A common thread in our research is a quest to understand collective biological phenomena from the perspective of physical sciences. To this end, we develop and deploy computational tools to address quantitative principles governing the behaviour of biological systems. I focus on building and refining models of molecular networks and in applying these models to address biological and medical problems.
Email reshmi@rgcb.res.in

My work involves development of a test system to identify leukemia patients who would be sensitive to therapy with a candidate anti tumor compound, Benzamide riboside (BR). BR is a pro-drug that is converted to its active metabolite benzamide riboside adenine dinucleotide (BAD), an analog of NAD, by the action of the enzyme nicotinamide mononucleotide adenyl transferase (NMNAT). The primary target of BR is inosine monophosphate dehydrogenase (IMPDH), a rate limiting enzyme in the purine nucleotide pathway, resulting in inhibition of cell proliferation, by causing depletion of GTP and dGTP pools. Two isoforms of IMPDH have been identified, of which, type II, is significantly up regulated in neoplastic and differentiating cells and hence identified as a major target in antitumor drug design. I am also looking into probable pathways involved in the tumor cytotoxicity induced by BR. Key collaborators in this study are Dr. HN Jayaram (Indiana University School of Medicine, Indiana, USA), Dr. N Geetha & Dr. Sreejith Nair, Medical Oncology, Regional Cancer Centre, Dr. TR. Santoshkumar, Rajiv Gandhi Centre for Biotechnology and Dr. Anne Abraham, Department of Biochemistry, University of Kerala.

My work is on the nutrigenomics of cervical cancer. Folate, owing to its unique role in DNA synthesis, methylation and repair, has been considered a target nutrient in the etiology of various cancers especially in cervical cancer. Folate deficiency also precipitates hyperhomocysteinemia, a factor associated with several degenerative diseases, including cancer. My preliminary findings indicate that folate deficiency has a strong association with cervical cancer and may influence the natural history of human papillomavirus infection. My principal collaborators in this work are Professor Asok Antony (School of Medicine, Indiana University, Indianapolis, IN, USA), Dr PG Jayaprakash and Dr Remani Wesley from the Regional Cancer Centre, Thiruvananthapram.

Human stem cells have a significant lifespan allowing the accumulation of multiple genetic aberrations required for carcinogenesis. While the concept of cancer stem cells is extremely useful and it is generally assumed that such cells are derived from normal stem cells, more work is needed to identify and characterize epithelial cancer stem cells, to address their precise relationship with normal stem cells, to study their markers and their proliferative and differentiation properties and to design new therapies that can overcome their unusual resistance to chemotherapy and other conventional tumor modalities. My research goal is to identify and evaluate the clinical significance of tumor progenitor cells in oral cancer. Major collaborators in this study are Dr. T.R Santhoshkumar from RGCB; Dr. K. Ramadas (Head & Neck Oncology) Dr. Paul Sebastian (Surgical Oncology) and Dr. Jem Prabhakar, (Surgical Oncology), Regional Cancer Centre, Thiruvananthapuram.

My work is on targeted knockout of the e6 gene from human papillomavirus(hpv16) genome by synthetic zinc finger nucleases.
Cervical cancer ranks second among female cancers and HPV 16 induced malignancy is the most predominant high-risk type worldwide. The high risk HPV types have been associated with the development of malignant lesions. The E6 and E7 proteins have been attributed with the ability to manipulate cell cycle regulators leading to transformation. Although prophylactic vaccines are available for blocking HPV infection, there is a growing need for novel treatment strategies for those who are already infected. A wide range of approaches including siRNA, ribozymes to peptides have been used to target E6 and E7. These however only suppress the actions of the two viral oncoproteins. Moreover, a viral delivery system is required for stable integration and continuous production of siRNA or ribozymes to have therapeutic effect.The E6 based siRNA approach has been shown to induce apoptosis, senescence in HPV 16 positive cells and hence knockout of the viral E6 gene would be of therapeutic significance. Targeted genome editing using Zinc finger technology has shown to be a promising approach in genomic research and therapy. Zinc finger nucleases are artificial restriction enzymes which bring about targeted double stranded breaks based on sequence specificity. A ZFN pair can knockout a gene of interest and the broken ends of chromosomes would be usually repaired by the cell’s error prone Non homologous End Joining (NHEJ) pathway. Since the Zinc Finger Nucleases are sequence specific, our hypothesis is that designed Zinc Finger Nucleases against E6 would selectively induce apoptosis in infected cells while keeping normal cells intact. Knockout of E6 gene would induce apoptosis and stop the transformation of cervical keratinocytes in HPV infected cells.

Curcumin has been extensively studied in cancer research and has shown to exhibit anti-oxidant, anti-inflammatory and pro-apoptotic activities. My project is a multicenter clinical trial based study which investigates the efficacy and safety of curcumin in oral premalignant lesions. We mainly focus on the effects of curcumin in the modulation of selected biomarkers like COX-2. An increase in the levels of prostaglandins reported in transformed cells and tumours has been associated with the enhanced expression of COX-2. Here, we analyze COX-2 expression in the leukoplakia samples by Real-time PCR. The study also involves HPV genotyping, ploidy and other biomarkers such as NF-kB, PCNA and cytokeratins.

Photodynamic therapy (PDT) is a promising cancer treatment modality. It involves targeted tumour destruction by the combined action of light and drugs called photosensitizers and this process is called photodynamic therapy. It can be used for drug-resistant tumors and in patients with conditions forbidding surgery. However, there is a critical need for better exogenous PDT sensitizers .We set our preliminary objectives to develop efficient photosensitizers that become activated in the NIR region based on squaraine, croconaine and expanded porphyrins and their metal complexes. These compounds were synthesized by our chemist colleagues at National Institute for Interdisciplinary Science and Technology led by Dr.D.Ramaiah. We initially studied in vitro photodynamic efficacy on sixteen compounds and found four of them to be potential photosensitizers in NIR region. Further validation by in vivophotodynamic experiments are being completed for taking these compounds to pre-clinical trials.

My work aims to understand the genetic profile of oral squamous cell cancers in patients below 45 years of age with or without tobacco and alcohol habits and compare this to the profile seen for oral cancers in patients above 45 years of age with extensive tobacco and alcohol habits and also with the profile seen in normal oral mucosa. The study would also investigate for the presence of human papilloma virus subtypes in the study groups. If this is established it may allow the reclassification of oral and tongue cancers in the younger patients and set the stage for alternate and more aggressive forms of therapy. The second part of my study focuses on the clinical and biological significance of Micro RNAs in oral carcinoma. Previous studies have repeatedly observed deregulated expression of miRNAs in cancers of the oral cavity. However, there is only preliminary knowledge about the molecular mechanisms linking these miRs to oral cancer progression. Only a handful of cellular targets (genes) for these miRNAs have been validated which are relevant to cancer. Thus, a clearer picture of the role of miRNAs in oral cancer, rather than recording their expression status alone, can help better evaluation of their potential as markers for the disease. My study proposes to develop and implement a systematic scheme for evaluating the role of specific miRNAs in oral carcinoma. This will enable us to integrate multiple types of information about a select sub-set of miRNAs which in turn will allow a better understanding of how they fit into the current paradigm of molecular carcinogenesis of oral tumors.