Pharmacogenetics of anticancer agents, Molecular genetics of leukemia, Anticancer drug resistance, Conditioning regimen in hematopoietic stem cell transplantation
Anticancer Drug Resistance- Mechanisms and Modulation
We are trying to understand the mechanisms of anticancer drug resistance in myeloid leukemias. Acute myeloid leukemia (AML) is a biologically, clinically and genetically heterogeneous disease characterized by increased proliferation and defective maturation affecting the cells of the myeloid lineage. The backbone of AML treatment for the last 30 years has been the combination of daunorubicin and cytosine arabinoside (Ara-C). The BCR/ABL tyrosine kinase Imatinib mesylate (IM) is the mainstay of treatment for CML but does not eliminate primitive leukemia stem and progenitor cells. Residual leukemia cells are a potential source of relapse, and there is considerable interest in identifying additional therapeutic targets to selectively induce apoptosis in leukemic stem and progenitor cells. We attempt to extend the understanding of novel biology of leukemias with an effort to understand potential novel targets in AML, as well as to better understand mechanisms of resistance and intolerance to therapy in Chronic myeloid leukemia (CML). Our research is proposed to identify novel NHR genes as drug targets to overcome drug resistance in myeloid leukemias.
Targeted therapy with BCR-ABL tyrosine kinase inhibitors has tremendously improved the outcome of chronic myeloid leukemia (CML). However, about 15-20% patients treated with imatinib develop resistance or intolerance to the drug resulting in disease progression. Hence adequate molecular tools are required to diagnose, prognosticate and monitor minimal residual disease to make appropriate decisions on continuing therapy or changing. This decision process is compounded by the high cost of these second generation drugs in a predominantly self-paying system as exists in our country. In this project we plan to work towards an integrated model with a combination of the existing and novel parameters to more accurately prognosticate response to therapy in these patients. We believe that such a model working towards a cost effective therapy in patients with CML is critical for patients in our country where the cost of second generation TKI is prohibitive for most. Using a multidisciplinary approach, we anticipate that this study will have sufficient strength to arrive at genetic/prognostic signatures to identify poor responders and personalize therapy which could result in better treatment outcome. By exploring the mechanisms of disease progression, intolerance and resistance to imatinib using various genomic and cellular approaches, we anticipate that this study will eventually aid in personalizing tyrosine kinase inhibitor therapy in this disease.
Personalizing conditioning regimen in hematopoietic stem cell transplantation
Another major area of research in our laboratory is personalizing the conditioning
regimen used in preparing patients for haematopoietic stem cell transplantation. Please
see the link below for more details.
( www.wellcomedbt.org/fellowsprofile/main/research/id/237)
Research Fellows
Senior Research Fellow
Ph.D student (Thiruvalluvar university, Vellore)
Modulation of tyrosine kinase resistance in chronic myeloid leukemia (CML)- Identification of novel nuclear hormone receptor (NHR) as a drug target in tyrosine kinase resistant CML.
Senior Research Fellow
My work focuses on targetting the nuclear hormone receptor family to overcome drug resistance and leukemic stem cells in acute myeloid leukaemia
Ph.D student (Thiruvalluvar university, Vellore)
UGC Senior Research Fellow
Ph.D student (Thiruvalluvar university, Vellore)
My work basically focuses on: The modulation of chemoresistance in Acute myeloid leukemia targeting epigenetic factors
DST-INSPIRE Senior Research Fellow
PhD Student (SCTIMST, Trivandrum)
My work focuses on modelling patient derived induced pluripotent stem cells (iPSCs) to understand drug resistant mechanisms in chronic myeloid leukaemia (CML)
DBT Senior Research Fellow
PhD Student (SCTIMST, Trivandrum)
My research involves personalizing conditioning regimen in Haematopoietic Stem Cell Transplantation. I specifically focus on exploring Pharmacokinetics (PK), Pharmacogenomics (PG) and Pharmacodynamics (PD) of Treosulfan/Fludarabine which could help in optimizing stem cell transplantation for patients with beta-Thalassemia.
Senior Research Fellow (ICMR-SRF)
PhD. Student (MAHE, Manipal)
My work primarily focuses on understanding the NRF2 mediated acquired drug resistance in AML to chemotherapeutic agents such as cytarabine, anthracycline and arsenic trioxide.
CSIR/UGC Junior Research Fellow
PhD Student (RCB, Faridabad)
My work focuses on understanding mechanisms mediating acquired resistance in acute myeloid leukemia.
CSIR/UGC Junior Research Fellow
PhD Student (RCB, Faridabad)
My work focuses on - "Optimizing cyclophosphamide usage in allogenic haematopoetic stem cell transplantation setting".
Research Technicians
Research Fellows:
Short term project students
Title of Project | Funding Agency | Amount (Lakhs) | Date of sanction and Duration |
---|---|---|---|
Modulation of chemoresistance in acute myeloid leukemia by Nrf2 and its downstream targets | Department of Science and Technology | 45.4 | September 2018, 36 months |
ICMR Advanced Centre for Clinical Pharmacology in Hematological DiseasesAiming at Personalized Medicine | ICMR | 93.7 | March 2018, 36 months |
Personalizing conditioning regimen in hematopoietic stem cell transplantation | Wellcome DBT | 445 | Oct2015, 60 months |
Identification of novel nuclear receptors (NHR) drug targets in myeloid leukemia | DBT | 75.75 | Nov2015, 60 months |
Exploring the mechanisms of disease progression, tyrosine kinase inhibitor resistance and intolerance in Chronic Myeloid Leukemia | DBT | 83.65 | Nov2015, 60 months |
Title of Project | Funding Agency | Amount (in lakhs INR) | Date of completion |
---|---|---|---|
Pharmacokinetic, pharmacogenetic and pharmacodynamic analysis of fludarabine based conditioning regimen for HSCT | DBT | 61.87 | Feb2013- Feb 2016 |
Pharmacogenetics of cytarabine and daunorubicin Resistance in the Leukemic Stem Cell Compartment in acute myeloid leukemia- Principal Investigator | ICMR-INSERM | 20.07 | December1, 2010 2 years |
Pharmacogenetics of cytarabine and daunorubicin in acute myeloid leukemia- Principal Investigator | DBT | 67.77 | Feb 28, 2009 -2014 5 years |
Mechanisms of imatinib resistance in chronic myeloid leukemia- Principal Investigator | DBT | 64.77 | Feb 28, 2009 -2014 5 years |
Degree | University/College | Year | Field of Study |
---|---|---|---|
Master of Science (Biochemistry) | Madras University | 1990-1992 | Clinical Biochemistry |
Ph.D. (Biochemistry) | Christian Medical College, Vellore Tamilnadu Dr. MGR Medical University |
1995-1999 | Biochemistry/ Pharmacology-Pharmacokinetics |
Post-Doctoral Fellowship | St Jude Children’s Research Hospital Memphis, TN, USA |
2007 | Pharmaceutical Sciences/Pharmacogenetics |
Post-Doctoral Fellowship | University of Chicago | 2007 March-September | Pharmacogenetics/Pediatrics |
University/College | Position | From (Date) | To (date) |
---|---|---|---|
Christian Medical College, Vellore | Professor | November 2008 | Till date |
Christian Medical College, Vellore | Associate Professor | November 2006 | November 2008 |
Christian Medical College, Vellore | Reader | November 2004 | November 2006 |
St Jude Children’s Research Hospital, Memphis, Tennessee-USA | Post-Doctoral Research Associate | September 2004 | February 2007 |
University of Chicago, Chicago, Illinois, USA | Research Professional | March 2007 | September 2007 |