The Indian Council of Medical Research (ICMR) had projected that in 2016 the total number of new cases of cancer is expected to be around 14.5 lakhs and 7.36 lakh people are expected to succumb to this disease. These numbers are forecasted to rise to more than 17.3 lakh new cases and 6.8 lakh cancer-related deaths annually by 2020. Cancer is a complex disease and our current understanding is insufficient to treat cancer patients. At ILS, scientists have adapted multi-disciplinary approaches to understand and identify novel strategies to combat various types of cancers such as leukemia, oral, pancreatic, prostate and breast cancer. Through an interdisciplinary program, the group aims to explore new avenues to develop diagnostics, therapeutics and prevention approaches for different cancers. To better understand the pathogenesis of specific cancers, scientists at ILS collaborate with clinicians and have observed various cellular and molecular alterations that are perturbed during onset and progression of cancer. Moreover, we have been able to utilize a large cohort of patient samples and identify novel markers which could be exploited for early diagnosis and targeted therapy. Currently, we are working to identify novel drug candidates through in silico and/or in-vitro drug screening, validation in cell culture and animal models, and their further modification through nanotechnology approach to enhance drug efficacy and delivery.
Molecular and biological characterization of oncogenes involved in leukemia and solid tumors
Nanotechnology (Cancer drug delivery)
Gene therapy for cancer
Tumor Microenvironment and Animal Models
Drug design and discovery, Bioinformatics
Characterization of chromatin remodelers and epigenetic factors in blood cell development
Genomic instability and Diseases
Cell and Cancer Biology
Major activities undertaken during last 5 years
Breast cancer group is actively involved in understanding the epigenetic mechanisms underlying the disease Estrogen Receptor (ER) positive breast cancer with special emphasis on Tamoxifen resistance, which is the second leading cause of deaths among women worldwide. In collaboration with clinicians this group is specifically investigating the role of Estrogen related receptor beta (ERR beta) in the above mentioned resistance. The roles of few other molecules are under investigation.
Leukemic stem cells group is investigating the mechanisms responsible for the survival of the lineage negative CD34+ leukemic stem cells against tyrosine kinase inhibitors. Studies are also undertaken to potentiate myeloid cell differentiation in advanced phases of the disease by identifying the factors that are deregulated during the progression of this disease. This group is also trying to decipher the role of post-translational modifications that regulate the activity of an oncogene.
Cancer nanomedicine group has interest and expertise in harnessing the strength of nanotechnology for different cancers’ diagnosis and therapy. The group specifically focuses on designing different drug-loaded nanocarriers and check their anticancer efficacy in different cell culture and animal models.
Oral cancer group has interest on understanding and targeting chemoresistance in Oral Squamous Cell Carcinoma (OSCC). Though cisplatin and 5-Fu are the most commonly used drugs for OSCC, resistance to cisplatin is the major hurdle for effective therapy. Hence, the group has actively undertaken different studies that will identify novel therapeutic approaches for this disease.
Tumor microenvironment group has the interest to understand and target inflammation-mediated events in prostate and pancreatic cancer. It specifically aims to understand the role of bacterial infection in prostate cancer pathogenesis, this group has undertaken multidisciplinary approaches to investigate the functional role of bacterial infection in prostate cancer. In a different study, this group is actively involved in deciphering the cross-talk between cancer-associated fibroblast and pancreatic cancer cells to target the key cellular and molecular events.
Tumor angiogenesis group is interested in understanding the mechanisms of endothelial gene expression during tumor angiogenesis using human endothelial cells and zebrafish as a model. The group is also interested in identifying and characterizing small molecule inhibitors that can block angiogenesis in human tumors.
Computational biology group is involved in identifying candidate genes that play an important role in the etiology of OSCC. The study has the potential for identification of the proteins that can be used for the development of new therapeutic strategies and diagnostic kits.
Immune modulation group has an interest in understanding the mechanisms of lysophosphatidic acid (LPA) in immune cell regulation and cancer. In many types of cancer, LPA is highly dysregulated, hence, the group is actively investigating the possible role of LPA in tumor associated macrophages.
Chromatin biology group is investigating the role of chromatin modifiers and epigenetic factors in myelopoiesis and how their misregulation leads to the onset of hematopoietic malignancies.
Genomic instability and cancer group is trying to understand the mechanism and regulation of DNA replication in humans and decipher the role of TLS DNA polymerases in chemoresistance in cancers. Fidelity of DNA polymerases is crucial for genome stability and function. As accumulation of somatic mutations due to dysregulated or error-prone DNA replication induces carcinogenesis and chemoresistance in cancers, DNA polymerases are the potential chemo-preventative and therapeutic drug targets.
Key achievements of the group
• We have identified downstream transcriptional targets of ERRβ in breast cancer.
• Our findings have shown that CASP7 is aberrantly expressed in breast cancer and contributes to cell growth and proliferation, suggesting that targeting CASP7-positive breast cancer could be one of the potential therapeutic strategies.
• Our results demonstrate that inorganic pyrophosphatase has a role in breast cancer wherein it is regulated by SP1 and histone acetylation/deacetylation.
• We have identified a miRNA-mRNA network in the lineage negative CD34+ cells isolated from the bone marrow of naive chronic myeloid leukemia cases. Combinatorial therapy of Imatinib, the drug of choice for CML and JAK inhibitor I, identified from the network, not only dissociated the network but also significantly affected the proliferation of CML cells.
• Spearman’s correlation test demonstrated the existence of a negative correlation between miR-223 expression level and the disease risk, which may be used as a disease-risk prediction marker.
• miR-223 down-regulation with the progression of the disease correlated with the up-regulation of the RNA binding protein, PTBP2. PTBP2 is a splicing regulator and its protein expression was observed only in the advanced stage of the disease.
• EVI1, a proto-oncogene, was reported to be up-regulated with the progression of the CML, AML and MDS-AML. We found that the acetylated/deacetylated form of EVI1 can divergently regulate several target genes that includes Bcl-xL, SIRT1 and ΔNp63.
• Our investigation has shown that arsenic trioxide, a drug known to act as an anti-leukemic agent for acute promyelocytic leukemia (APL) not only enhanced EVI1 sumoylation but also enhanced the co-localization of EVI1 and SUMO1 in nuclear bodies distinct from PML nuclear bodies, deregulated Bcl-xL and eventually induced apoptosis in EVI1 positive cancer cells. This finding may pave a way to understand the significance of arsenic trioxide (Trisenox) that was used to treat EVI1 patients with myelodysplastic syndrome (MDS).
• Our research expertise has resulted in the development of different drug-loaded nanocarriers, which have shown a promising anticancer effect in different cancer models. One of the PEGylated product (PEG-Gemcitabine) in combination with other drug treatments, eliminate cancer stem cells and promotes survival in pancreatic cancer xenograft model.
• We have developed an aqueous dispersible highly stable polymer coated magnetic nanoparticle formulation (US Patent granted: US 9271934 B2) for biomedical applications and this is being used as a theranostic agent for the management of cancer.
• We have identified that among all anti-apoptotic proteins Mcl-1 is essential for survival of chemoresistant OSCC cells.
• We have identified ketorolac salt as a small molecule inhibitor of RNA helicase DDX3, which blocks the growth of OSCC cells in-vitro as well as in-vivo.
• Using clinical samples, cell culture and animal models we have observed that human prostate tissues do get infected with different bacteria and bacterial components promote prostate cancer progression.
• Through drug library screening we have identified 15 FDA-approved drugs that could inhibit the constitutively active basal NF-κB levels in prostate cancer cells.
• We have characterized a rapid and predictable hamster orthotopic pancreatic cancer model that shows an extensive desmoplastic reaction. Using this model we have identified that Pirfenidone and NAC combination therapy has a better effect in suppressing tumor-associated desmoplasia than individual drugs.
• We have identified 149 lead compounds that have the potential to inhibit CLEC14A functions, a novel regulator of tumour angiogenesis.
• We have identified the cis-regulatory elements that can regulate endothelial cell-specific expression of CLEC14A.
• We have generated human cancer gene network (HCGN) using the latest protein-protein interaction data and have characterized the network.
• Through an integrated bioinformatics approach followed by validation in clinical samples, we have identified four genes (HTT, CALM3, FLNA and ARRB1) that might have a potential role in the invasion and metastasis of OSCC cells.
• Lysophophatidic acid (LPA) was identified as a novel phospholipid converting monocytes into macrophages.