Bacterial proteins and peptides in cancer therapy

The primary treatment modality for cancer involves surgical resection of the tumor(s) followed by radiation and chemotherapy. In some cases where the cancer, particularly pancreatic cancer, has advanced to a stage that precludes surgery, chemotherapy remains the standard of care. There are two types of drugs that are normally used in chemotherapy, both types usually guided by rational or structure based drug design. The first type are the small molecule drugs that target a single or limited number of key steps in cancer progression pathways, thereby significantly slowing down their growth. An advantage of such drugs is that they can often be administered orally. A second group of drugs comprises human and/or mammalian (but humanized) proteins, often monoclonal antibodies. A typical example of a structureguided small molecule drug that inhibits a tyrosine kinase BCRABL is imatinib (Gleevec, Novartis) that was approved by the US FDA for the treatment of chronic myelogenous leukemia (CML), a cancer of bone marrow white blood cells triggered by the loss of regulation of a proto-oncogene protein tyrosine kinase. As CML cells became increasingly resistant to imatinib, other inhibitors such as dasatinib, nilotinib or bosutinib were developed and were approved by the US FDA for CML therapy. The receptor tyrosine kinases (RTKs) are members of a group of transmembrane proteins with extracellular and intracellular domains. The ligand binding at the extracellular domain allows autophosphorylation of the tyrosine residues at the intracellular domain of such tyrosine kinases as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), etc., leading to downstream signaling and enhancement of proliferation, differentiation, and cellular growth of the cancer cells. Indeed, several inhibitors of the RTKs have been developed and approved by the FDA to treat a number of cancers (Table 1).