Most approaches to cancer therapy have centered around the idea that cytotoxic drugs can be used to eradicate proliferating neoplastic cells. Cytotoxicity is generally thought to evolve from the presence of drug-induced damage to genetic material, and DNA has served admirably as a primary focus for drug development. However, improved understanding of receptor-mediated signal transduction and growth control pathways in the last decade has reshaped the strategy for drug development: the inhibitors and monoclonal antibodies that disrupt signal transduction pathways now provide a useful basis for the rational design of new cancer therapies and may represent a new class of chemotherapeutic agents. Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and pyrimidine nucleotide synthesis. The applicant's recent studies of the lymphoproliferative and autoimmune disease in MRL-lpr/lpr mice have demonstrated that inhibition of protein tyrosine phosphorylation but not interference with pyrimidine nucleotide synthesis by leflunomide represents its in vivo mode of action. This observation opens the possibility that leflunomide might be exploited as a novel antitumor agent to be used for controlling tyrosine kinase dysregulated-tumors. The applicant's preliminary results show that leflunomide is very effective in the control of platelet-derived growth factor-overexpressed C6 glioma implanted in athymic mice. Here he proposes to extend these observations by examining the mechanisms of leflunomide-mediated antitumor activities in several types of tyrosine kinase-dysregulated tumor cell lines in vitro and in vivo. He will also test whether combination therapy of leflunomide with anti-growth factor receptor mAbs will achieve synergistic therapeutic effects. Finally, he will test whether leflunomide can inhibit the kinase activity of vascular endothelial growth factor receptor and control angiogenesis, and to test whether the antitumor activity of leflunomide is mediated by control of angiogenesis in solid tumors. Demonstration that leflunomide can inhibit the proliferation of tumor cells through inhibition of tyrosine kinase activity, rather than cytotoxic mechanisms, would suggest its use as a novel class of differentiation agent for the treatment of tyrosine kinase-driven tumors. In addition, the identification of an agent that has both immunosuppressive as well as anti-tumor potential could be of clinical significance to transplant patients who, under currently available immunosuppression, become susceptible to lymphoproliferative disorders.
