基本信息
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个人简介
Dr. Chauhan received his PhD in India. He joined DFCI in 1991 to pursue research work in the laboratory of Dr. Kenneth C. Anderson, and was promoted to principal associate in 2000. His research focuses on the mechanisms of drug resistance in multiple myeloma. His studies in oncogenomics and cell signaling have defined mechanisms of sensitivity and resistance to both conventional and novel drugs, providing the rationale for combining various therapeutic agents to enhance antiMM activity and overcome drug resistance.
Recent Awards:
Multiple Myeloma Research Foundation Senior Research Scientist Award, 2009-2010。
Apoptotic and Survival Signaling in tumor cells: Therapeutic Implications。
Another major area of research in our laboratory is the ubiquitin-proteasome pathway (UPP). Previous reports have established that UPP modulates intracellular protein degradation. Specifically, the multi-enzyme protease 26S proteasome degrades misfolded or redundant proteins, while blockade of the proteasomal degradation pathways results in the accumulation of unwanted proteins and cell death. Because cancer cells proliferate more than normal cells, the rate of protein translation and degradation is also higher in cancer cells. This discovery led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory MM. However, prolonged treatment with bortezomib is associated with toxicity and the development of drug resistance.
Our recent study shows that the novel proteasome inhibitor NPI-0052 induces apoptosis even in bortezomib-resistant MM cells. NPI-0052 is distinct from bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, toxicity profile against normal cells, and bioactivity. In animal model studies, NPI-0052 cured 57% of treated mice, was well tolerated, and prolonged survival. Combining NPI-0052 and bortezomib induces synergistic apoptosis in MM cells; therefore, our study provides rationale for clinical protocols evaluating NPI-0052, alone or in combination with bortezomib.
Select Publications:
Chauhan D, Li G, Podar K, Hideshima T, Mitsiades C, Schlossman R, Munshi N, Richardson P, Cotter FE, Anderson KC. Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells. Blood 2004;104:2458-66.
Chauhan D, Catley L, Li G, Podar K, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao T, Neuteboom S, Richardson P, Palladino M, Anderson KC. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 2005;8:407-19.
Chauhan D, Li G, Podar K, Hideshima T, Neri P, He D, Mitsiades N, Richardson P, Chang Y, Schindler J, Carver B, Anderson KC. A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res 2005;65:8350-8.
Chauhan D, Li G, Sattler M, Podar K, Mitsiades C, Mitsiades N, Munshi N, Hideshima T, Anderson KC. Superoxide-dependent and -independent mitochondrial signaling during apoptosis in multiple myeloma cells. Oncogene 2003;22:6296-300.
Chauhan D, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003;63:6174-7.
Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Munshi N, Kharbanda S, Anderson KC. JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J Biol Chem 2003;278:17593-6.
Chauhan D, Singh AV, Ciccarelli B, Richardson PG, Palladino MA & Anderson KC. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 2010; 115, 834-845.
Chauhan, D., Singh, A., Brahmandam, M., Podar, K., Hideshima, T., Richardson, P., Munshi, N., Palladino, M.A., and Anderson, K.C. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008;111:1654-1664.
Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, Raje N, Jaye DL, Kumar SK, Richardson P, Munshi N, and Anderson KC: Functional Interaction of Plasmacytoid Dendritic Cells with Multiple Myeloma Cells: A Therapeutic Target. Cancer Cell 2009; 16:309-323.
研究兴趣
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