DBT Ramalingaswami Fellow,
Department of Life Sciences,
School of Natural Sciences
Email Contact: firstname.lastname@example.org
Ph.D. in Molecular Biology, University of Missouri-Columbia, USA, Advisor: Dr. R. Michael Roberts.
M.Sc. in Biochemistry and Molecular Biology, University of Calcutta, India
B.Sc. in Chemistry, University of Calcutta, India
Research Instructor of Cancer Biology, Vanderbilt Ingram Cancer Center, USA
Postdoctoral Research Fellow of Hematology and Oncology, Vanderbilt University Medical Center, USA, Advisor: Dr. Carlos L. Arteaga.
Postdoctoral Research Fellow of Reproductive and Developmental Biology, Vanderbilt University Medical Center, USA, Advisor: Dr. Sudhansu K. Dey.
In recent decades, despite of the complex biological nature of cancer as a collection of diseases, significant achievements have been made in anti-cancer therapeutics. However, development of drug resistance and relapse remain major impediments in clinical oncology that directly contribute to patient mortality. Drug resistance can occur prior to as well as after the exposure to the drug. Understanding the mechanisms that enable cancer cells to adapt to and eventually overcome therapy can help circumvent resistance, improve treatment and enhance survival of patients.
We are involved in identifying the mechanisms of drug resistance in breast cancer, the major cancer type found in women, worldwide. Our specific interest lies in various oncogene-directed signaling pathways involved in breast tumorigenesis and disease progression. Our ultimate aim is to increase patient life expectancy by improvising effective therapeutic combinations with drugs that are either in clinic or under clinical trials.
i) Oncogenic PI3K signaling and drug resistance in breast cancer: One of our major projects focuses on the effect of the phosphatidylinositol 3-kinase (PI3K), a signaling pathway frequently mutated in breast cancer, on the cancer stem cell component and anti-cancer drug resistance. We aim to show that inhibition of this particular signaling pathway can eradicate cancer stem cells, the seed of breast tumors, and thus can effectively block disease recurrence in patients.
The Human epidermal growth factor receptor 2 (HER2)-oncogene positive breast cancer represents one of the most aggressive subtypes. Despite of the availability of numerous anti-HER2 agents, patients often have low overall survival rate. This is due to the development of anti-HER2 drug resistance, which largely is conferred by a hyperactivated PI3K signaling pathway. Thus direct inhibition of PI3K signaling has been thought to be effective in treating HER2 positive breast cancer cells. However, PI3K inhibition alone has shown limited anti-tumor effect. We are interested in deciphering the role of the transcription factor Forkhead box 3 (FoxO3) in conferring resistance against PI3K pathway inhibitors. FoxO3 is located downstream of the PI3K signaling pathway and despite being a bona fide tumor suppressor, it helps in adapting the tumor cells to PI3K inhibitor by activating several pro-survival genes. Our goal is to identify the whole range of FoxO3 target genes that are modulated in response to PI3K pathway inhibition in HER2 positive tumor cells. This will ultimately broaden the treatment choices for HER2 positive breast cancer patients.
We are also interested in identifying the role of FoxO3 in triggering autophagic response in PI3K inhibitor treated cells. Autophagy, an evolutionary conserved pathway, although, known to be part of the programmed cell death program in normal cells, often utilized by cancer cells as pro-survival mechanism in response to drug treatment. In fact, many clinical trials are underway with combination of different anticancer agents and autophagy inhibitor chloroquine.
ii) Survivin as a Therapeutic target in breast cancer: Another major focus is on the anti-apoptotic molecule survivin, one of the most well-known cancer-specific molecules with a wide range of cellular functions required for tumor cells to survive and metastasize. Multiple drugs targeting survivin are being actively pursued in clinical trials against a variety of solid and hematological cancers. Because of its tumor cell specificity and nodal function, one of our aims is to test whether blocking of this molecule can effectively inhibit all sub-classes of breast cancer. Since survivin also plays important roles in anti-cancer drug resistance and stem cell maintenance, another goal is to overcome resistance against conventional therapies in breast cancer by combining with an anti-survivin molecule. We are also engaged in identifying predictive biomarkers of Sepantronium Bromide, a survivin suppressant, currently undergoing clinical trials in breast cancer, for preselection of patient population likely responsive to the anti-survivin therapy. We are planning to exploit Sepantronium bromide-induced autophagy, senescence and polyploidy in eradicating drug resistant cells.
iii) Metabolic reprograming and drug resistance in HER2 positive breast cancer: Metastasis or spreading of cancer cells to distant organs from the tissue of origin is the cause of about 90% cancer-related deaths. Although, within the past decades or so, our knowledge on the biological processes dictating metastasis has expanded significantly, we still are far from controlling this process. It is known that disseminated primary tumor cells undergo extensive metabolic reprogramming in order survive through the blood circulation, colonize to a distant organ and metastasize. We are interested in several aspects of this interesting phenomena such as identifying the true nature of metabolic reprograming that takes place in HER2 positive breast cancer cell during epithelial mesenchymal transition, a process prerequisite for cancer cells to break through the tissue boundary and spread over the circulation. We also would like to know whether metabolic reprogramming is a common feature of anti-HER2 drug resistant cells and if we can overcome development of resistance by pharmacologically hindering this process.
- Surendran, S.; Wani, T. H.; Chaturvedi, J.; Chakrabarty, A.*; Chowdhury, G.*. The survivin supressant Sepantronium Bromide (YM155) causes extensive tumor specific oxidative DNA damage following an atypical cyclic mechanism. * Corresponding author.
- Kandasamy, Ganeshlenin; Surendran, Sreeraj; Chakrabarty, Anindita; Kale, S.N. and Maity, Dipak. Facile synthesis of novel hydrophilic and carboxyl-amine functionalized superparamagnetic iron oxide nanoparticles for biomedical applications.
RSC Advance. Accepted.
- Rexer, B. N.; Ghosh, R.; Narasanna, A.; Estrada, M. V.; Chakrabarty, A.; Song, Y.; Engelman, J. A. and Arteaga C. L. Human breast cancer cells harboring a gatekeeper T768M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2.Clinical Cancer Research
2013, 19(19), 5390-5401.
- Chakrabarty, A.; Bhola, N.; Rinehart, C.; Ghosh, R.; Kuba, M. G.; Dave, B.; Chang, J. C. and Arteaga, C. L. Trastuzumab-resistant cells continue to rely on a HER2-PI3K-Survivin axis in a F o xO- d ep en d en t ma n n e r and a r e sensitive to PI3K inhibitors.
Cancer Research 2013, 73(3), 1190-1200.
- Garrett, J. T.; Chakrabarty, A. and Arteaga, C. L. Will PI3K pathway inhibitors be effective as single agents in patients with cancer?
Oncotarget 2011, 2(12), 1314-1321.
- Chakrabarty, A.; Sanchez, V.; Kuba, M. G.; Rinehart, C. and Arteaga, C. L. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Breast Cancer Special Feature:
Proc. Natl. Acad. Sci. USA. 2012, 109(8), 2718-2723.
- Garrett, J.; Olivares, M.; Rinehart, C.; Granja-Ingram, N.; Sanchez, V.;
Chakrabarty, A.; Dave, B.; Cook, R.; Pao, W.; McKinely, E.; Manning, H.; Chang, J. and Arteaga, C. Transcriptional and post- translational upregulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase.
Proc. Natl. Acad. Sci. USA. 2011, 108(12), 5021-5026.
- Cook, R. S.; Garrett, J. T.; Sanchez, V; Stanford, J.; Young, C.; Chakrabarty, A.; Rinehart, C.; Zhang, Y.; Wu, Y.; Greenberger, L.; Horak, I. and Arteaga, C. ErbB3 ablation impairs phosphatidylinositol 3-kinase (PI3K)/AKT-dependent mammary tumorigenesis.
Cancer Research 2011, 71(11), 3941-3951.
- Ghosh, R.; Narasanna, A.; Wang, S E.; Liu, S.; Chakrabarty, A.; Balko, J M.; González-Angulo, A. M.; Mills, G. B.; Penuel, E.; Winslow, J., Sperinde, J.; Dua, R.; Pidaparthi, S.; Mukherjee, A.; Leitzel, K.; Kostler, W. J.; Lipton, A.; Bates, M.; Arteaga, C. L. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.
Cancer Research 2011, 71(5), 1871-1882.
- Dave, B.; Migliaccio, I.; Gutierrez, M. C.; Wu, M-F.; Chamness, G. C.; Wong, H.; Narasanna, A.;
Chakrabarty, A.; Hilsenbeck, S. G.; Huang, J.; Rimawi, M.; Schiff, R.; Arteaga, C.; Osborne, C. K. and Chang J. C. Loss of PTEN or PI3-kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancers.
Journal of Clinical Oncology 2011, 29(2), 166-173.
- Chakrabarty, A.; Rexer, B. N,; Wang, S. E.; Cook, R. S.; Engelman, J. A.; and Arteaga, C. L. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation via heregulin production and activation of HER3.
Oncogene 2010, 29(37), 5193-5203.
- Chakrabarty, A.; Tranguch, S.; Daikoku, T.; Jensen, K.; Furneaux, H. and Dey, S. K. MicroRNA regulation of Cyclooxygenase-2 during embryo implantation.
Proc. Natl. Acad. Sci. USA. 2007, 104, 15144-15149.
- Tranguch, S.; Chakrabarty, A.; Guo, Y.; Wang, H.; Dey, S. K. Maternal Pentraxin 3 Deficiency. Compromises Implantation in Mice.
Biol Reprod. 2007, 77, 425-432.
- Daikoku T.; Tranguch S.; Chakrabarty A.; Wang D.; Khabele D.; Orsulic S.; Morrow J. D.; Dubois R. N. and Dey S. K. Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer.
Cancer Research 2007, 67, 5285-5292.
- Chakrabarty, A. and Roberts, R. M. Ets-2 and C/EBP-beta are important mediators of ovine trophoblast Kunitz domain protein-1 gene expression in trophoblast.
BMC Mol Biol. 2007, 8:14.
- Chakrabarty, A.; Green, J. A. and Roberts, R. M. Origin and evolution of the TKDP gene family.
Gene 2006, 373, 35-43
- Chakrabarty, A.; MacLean, J. A.; Hughes, A. L.; Roberts, R. M. and Green, J. A. Rapid evolution of the Trophoblast Kunitz Domain Proteins (TKDPs) – A multi-gene family expressed in the trophoblasts of ruminants.
J. Mol. Evol. 2006, 63, 274-282.
- MacLean, J. A.; Chakrabarty, A.; Xie, S.; Bixby, J. A.; Roberts, R. M. and Green, J. A. Family of Kunitz proteins from Trophoblast: Expression of the Trophoblast Kunitz Domain Proteins (TKDP) in Cattle and Sheep.
Mol. Repro. Dev. 2003, 65, 30-40.
National & International Recognition:
- Ramalingaswami Re-entry Fellowship, Department of Biotechnology, Government of India 2012-2013.
- Postdoctoral Fellowship (2009-2012) in Basic Research from the Susan G. Komen for the Cure foundation on Role of PIK3CA oncogenic mutations in HER2-mediated transformation and drug resistance in breast cancer.
- Recipient of the Larry Ewing Memorial Trainee Award for presenting at the 2003 Annual meeting of the Society for the Study of Reproduction at Cincinnati, OH, USA.
- Rank first in M.Sc. from the department of Biochemistry, University of Calcutta, Kolkata, India in 1997.
- Rank sixth (99.55 percentile all India) in Graduate Aptitude Test in Engineering (GATE Biotechnology) in 1997.
Our primary research focus is to develop personalized therapeutic strategies for treatment of HER2 positive breast cancers. We employ mechanistic studies to uncover new therapeutic targets in anti-HER2 drug-resistant breast cancer cells. Another area of interest involves testing PI3K signaling pathway as an alternative and less toxic therapeutic target for inhibition of HER2 positive tumor cell growth and survival. My research findings from HER2 positive breast cancer models will be extrapolated to understand the biology and conceive better therapeutic strategies for some other aggressive cancer types that also harbour coexisting mutations in the components of the HER2 and PI3K signaling pathways. The ultimate goal of these research is to increase survival of cancer patients.