contributed to the identification and development of several selective inhibitors of PKA-I, such as 8-Cl-cAMP and a hybrid DNA/RNA antisense oligonucleotide of a novel class (AS-PKA-I) and of EGFR, including mAbC225 and ZD1839 (Iressa). All these agents have been investigated in cancer patients. We demonstrated the therapeutic potential of the combined blockade of PKA-I and EGFR, reporting a synergistic antitumor effect when their inhibitors are used in combination. We have also shown that PKA-I and EGFR inhibitors are able to cooperate with selected class of cytotoxic drugs and with ionizing radiation, causing a synergistic inhibition of tumor growth in vitro and in vivo, accompanied by inhibition of expression of growth and angiogenic factors and by suppression of vessel production. Moreover, PKA-I is implicated in a bcl-2-dependent apoptotic pathway, and we have recently reported a cooperative antitumor and proapoptotic effect of AS-PKA-I in combination with an AS-bcl-2. Finally, we have shown that AS-PKA-I also has antitumor and antiangiogenic effects following oral administration and that they can be greatly enhanced in combination with oral ZD1839 and oral taxanes.