A Joint Centre for Cancer Biology & Therapeutics
Lead Research Organisation:
University of Cambridge
Department Name: MRC Cancer Unit
Abstract
There is little scientific understanding of the mechanisms that normally maintain cellular and
molecular homeostasis in epithelial tissues, or how derangements in these mechanisms foster carcinogenesis. However, there is remarkable potential that better understanding of these mechanisms will engender novel methods for early diagnosis, risk stratification and cancer therapy. Therefore, translational research in this important area is an urgent strategic priority in India, at a time when epithelial cancers are already a major cause of morbidity and mortality, and their importance is increasing sharply with changing disease demographics. However, few institutional efforts in India currently address this need.
The proposed Joint Centre will exploit a timely opportunity for a synergistic strategic partnership in this important area between the MRC Cancer Unit (CU) in Cambridge, and NCBS / inStem in Bangalore. The CU seeks to advance understanding of the earliest steps in epithelial carcinogenesis, and to exploit this knowledge in new approaches for clinical intervention, through innovative enabling technologies. The CU's internationally recognized programmes led by clinicians and scientists closely complement those of multiple NCBS and inStem faculty leading outstanding basic science programmes investigating epithelial tissue homeostasis, receptor signalling, inflammation, stem cells and regeneration, and mathematical biology. An extensive collaboration between the institutions has been led since 2011 by Ashok Venkitaraman, the Director of the MRC CU, and Satyajit Mayor, Director of NCBS and inStem. They attracted significant DBT funding to establish in 2013 a new Centre for Chemical Biology & Therapeutics (CCBT) in Bangalore that complements MRC-funded research at the CU, with the support of Cambridge University and the MRC.
The proposed Joint Centre will build on this strong foundation to (a) further develop joint research on the maintenance of homeostasis in epithelial tissues, on mechanisms underlying the pre- neoplastic to neoplastic transition, and on knowledge-directed clinical interventions for early diagnosis, risk stratification and cancer therapy, (b) enrich in Bangalore a framework for translational cancer research leading to clinical intervention, and (c) provide a unique trans- national training environment to build capacity in India for researchers and clinicians in translational cancer research.
molecular homeostasis in epithelial tissues, or how derangements in these mechanisms foster carcinogenesis. However, there is remarkable potential that better understanding of these mechanisms will engender novel methods for early diagnosis, risk stratification and cancer therapy. Therefore, translational research in this important area is an urgent strategic priority in India, at a time when epithelial cancers are already a major cause of morbidity and mortality, and their importance is increasing sharply with changing disease demographics. However, few institutional efforts in India currently address this need.
The proposed Joint Centre will exploit a timely opportunity for a synergistic strategic partnership in this important area between the MRC Cancer Unit (CU) in Cambridge, and NCBS / inStem in Bangalore. The CU seeks to advance understanding of the earliest steps in epithelial carcinogenesis, and to exploit this knowledge in new approaches for clinical intervention, through innovative enabling technologies. The CU's internationally recognized programmes led by clinicians and scientists closely complement those of multiple NCBS and inStem faculty leading outstanding basic science programmes investigating epithelial tissue homeostasis, receptor signalling, inflammation, stem cells and regeneration, and mathematical biology. An extensive collaboration between the institutions has been led since 2011 by Ashok Venkitaraman, the Director of the MRC CU, and Satyajit Mayor, Director of NCBS and inStem. They attracted significant DBT funding to establish in 2013 a new Centre for Chemical Biology & Therapeutics (CCBT) in Bangalore that complements MRC-funded research at the CU, with the support of Cambridge University and the MRC.
The proposed Joint Centre will build on this strong foundation to (a) further develop joint research on the maintenance of homeostasis in epithelial tissues, on mechanisms underlying the pre- neoplastic to neoplastic transition, and on knowledge-directed clinical interventions for early diagnosis, risk stratification and cancer therapy, (b) enrich in Bangalore a framework for translational cancer research leading to clinical intervention, and (c) provide a unique trans- national training environment to build capacity in India for researchers and clinicians in translational cancer research.
Organisations
People |
ORCID iD |
| Ashok Venkitaraman (Principal Investigator) |
Publications
Al-Lamki RS
(2016)
Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.
in Oncotarget
Clarke M
(2019)
Automated Reasoning for Systems Biology and Medicine
Hall BA
(2020)
Constructing and Analyzing Computational Models of Cell Signaling with BioModelAnalyzer.
in Current protocols in bioinformatics
Hall MWJ
(2019)
Relating evolutionary selection and mutant clonal dynamics in normal epithelia.
in Journal of the Royal Society, Interface
Hu Z
(2016)
Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.
in Breast cancer research : BCR
Miragaia R
(2019)
Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation
in Immunity
| Description | 1. Joint work in this Programme between Cambridge and India led to the the development of Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, opening avenues to block intracellular signaling via a family of related targets (Periasamy et al., Cell Chem Biol (2018); Kurdekar et al., ChemMedChem (2019). Bractoppin selectively blocks phosphopeptide recognition by the BRCA1 tBRCT domain, engaging tBRCT residues recognizing pSer, plus an adjacent pocket. Bractoppin interrupts BRCA1 tBRCT-dependent cellular signals evoked by DNA damage. This work opens avenues to inhibit intracellular signaling by the tBRCT domain family, a previously "undrugged" group of structures implicated in human diseases. 2. RNA-Seq data, consisting of 3 normal lung samples, 14 low grade and 14 high- grade tumours derived from a murine model of mutant KRAS adenocarcinoma (ADC) were analysed. This dataset using rsem package to extract gene and transcript level read count information and edgeR to identify genes differentially deregulated between the different cohorts of samples. The differentially expressed genes in normal and lung tumour samples that were up- or down- regulated (logFC 0.58 and FDR < 0.05) were used to perform pathway enrichment analysis using Ingenuity Pathway Analysis (IPA). Relevant signalling and metabolic pathways, molecular networks, and biological functions for the lists of genes deregulated in low and high-grade tumours were identified. We also identified potential murine lung adenocarcinoma driver genes in our dataset by comparative analysis with already published data. 3. To screen for metabolic enzyme dysregulation, we used TCGA RNA-sequencing data from 21 different types of cancer with matched normal samples applying a custom analysis pipeline. We identified 4047 metabolic enzymes that were condensed into seven major categories based on enzyme classifications. We identified unique metabolic pathway enzymes, altered in one disease site. Analysis of pathways within major metabolic categories revealed patterns of dysregulation reflective of common metabolic reprogramming in cancer. While these results are in agreement with the literature, the method also discovered additional metabolic disruption across the 21 cancers examined. 4. We identified upregulation of SLC2A5 (fructose transporter) and repression of enzyme Aldolase B - key in fructose metabolism. Combined metabolic and qPCR-based analysis suggest impairment in fructose metabolism, this could a possible factor driving ccRCC. |
| Exploitation Route | 1. J This work opens avenues to inhibit intracellular signaling of a previously "undrugged" group of structures implicated in human diseases. 2. identification of potential murine lung adenocarcinoma driver genes enabling further research into these 3. To screen for metabolic enzyme dysregulation, the method also discovered new metabolic disruption across the 21 cancers examined. 4. Enable further research into factor driving ccRCC. |
| Sectors | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | It has enabled capacity building and knowlede transfer between both organisations and has helped in thetraining experience for staff at both institutes |
| First Year Of Impact | 2016 |
| Sector | Education,Healthcare |