The overall goal of this proposal is to discover novel anti-cancer drugs and anti-angiogenic drugs based on designing small synthetic molecules that bind polypeptide growth factors and disrupt receptor tyrosine kinases (RTK) oncogenic signaling. Growth factors (GF) such as EGF, PDGF and VEGF and their receptors play a central role in oncogenesis and angiogenesis. The majority of human cancers overexpress GF and/or RTKs, and this has been associated with metastasis, poor prognosis, resistance to chemotherapy and shortened patient survival time. Furthermore, human cancers secrete pro-angiogenic GF such as VEGF and PDGF which promote new blood vessel formation, a required step for substantial tumor growth. Further validation for targeting GF/RTK signaling to discover novel anti-cancer drugs comes from studies that demonstrated that anti-GF and anti-RTK antibodies, dominant negative forms of GF and tyrosine kinase inhibitors of RTKs lead to inhibition of human tumor growth and angiogenesis in animal models. The hypothesis upon which this project is based is that synthetic molecules that bind PDGF, EGF and VEGF will block their biological function, will disrupt RTK signaling and will block oncogenesis and angiogenesis. To test this hypothesis, the following specific aims are proposed: (1) to design libraries of protein surface binding compounds and to evaluate their ability to disrupt PDGF, EGF and VEGF activation of their respective RTKs by using a whole cell high throughput receptor tyrosine phosphorylation assay. (2) To determine the ability of the compounds, identified by the structure activity relationship studies of specific aims #1, to bind their respective GF, to inhibit binding of the GF to their RTK, to suppress RTK-dependent signaling, DNA synthesis, cell cycle progression, proliferation, malignant transformation and to induce apoptosis. To establish the selectivity of the GFBs by using human cancer cells that are known to be dependent on specific GFs and/or their RTKs for malignant transformation. NIH 3T3 cells that were engineered to overexpress specific RTKs such as EGFR, PDGFR, and Flk-1 (VEGFR) as well as those transformed by other oncogenes such as Ras, Src and ErbB2 will also be used to establish selectivity. (3) To determine the anti-angiogenic potential of GFBs by in vitro and in vivo assays such as capillary network formation, endothelial cell proliferation and migration and rat artery and cornea angiogenesis assays. (4) To evaluate the ability of growth factor binding molecules that selectively disrupt RTK oncogenic signaling, to inhibit tumor growth and angiogenesis in animal models using murine and human tumors where GF/RTK signaling is aberrantly activated. To determine toxicity in animals of GFB leads. The studies proposed will lead to the discovery of GF binding synthetic molecules with anti-oncogenic and anti-angiogenic activities, and will ultimately broaden the spectrum of human tumors that can be successfully treated.
| Zhou, Huchen; Wang, De-an; Baldini, Laura et al. (2006) Structure-activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation. Org Biomol Chem 4:2376-86 |
