Ajit K Bharti, PhD
Ajit Bharti, PhD Research Assistant Professor of Medicine 650 Albany St Evans Biomed Research Ctr
Boston MA 02118
Research Summery: The focus of my research work is to understand the regulation of topoisomerase I (topoI), particularly in response to its inhibitor camptothecin (CPT). Camptothecins (CPTs) represent one of the most potent classes of anti-cancer agent. Two topoI inhibitors, topotecan and irrinotecan are in clinical use and several others are either in preclinical or clinical phases of development.
However, only 13- 332% patient responds to the drug. It has been demonstrated that topoI is ubiquitinated and degraded in the response to CPT by ubiquitin proteosomal pathway (UPP). To understand this mechanism, we have isolated a topoI-associated protein complex and have defined the topoI degradation by UPP. Based on our understanding of the molecular determinants of UPP mediated topoI degradation in the response to CPT, we have developed an IHC based predictive biomarker and have started a retrospective clinical trial in colon cancer. We have developed and patented our monoclonal antibody and have completed retrospective study with colon cancer tissues from patients treated with CPT to develop the IHC based test to stratify responders vs non-responders. We have initiated the collaborations to set up prospective studies to bring the test to clinic.
Rubin E, Pantazis P, Bharti A,Toppmeyer D,Giovanella B and Kufe D. Identification of mutant human topoisomerase I with intact catalytic activity and resistance to 9 nitro camptothecin. J.of Biol.Chem.1994 269:2433-2439.
Rubin E, Wood V, Bharti A, Trites D, Lynch C, Hurwitz S, Bartel S, Levy S, Toppmeyer D, Rosowsky A, and Kufe D. A phase I and pharmacokinetic study of a new camptothecin derivative,9-amino-camptothecin. Clin.cancer Res 1995;1;269-276.
Bharti A, Olson MOJ, Kufe D, Rubin E. Identification of a nucleolin binding site in human topoisomerase I. J. Biol.Chem.1996:271:1993-1997.
Kharbanda S, Bharti A, Pei D, Wang J, Pandey P, Ren R,Weichselbaum R,Walsh CT,and Kufe D. The stress response to ionizing radiation involves c-Abl dependent phosphorylation of SHPTP1. Proc.Natl.Acad.Sci.USA.1996;93: 6898-6901.
Li XG, Haluska P Jr, Hsiang YH, Bharti A, Kufe DW, Rubin EH. Identification of topoisomerase I mutations affecting both DNA cleavage and interaction with camptothecin. Ann N Y Acad Sci. 1996 Dec 13;803:111-27
Li Xi, Haluska,P Jr, Hsiang,Y ,Bharti,A ,Kufe,D ,Liu L, and Rubin E. Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis. Biochem. Pharm. 1997;53: 1019-1027.
Kharbanda S, Pandey P, Jin S, Inoue S, Bharti A, Yuan Z, Weichselbaum, Weaver D, and Kufe D. Functional interaction between DNA-PK and cAbl in response to DNA damage. Nature,1997;386:732-735.
Bharti A, Kraeft S, Gounder M, Pandey P, Jin S,Yuan Z,Lees-Miller S, Weichselbaum R,Weaver D,Chen L,Kufe D and Kharbanda S. Inactivation of DNA-Dependent protein kinase by protein kinase C δ: Implications for apoptosis. Mol.Cel.Bio.1998;18:6719-6728.
Li Y, Bharti A, Chen D, Gong J acarcinoma associated antigen and β-Catenin. Mol.Cel.Bio. 1998: 18: 7216-7224.
Bharti A , Patrick C. Ma, Maulik G , Singh R, Skarin A T., Khan E, and Salgia R – Haptoglobin α subunit and Hepatocyte Growth Factor can potentially serve as tumor markers in small cell lung cancer. Anticancer Research, 2004;24(2C):1031-8.
Maulik G, Bharti A, Khan E, Broderick R, Kijima T and Salgia R. Modulation of c-Kit/SCF pathway leads to alteration in topoisomerase I activity in small cell lung cancer. J.Environ. Pathol. Toxicol Oncol.2004;23(4):237-51.
Yu D, Khan E, Khaleque A, Laco G, Lee J, Kohlhagen G, Kharbanda S, Cheng Y Pommier Y and Bharti A. Phosphorylation of DNA topoisomerase I by c-Abl tyrosine kinase confers camptothecin sensitivity. J. Biol. Chem.2004; 279(50): 51851-61.
Bharti A, Ren J, Raina D, Chen W, Ahmad R, Kufe D. MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene;2006. Jan5;25(1):20-31.
Bharti A, Ma P, Salgia R. Biomarker discovery in lung cancer–promises and challenges of clinical proteomics. Mass Spectrom Rev. 2007 May-Jun;26(3):451-66.
Shah A, Singh H, Sachdev V, Lee J, Yotsukura S, Salgia R and Bharti A. Differential serum level of specific haptoglobin isoforms in small cell lung cancer. Current Proteomics: 2010 Apr 1;7(1):49-65.
Department of Medicine, Boston University
Medical School, Boston, MA