Identification of the Her-2 Functional Site: Blockage of Receptor Heterodimerization

PUBLIC ABSTRACT

The aim of the proposed study is to design novel therapeutic strategies for the treatment of carcinomas that overexpress the HER-2 oncogene product. HER-2 is a tyrosine kinase growth factor receptor that is overexpressed in 25%-30% of invasive breast carcinomas and in 70% of ductal carcinomas in situ. Its overexpression in invasive breast, prostate, ovarian, and lung carcinomas correlates with poor prognosis and poor overall survival. It is known that tumors that overexpress HER-2 respond poorly to chemotherapy, making HER-2 a critical target for therapy. We have identified a sequence of the extracellular domain of HER-2 that prevents its autophosphorylation and selectively blocks cell growth. We now would like to build up a "fragment" based on the receptor sequence and develop this agent into a therapeutic drug. The best hits will be studied for their effects on the HER-2-overexpressing breast cancer cells. The best candidate drugs from these studies will then be modified for stabilization, and preclinical trials will be designed for future studies. We anticipate that the specific targeted therapy will be used alone or in combination with lower doses of the chemotherapeutic drugs that are currently used in the clinic. We hope that this strategy will both increase the efficacy of a chemotherapeutic regimen as well as decrease the systemic cytotoxicity to prevent or delay drug resistance, a frequent consequence of HER-2 overexpression.