- Ph.D Biotechnology – 2002 (Rajiv Gandhi Centre for Biotechnology)
- M.Sc Biotechnology – 1996 (Cochin University of Science and Technology)
- 2008-2010: Visiting Fellow, National Centre for Biological Sciences, Bangalore
- 2005-2008: FAST TRACK young Scientist, National Centre for Biological Sciences, Bangalore
- 2004-2005: Research Associate, National Centre for Biological Sciences, Bangalore
- 2002-2004: Research Associate, Regional Cancer Centre, Thiruvananthapuram
- 2008: Indo-French Scientific Co-operation Programme
- 2005: DST FAST TRACK
Oral squamous cell carcinoma (OSCC) is a leading cause of cancer death in India.The major treatment modalities for oral carcinoma are surgery with chemotherapy or radiation therapy. The mortality rate for oral cancer is high because almost 60% of Stage III and IV OSCC patients show relapse within 2 years after remission. Development of drug resistance is a major impeding factor in the treatment outcome. Recently a sub-population of cancer cells called cancer stem cells (CSCs) have been identified as the culprits in relapse. Moreover, CSCs are reported to be important for tumor initiation and metastasis (the spread of the disease), making this subset an important candidate for prognostic prediction as well as targeted therapy. My lab is interested in understanding the oral cancer stem cell biology and its relevance in oral cancer recurrence after chemotherapy. Further, my lab is trying to develop new detection methods for oral cancer. Developing animal models for studying the oral cancer biology is also one of my interests.
Identifying surface marker signature of oral cancer stem cells to develop a prognosis marker for oral squamous cell carcinoma using peptide-based CSC detection
Funding Agency: Department of Biotechnology
One of the interests of our lab is to identify the surface molecular signature of oral cancer stem cells using proteomic approach. We have used membrane fractions from monolayer culture and sphere culture (a method to enrich CSCs) for proteomic analysis by label free ESI-QTOF as well as SILAC. The molecules common to both the analyses were selected for further study. Based on the selected molecules specifically present in the Sphere culture, peptides are being designed to detect those molecules. The sub-population of oral cancer cells expressing those markers from different OSCC samples will be used to confirm whether these molecules can be used as a target molecule to identify oral cancer stem cells.
Identifying the signaling network that sustains oral cancer stem cells for developing a targeted therapy
Funding Agency: Department of Science and Technology
Recent research points out that the failure of cancer chemotherapy and radiotherapy is due to the existence of CSCs that are resistant to the treatment. As conventional therapies enrich the CSC population, a targeted therapy for CSCs will be a choice to enhance the efficacy of disease management.Understanding the signaling networks of CSCs that keep them in the “CSC-state” will help to design chemotherapeutic drugs that could be used against them. Since majority of the signaling events are mediated through phosphorylation, a phosphoproteome analysis of sphere cultured cells (with enriched CSCs) in comparison to monolayer cells will help us to understand the signaling events that sustain the CSC characteristics. Samples are being analyzed for phosphoproteome by SILAC.
TGF-β mediated regulation of self-renewal and chemoresistance in oral carcinoma
Even though it is accepted that CSCs escape chemotherapy, we cannot explain how CSCs reappear after surgery. Recent evidences show that tumor niche formed by the stromal cells, tumor cells and CSCs play a role in the induction of CSC properties. We have evaluatedthe role of TGF-β signaling in modulating self-renewal ability and chemoresistance. Even though the classical TGF-β mediators are Smad proteins, other mediators like TIF1γ are also implicated in TGF-β mediated responses. We are evaluating the role of Smad 4 and TIF1γ in oral carcinoma.
Detection of oral carcinoma by optical imaging using GRPR-detecting peptides
Even though the precancerous stage of oral carcinoma can be easily detected, majority of the cancer cases are presented to the clinics after the spread of cancer to nearby tissues and lymph nodes. MRI is one of the detection methods that can be employed to estimate the extent of invasion of the cancer. Since it takes a longer duration for imaging, the MRI of the tongue or floor of the mouth is difficult. So in majority of the cases, clinicians depend on visual examination to determine the tumor margins for surgical excision. In a significant number of cases, that results in the residual disease, a major reason for relapse. In this scenario, a detection technique that can be achieved in a shorter time span, like optical imaging using infrared dyes can be considered. For this, a molecule targeting the tumor should be tagged with the near infra red dyes, and the fluorescence of this dye can be used for the detection. Synthetic peptides can be labeled with dyes for in vitro or in vivo detection of tumor. Peptide-based diagnosis is relatively safer as peptides have fast clearance rate, rapid tissue penetration, and are non-toxic. We have synthesized peptides that can detect oral carcinoma based on the detection of GRPR, which is over-expressed in OSCC. The efficacy of the peptide is confirmed in mouse models of oral carcinoma by in vivo imaging.
Making animal models for evaluating the oral carcinoma progression and treatment response
Usually OSCC is treated with surgery in combination with radiotherapy or chemotherapy. Platinum drugs, 5-FU, paclitaxel and docitaxel are the major chemotherapeutic drugs used in OSCC treatment. Because of the high recurrence rate, OSCC’s treatment is often more aggressive. If we can predict which patient will show recurrence, and will develop resistance to which chemotherapeutic drug, appropriate treatment regimen could be decided for each patient, which will improve patient’s survival rate. In this scenario, development of a model in which we can predict the prognosis of the disease will be of immense help in the treatment of OSCC. Majority of the oral carcinoma cases are of OSCC of tongue or floor of the mouth. We have developed orthotopic models for both these kind of oral carcinoma. We could develop the tumor model within three weeks of implantation of the tumor material. Thus we can do the evaluation of the treatment responses within a short span of time. These models are being used for understanding oral cancer biology.
- Balagopal P.Gand Paul Sebastian, Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram
- Harsha, Gowda and Pandey A., Institute of Bioinformatics, Bangalore, Karnataka, India
- Santhosh Kumar K, Chemical Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram
- Rajagopal R and Santhosh Sankaran, Animal Research Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram
- Richard, V., Sebastian, P., Nair, M.G., Nair,S.N., Maliekal,T.T., SanthoshKumar, T.R. and Pillai M. R. (2013) Multiple drug resistant, tumorigenic stem-like cells in oral cancer. Cancer Letters 338: 300-316.
- Vinod, B. S., Maliekal, T. T., and Anto, R. J. (2013). Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance. Antioxid Redox Signal 18, 1307-1348.
- Jeevisha Bajaj*, Tessy T. Maliekal*, Eric Vivien, Chitra Pattabiraman, Sweta Srivastava, H Krishnamurthy, G. V. Giri, Deepa Subramanyam and Sudhir Krishna. Notch signaling in CD66+ cells drives the progression of human cervical cancers. Cancer Res 2011; 71: 4888-4897.