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2014 Featured Talks » Reversing Cancer Stemness and Drug Resistance
David Cheresh, part 1 from MCC Industry Relations on Vimeo.
David Cheresh, part 2 from MCC Industry Relations on Vimeo.
David Cheresh, PhD
Distinguished Professor, Vice Chair for Research and Development, Department of Pathology
Associate Director for Innovation and Industry Alliances, Moores Cancer Center
David Cheresh studies the mechanism of action of signaling networks that regulate tumor growth, stemness, drug resistance and metastasis. He discovered the avb3 integrin is a functional marker of angiogenic blood vessels. His work is basic and translational focusing on new strategies for biologically-based drug development. In particular, he studies how integrins and growth factor receptors promote, cell survival, angiogenesis and tumor invasion. His work has lead to the development of several drugs now in various stages of clinical development. Cheresh’s research in this area has been widely cited with seven of his peer-reviewed publications being cited >1000 times. David Cheresh was the scientific founder of TargeGen a San Diego based Biotechnology Company which developed a number of small molecules based in part on discoveries made in the Cheresh laboratory. TargeGen's JAK2 inhibitor has shown clinical activity in patients with myeloproliferative disease. Most recently, Cheresh and his colleagues have developed a novel scaffold based chemistry approach to stabilize kinases in their inactive state. These studies have lead to the discovery of a first in class Raf inhibitor that has distinct advantages relative to ATP mimetics of RAF. Cheresh and his colleagues at UCSD have founded a new startup company (Amitech Therapeutic Solutions, ATS) which focuses on the discovery of allosteric inhibitors of kinases such as those targeting Raf and other important molecules/pathways relevant to cancer and inflammatory disease.
Cheresh and colleagues are now focused on tumor cells that display stem like properties, and are highly aggressive often showing drug resistance. It was found that integrin αvβ3 serves as a marker of breast, lung and pancreatic tumors with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumor xenographs or in clinical specimens from lung cancer patients that had progressed on erlotinib. Mechanistically, αvβ3, in the unligated state, recruits KRAS and RalB to the tumor cell plasma membrane, leading to the activation of TBK-1/NFkB. In fact, αvβ3 and the resulting KRAS/RalB/NFkB pathway are both necessary and sufficient to promote tumor initiation, anchorage-independence, self-renewal, and erlotinib resistance. Pharmacological targeting this pathway reverses both tumor stemness and drug resistance. These findings not only identify ανβ3 as a marker/driver of tumor stemness but they reveal a therapeutic strategy to sensitize such tumors to RTK Inhibition.
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