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Description
The WNT signaling pathway is a highly conserved pathway involved in multiple biological processes, including stem cell maintenance and self-renewal and the initiation and progression of many human cancers. Recent comprehensive analyses of human colorectal cancers found that over 90% of cancers harbor mutations in genes associated with WNT signaling. Mutations in WNT signaling components leading to deregulated WNT activities have been observed in cancers of the skin, liver, blood, brain, breast, and ovary and are thought to promote the growth tumors. Therefore, targeting this pathway represents a viable approach in treating cancer. Prior studies established that expression of FRIZZLED7 (FZD7), a WNT receptor encoded by the FZD gene family, is highly restricted, with high expression occurring during embryonic development. FZD7 expression is minimal to absent in many mature tissues but re-emerges in many tumors. This restricted onco-fetal expression profile together with WNT’s critical role in promoting tumorigenesis makes FZD7 an ideal marker to target WNT signaling and thereby disrupting cancer cell growth. We hypothesize that targeting FZD7 represents a viable strategy to target and kill human cancers. Our lab has developed a highly specific antibody to FZD7, which disrupts its functions in human embryonic stem cells (hESCs). Preliminary experiments indicate that this antibody is also effective in disrupting the growth of cancer cells that express high levels of FZD7. Thus, the goal of my project is to develop this antibody for use in a cell-based immunotherapy with natural killer (NK) and T cells. Towards this goal, I have engineered and characterized single chain antibodies (scFv) to FZD7 that will be incorporated into chimeric antigen receptors (CARs). NK and T cells expressing such FZD7-specific CARs will then be able to target and kill FZD7-positive cancers.
