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Pharmacological targeting of Wnt and Hedgehog pathways in lung cancer / by Alexander M. Busch

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Author	Busch, Alexander M.
Title	Pharmacological targeting of Wnt and Hedgehog pathways in lung cancer / by Alexander M. Busch
Date	2013
Abstract	The Hedgehog (Hh) and Wnt pathways are key biological signaling pathways responsible for embryonic development, cellular proliferation, stem cell maintenance and self-renewal, and adult somatic tissue homeostasis. Because these pathways serve as the nexus of converging growth and proliferation signals, cancers are known to deregulate and/or mutate both the Wnt and Hh pathways as driving mediators of tumorigenicity, metastatic potential, and resistance to chemotherapy. This occurs in lung cancer, the most common cause of cancer death for men and women, and testicular cancer, a potentially curable malignancy that has a therapy-resistane clinical population. This thesis was undertaken to explore Hh- and Wnt- targeted agents as antineoplastic agents to combat specific cancers and to describe new molecular pharmacological mechanisms that inhibit these pathways. High-throughput robotic screening of diverse epithelial cancer cell lines revealed a profile of response to Hh pathway Smoothened (Smo) inhibitors. Comprehensive gene profiling studies identified previously-unrecognized upregulation of Hh regulator Patched 1 (Ptch 1) in the course of all-trans-retinoic acid (RA) induced differentiation independent of Smo activity, as well as deregulation of specific components of the Wnt pathway in lung cancer. In vitro studies confirmed these findings in well-characterized panels of murine and human cancer cell lines. Translational relevance was found in vivo through treatments of a spontaneous murine lung cancer model, syngeneic murine lung tumors, and their xenografts, in addition to analysis of specimens obtained from cancer patients. These studies revealed a distinct profile of growth response for epithelial cancer cell lines to Hh inhibition. A previously-unrecognized mechanism of Hh pathway inhibition through the induction of Ptch 1 by RA was found. In addition, the tankyrases (TNKS) were identified as antineoplastic targets in the Wnt pathway in lung cancer, as they stabilized Wnt pathway components and inhibited ac
Description	xv, 163 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Ethan Dmitrovsky, Sarah J. Freemantle, Michael J. Spinella, James DiRenzo, Yashi Ahmed, David J. Robbins
College	Dartmouth Medical School.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.943

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