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Vrushank  Davé

Vrushank Davé

Vrushank Davé
Assistant Professor


Phone: 813/974-0930


M.Sc. Biotechnology, MS University, Baroda, India, 1987
Ph.D., Jawaharlal Nehru University, 1994
Postdoctoral Fellow, University of Cincinnati College of Medicine, 1994-96
Research Associate, Molecular Development Biology, University of Cincinnati
Children's Research Foundation, 1996-200
Research Scientist & Instructor, University of Cincinnati College of Medicine &
Children's Hospital Research Foundation 2001-06
Research Assistant Professor, University of Cincinnati College of Medicine &
Children's Hospital Research Foundation, 2006-10


Our lab focuses on elucidating feed-back and cross-regulatory signaling loops that are generated after treatments with inhibitors of PI3k/mTOR, K-RAS/pan-RAF and AMPK pathways. It is generally accepted that these robust alternative loops confer chemo- and radio-resistance and contribute to poor prognosis in patients. In addition, we are also identifying unique transcriptional networks associated with EMT and cancer stem cells that can be exploited to develop targeted drugs. KRAS inhibitors are hard to develop, and rapamycin-analogues (rapalogs) targeting mTOR are toxic and induce compensatory activation of AKT, causing resistance to apoptosis. Hence, development of effective inhibitors of KRAS, AMPK and PI3K/mTOR pathways is imperative. Second, clinical studies implicate that tumors with aberrant KRAS and PI3K/mTOR signaling are associated with loss of epithelial polarity, epithelial-mesenchymal transition (EMT), metastasis, poor differentiation, and chemo/radio-resistance. Molecular details of EMT mediated by KRAS, PI3K/mTOR and AMPL/TSC/mTOR pathway is lacking. While PTEN and LKB-1 are implicated in maintenance of cell-polarity thereby opposing EMT signals, knowledge of mechanisms and functional roles of their involvement in polarity complexes remains limited. This important area has been an area of intense focus in our lab that can lead to development of drugs targeting EMT-mediators.

To this end, our lab has designed molecularly defined mouse models of lung cancer associated with hyper-activated PI3K/mTOR, AMPK/TSC/mTOR and KRAS-pathway that demonstrate EMT. We are utilizing these models for pre-clinical trials, and to ascertain the mechanisms of selective inhibitors of RAS, LKB-1 and mTOR pathways in vivo. Components of the mTOR pathway are attractive therapeutic targets because mTOR serves as a hub for many growth stimuli that promote tumor initiation, maintenance, apoptotic resistance and epithelial-mesenchymal transition (EMT), contributing to cancer metastasis. The PI3K/PTEN/AKT pathway and LKB-1/AMPK/TSC pathway control mTOR activity. We are testing the hypothesis that presence of oncogenic KRAS or mTOR hyper-activation due to loss of PTEN or LKb-1 in the lung in vivo causes aggressive lung tumors associated with EMT, and that combination therapy with novel selective inhibitors of AMPK, AKT, PI3K, mTOR and pan-RAF will reduce tumor growth, cause apoptosis and inhibit EMT. We have generated inducible, lung epithelial specific conditional deletion of PTEN and LKB-1and hyper-activated the PI3K/mTOR pathway in an activated K-RAS status–a combinatorial aberration that underlies human lung cancers. We are currently assessing the efficacy of combination therapy with multiple inhibitors of AKT, AMPK, PI3K, mTOR and pan-RAF in vivo.

In the future, this mouse models will provide an ideal entrée to scrutinize molecular changes in the PI3K/mTOR, LKB1/mTOR and canonical RAS pathways after treatment, specifically in identifying feed-back and cross-regulatory loops that are influenced by inhibitor treatment likely conferring chemo-resistance. These studies in mouse models will validate safer and effective mTOR targeted therapies that should aid in developing clinical trials in lung cancer patients.

The second project in my lab is focused on defining molecular mechanisms of pulmonary epithelial-mesenchymal transition (EMT) and epithelial cell polarity in lung injury and fibrosis. We are particularly interested in the role of pVHL & HIFs in genetic/epigenetic regulation of EMT.

Other ongoing projects include epigenetic signatures that characterize cancer initiating stem cells (CISCs) and structure-function studies on transcription factor-DNA & protein-protein interactions involving EMT-mediators.