Inhibition of Embryonic Genes to Control Colorectal Cancer Metastasis
Annual rept. 1 Sep 2012-31 Aug 2013
GENEVA FOUNDATION LAKEWOOD WA
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Embryonic core transcription factors TFs, primarily the retrogene NanogP8, are the master regulators of cancer stem cells CSC in human colorectal carcinoma CRC. The corollary is that inhibition of NanogP8 will inhibit neoplastic progression of CRC. During the second year of funding we confirmed that NANOG is expressed in the majority of primary human colon carcinomas and that its expression is a significant prognostic factor, especially when associated with expression of the cell adhesion scaffold protein NEDD9. We also elucidated that inhibition of NANOGP8 andor NANOG induces apoptosis through inhibition of MCL-1 as well as proof of the principle that vector-delivered shRNA to NANOGP8 andor NANOG complements inhibition of BCL-2 and BCL-XL as a means to inhibit and kill human colorectal cells. Finally we have demonstrated that intralesional injection of LV-delivered shRNA to NANOGP8 or NANOG transduces tumor cells within xenografts growing in vivo in NODSCID mice as well as the probable need to create a conditionally replicating adenovirus to achieve control of tumor growth in our human colorectal carcinoma preclinical models.
- Anatomy and Physiology
- Medicine and Medical Research