Ph.D. Research Proposal - Targeting the Colorectal Tumor Marker Guanylyl Cyclase C (GCC) to Mediate Subcellular Toxin Delivery
Date: March 19, 2013
Time: 12:15 PM
Location: Bossone Research Enterprise Center, Room: 705
Advisor: Kambiz Pourrezaei, PhD
Colorectal cancer is the second deadliest cancer in the US due to mortality from eventual metastatic outgrowth. The National Cancer Institute estimates that approximately 150,000 men and women were diagnosed with colorectal cancer in 2012 alone, while greater than a third of that number will have died from the disease during the same period. While primary tumors can be effectively treated with surgical resection, only 39% of cases are diagnosed prior to the cancer spreading from the primary site, providing the early diagnosed patients a 69% rate of survival over 5 years. The 5-year survival rate for cases with distant metastasis upon diagnosis drops precipitously to 11.3%, despite current therapeutic intervention, highlighting the unmet need for a more efficacious approach.
Targeted cancer therapy has been an emerging field with much promise but few standout successes because the targets are broadly expressed in both healthy and diseased tissue. The transmembrane protein guanylyl cyclase C (GCC), however, provides the specificity for targeted therapy: it is selectively expressed in intestinal epithelium; absent in healthy extra-intestinal tissues; and expressed through the metastatic event. Furthermore, preliminary data demonstrates that internalized GCC localizes in the acidic, reductive environment of the lysosomal compartment. Ricin, a two-part toxin derived from the castor oil plant Ricinus communis which depurinates the ribosome to halt protein synthesis, also travels through the endosomal-lysosomal pathway causing cytotoxicity. Therefore the aim of this study is to leverage these shared characteristics, and provide the proof of concept for GCC-dependent intracellular payload delivery. These studies will include construction of a GCC targeting moiety linked via disulfide bond to the catalytic A chain of ricin toxin (RTA). Targeting GCC provides cellular specificity, while disulfide linkage endows subcellular activity, as endosomal-lysosomal reduction is required for conjugate cleavage and the cytoplasmic release of RTA to act on the ribosome and inhibit protein synthesis.
The Bossone Research Enterprise Center is located at the corner of 32nd and Market Streets.