Project Co-Leader: Haian Fu, PhD Project Co-Leader: James Snyder, PhD Co-Investigators: -Fadlo Khuri, MD -Dennis Liotta, PhD -Rebecca Pentz, PhD -Suresh Ramalingam, MD -Mamoru Shoji, MD

Tumeric or "Indian Saffron" Click for more detail

Long term objectives: treat tumor angiogenesis and tumor growth of HNC cancers. Specific Aims: 1) To measure tissue factor (TF) and VEGF expression of various human HNC cell lines in vitro and in vivo. 2) To test the efficacy of EF24-FFRck-Nlla and paclitaxel-FFRck-Nlla on the growth of HNC cell lines in vitro. 3) To test the efficacy of EF24-FFRck-Nlla on the growth of HNC tumor xenografts in athymic nude mice. 4) To test the efficacy of paclitaxel-FFRck-Nlla on the growth of HNC tumors xenografts in athymic nude mice. Research deslgns:_chemically conjugate PTX and EF24 to the endogenous ligand factor Vila (Nlla) for the receptor TF that is universally expressed on tumor-associated vascular endothelial cells (VECs) and the most tumors, compare the cytotoxicity of the two conjugates in vitro and in vivo human tumor xe nog rafts, demonstrate the efficacy of the EF24-conjugate and EF24 against PTX-resistant tumors, and reduce the PTX neurotoxicity. Rationales: (1) Tumors secrete VEGF to attract VECs. VEGF, in turn, induces TF on the tumor-associated VECs. The natural ligand has high affinity to TF, less chance to develop antibody to drug-conjugate, and less side effects than drug-antibody conjugates. (2) active concentration of PTX is at nM, whereas EF24 is at M. Thus. conjugating PTX will require less carrier and economical. (3) EF24 induces apoptosis via redox-dependent mechanism and possesses multiple targets. EF24 is active against PTX resistant cell lines. (4) The peripheral nerves do not express the receptor for the carrier. Therefore. the PTX-conjugate will not bind to the peripheral nerves to cause neuropathy. The PTX-conjugate will be endocytosed by a ligand-receptor mechanism and will by-pass the p-glycoprotein efflux pump. Relevance: PTX is now effective to most cancers. The drug-conjugate will effectively destroy any tumor-associated VECs and starve the tumors to death. This will occur regardless of drug-resistance of tumor, because VECs are normal cells and least likely to develop resistant mutants. The drug-conjugate will seek out any tumor-associated VECs in the body. even too small to be detected by conventional methods. Thus, it will reduce recurrences. The EF24- and PTX-conjugate will be effective against drug- resistant tumors and the PTX-conjugate will reduce the PTX-induced-neuropathy. In sum, the method will destroy any tumor angiogenesis and inhibit tumor growth

EF24 treated HNCC Click for more details

Structure of EF24 Click for more details