Discovery of immunotherapeutic biologics against the RAS-driven extracellular proteome

University Of California, San Francisco, San Francisco CA

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Abstract

? DESCRIPTION (provided by applicant): The goals of this proposal are to (i) understand how Ras oncogene transformation changes the cell surface proteome and to (ii) generate recombinant antibodies against the extracellular proteome of Ras-driven cancer cells to serve as diagnostic biomarkers and potential therapeutic reagents. Ras is the most common oncogene and is mutated in over 30% of cancers. Transformation of a normal cell to a malignant state is associated with many changes in the proteome including proteins at the cell surface, as well as changes in cell morphology, and result in aberrant signaling and proliferation. Identification of extracellular proteome changes at the surface of Ras-driven cancer cells will lead to a better understanding of the underlying mechanisms that cause these phenotypic alterations. The changes induced by K-Ras mutants will be investigated using several approaches: (i) determination of the differentially expressed protein targets on the extracellular surface of the Ras-induced cells in comparison to normal cells, (ii) antibody generation against the identified extracellular targets, and (iii) assessment of the therapeutic potential of the antibodies against patient-derived cancer cell lines and tissues. Thus, this proposal will be aimed at creating a general platform for understanding and interrogating oncogenic cellular surfaces with novel membrane proteomics and new immunotherapeutic technologies, which can ultimately be extended to many other cancers. The development of these data sets, technologies, and molecular toolkits will provide new insights into how oncogene transformed cells remodel their surfaces.