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Cancer Biology

Drugs to combat antimicrobial resistance

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Cancer of oral cavity and lip has the highest incidence and the highest mortality among men in India. About 90% of the oral malignancies are squamous cell carcinoma- one of the most common histologic forms of head and neck squamous cell carcinoma (HNSCC). Oral squamous cell carcinoma of the gingiva-buccal region (OSCC-GB), comprising buccal mucosa, gingiva-buccal sulcus, lower gingiva, and retromolar trigone, is the major subtype in India. Currently, the treatment of head and neck cancer is surgical resection followed by adjuvant radiotherapy with or without chemotherapy. It is the leading cause of cancer-associated death in the Indian male population. Annually, more than 72,000 deaths are attributed to this disease in this country. Tobacco (smoking/smokeless), alcohol and human papillomavirus (HPV) infection are the primary risk factors for Head and neck cancers. Chewing of areca nut, betel leaf, poor oral health hygiene, and are common oral habit in most of Indian HNSCC patients. Despite availability of risk information from histopathology, the pattern and timing of relapse and metastasis are difficult. Prognosis in oral cancer is difficult due to genetic heterogeneity and hence new biomarkers are urgently required that will guide the suitable treatment strategy. Late stage diagnosis and use of similar treatment regimens for all HNC sites indicate limitations of current therapeutics in HNSCC. In this regards, our lab is working towards the molecular pathogenesis of Head and neck cancer by exploring different aspects of HNSCC such as miRNA profile, KRAS variant in Indian patients (non-resposive to Cetuximab therapy) and Cancer stem cell heterogeneity (to understand the heterogeneity within HNSCC tumor microenvironment). 

  1. miRNA profile in Indian OSCC patients
  2. Cancer stem cell heterogeneity
  3. KRAS variant in Indian patients

miRNA profile in Indian OSCC patients: Oral cancer is the most common type of head and neck cancers, characterized by high mortality rates, low long-term survival, and an increasing incidence among younger people. As the complexity of oral cancer is still challenging contemporary medicine, further molecular characterization of this cancer type is required. Identification of novel accurate molecular biomarkers will facilitate early detection and confirmation of the oral cancer diagnosis at the molecular level. Identification of deregulated miRNAs in oral cancer is important in the search for new sensitive molecular biomarkers with diagnostic, predictive, and prognostic value. Nowadays, the development of high-throughput technologies has enabled the identification of differentially expressed miRNAs between cancer and non-cancerous tissue samples on a large scale. However, the technologies used in different studies are diverse, and the obtained results are not entirely consistent. Therefore, our aim is to identify commonly deregulated miRNAs in oral cancer and characterize their biological meaning by performing a comprehensive meta-analysis of previously published miRNA expression profiling studies, followed by bioinformatics enrichment analysis. The candidate miRNA will be studied for the role in oral carcinogenesis through in vitro and in vivo studies.

Cancer stem cells heterogeneity :

Recently, challenges involved in the treatment of head and neck cancer were attributed to heterogeneity of cancer cells. The development of metastasis, treatment failure, recurrence portends in poor prognosis of HNSCC. Despite intense efforts to understand molecular mechanisms responsible for treatment failure/relapse in HNSCC, no significant progress has been made in terms of patient survival. CSCs targeted therapy might be useful in HNSCC. However, emerging evidence suggest that CSCs are heterogeneous in nature. They display phenotypic and functional heterogeneity.  For example based on functional phenotype, CSCs can be called quiescent CSCs, tumor initiating cells (TICs), metastasis-initiating cells (MICs), and drug-resistant CSCs. Subpopulations of highly tumorigenic cells or CSCs were first described in HNSCC tumour cells using the cellular marker CD44, and later it was concluded that subpopulation of CSCs work as mediator of tumorigenesis, metastasis, recurrence and treatment failures. The differentiation of tumorigenic cancer stem cells into non tumorigenic cancer-cells confer heterogeneity to HNSCC beyond that is explained by clonal evolution or environmental differences. In such scenario, functional differences between tumorigenic and non-tumorigenic cells influence response to therapy and prognosis. To answer these uncertainties, we will transplant phenotypically different subpopulations of CSCs from HNSCC patients in mice to study, whether they give rise to tumorigenic or non-tumorigenic population.

First objective is generation of patient-derived xenograft mice model for functional validation of CSCs. Second objective is to carry out exome and transcriptome sequencing of different phenotypic subpopulations of CSCs obtained from PDX to analyze differential gene expression and mutational landscapes. Transcriptome may reveal set of new genes in functionally different CSCs. The exome-sequencing will suggest whether, sub population of CSCs are from same or different genetic lineage. These functionally validated subpopulations of CSCs will be exposed to radiation and/or challenged with standard chemotherapy drugs to evaluate the differential sensitivity. The role of reactive oxygen species in subpopulations will be studied which may help in designing better therapeutic strategies. Head and neck squamous cell carcinoma encompasses a variety of malignancies arising in the oral cavity, nasal cavity, paranasal sinuses, pharynx and larynx. HNSCC is the sixth most common type of cancer worldwide. The mortality of HNSCC is mainly caused by local recurrence and lymph node metastasis as well as by treatment failure or acquisition of resistance to therapy. Cancer stem cells are present within a tumor that possesses the capacity of self-renew and to give rise to the heterogeneous lineage of cancer cells that comprise the original tumour. Interestingly, not all CSCs are equal, and distinct subpopulations exist that can lead to functionally different processes. Cancer stem cells have been previously identified using specific markers, the most common being CD44, ALDH1 and CD133. Only, CSCs have an increased tumorigenic potential following xenograft transplantation to mice and when the number of transplanted cells are examined, a much smaller number of CSCs are able to initiate tumour formation compared to non-CSCs. Accumulating evidence suggests that therapeutic resistance and metastasis are mainly driven by cancer initiating cells (CICs). CSCs have shown drug resistance to chemotherapeutic agents such as cisplatin, 5-FU, and doxorubicin. Also, an increased expression of certain stemness markers such as Oct4, Sox2, and Nanog has been demonstrated in radio- and chemo-resistant HNSCC cells and CSC-like signature CD44 has been reported to be significantly correlated with an incomplete response to radio- and chemotherapy in patients with locally advanced HNSCC. Evidence for a role of CSCs in immune resistance in HNSCC also exists. In particular, it has been reported that CSCs contribute to the downregulation of antitumor immunity in the tumour microenvironment. In addition, the controlled regulation of reactive oxygen species (ROS) is one of the key components in CSCs that drives disease recurrence, cell signaling and therapeutic resistance. As hypoxia promotes and sustains major stemness pathways, further consideration of ROS impacts on CSCs in the tumor microenvironment is important. In this study the Identification and characterization of cancer stem cell heterogeneity in head and neck cancer patients followed by study of ROS produced by altered tumor metabolism will help us to elucidate the role of CSC and the impact of ROS on CSC maintenance. 

KRAS variant in Indian HNSCC patients: The KRAS gene belongs to a Ras family of oncogenes which provides instructions for making a protein called K-Ras. The K-Ras protein is a GTPase, that converts GTP molecule into another molecule called GDP. RAS proteins are first synthesized in the cytosol, where their CAAX motif is recognized by farnesyltransferases, which prenylate RAS. This results in the incorporation of RAS into the inner cell membrane and is followed by proteolytic cleavage of the AAX sequence catalyzed by RAS-converting enzyme-1 (RCE1) and carboxymethylation of the farnesylated cysteine residue catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT). These reactions modulate the ability of RAS proteins to incorporate into the inner cell membrane and be activated. Once activated by extracellular stimuli such as activated EGFR, RAS proteins activate downstream cytosolic effectors RAF/MEK/ERK pathway and the PI3K/AKT/mTOR pathway. There are mainly three factors for targeting Kras in Cancer therapy. First, K-RAS plays a distinct role in tumorigenesis. Secondly, K-RAS mutant cancer cells are K-RAS dependent. Last but not least, K-RAS mutant cancers represent about 30% of all human cancers.

MicroRNA (miRNA)-binding site variants in 3′ untranslated regions (3′UTRs) are a novel class of germ-line, functional mutations, which are now recognized as powerful biomarkers of human cancer risk and biology. The first mutation discovered in this class is the KRAS-variant, a let-7-binding site mutation in the 3′UTR of the KRAS oncogene. Kras variant carrying HNSCC patients do not respond to the standard treatment of cisplatin along with radiotherapy in the presence of cetuximab, suggesting that EGFR is no longer considered as a biomarker for a drug target. Therefore, identification of new biomarkers to treat HNSCC patients targeting the Kras variant is needed. A recent study on HNSCC patients published in the JAMA Oncology indicated approximately 17 % of patients with Kras variants do not respond to the normal HNSCC treatment regimen, and their survival rates are very low. Our lab has previously worked upon the radiosensitizing effect of Prochlorperazine (FDA approved antipsychotic drug) in the Kras mutant lung cancer and it has shown as a radiosensitizers and has an anticancer activity. However, its impact in the HNSCC is still unknown. The need of the hour is to explore Prochlorperazine as a novel radiosensitizing agent and to elucidate their mechanism of action for radiation at the molecular level.