Hedgehog Pathway Activity and Targeting in KCOT

University Of Alabama At Birmingham, Birmingham AL

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Keratocystic odontogenic tumors (KCOT) patients are treated surgically with more conservative surgical approaches leading to higher rates of recurrence. Research to reduce recurrence of KCOT is very limited and only focused on surgical technique, primarily owing to the severe lack of cellular models for preclinical studies fr the identification and testing of therapeutic options. The aims of this project are designed to utilize novel cell models of KCOT to explore hedgehog (HH) pathway signaling, the role of HH receptor polymorphisms in KCOT, and the potential to use HH as a therapeutic target for KCOT and other craniofacial tumors. KCOT can be non-syndromic or syndromic in association with Nevoid basal cell carcinoma syndrome, an autosomal dominant genetic disease characterized by a mutation in the inhibitory receptors of the HH pathway, Patched 1/2 (PTCH1/2). When the receptor in mutated, it is believed to be unable to inhibit Smo and cause ligand-independent HH signaling, cell proliferation, and tumorigenecity. The K99 phase proposes to (1) to determine if the PTCH1 receptor polymorphism Pro1315Leu, identified in 75% of our KCOTs, has a functional significance in HH pathway activity by accessing cell proliferation, HH transcriptional activity, and tumorigenic and invasive properties in cells expressing PTCH with and without the polymorphisms; and (2) examine the biological effects and therapeutic efficacy of HH inhibition on primary KCOT cell populations, using clinically relevant HH inhibitors (GDC-0449 and LDE225, both currently in clinical trials) as well as selectively targeting the Smo protein using siRNA knockdown. During this time the candidate will complete mentored training in molecular biology and courses in clinical translation research and professional development in preparation for the independent R00 phase where it is proposed to develop animal model of KCOT for testing in vivo efficacy of HH inhibitors, starting with xenograft models of KCOTs. Information gleaned from this work may be useful in understanding the role of PTCH1 in fundamental HH signaling in human neoplasias and used in the generation of future clinical trials focusing on preventing KCOT recurrence.