Cancer Pharmacology Division

Overview

Cancer is a pathologic condition that involves genetic and epigenetic events culminating in neoplastic transformation. The major challenges to cancer prevention and treatment include inappropriate diagnosis, poor prognosis leading to recurrence and anticancer drug resistance to current treatment regimens. Nevertheless, the targeting of key pathways specific to cancer cells by the drugs is very challenging, which has therefore resulted in low potency, poor target or isoform or kinase selectivity by the existing drugs or molecules in clinical trials. In addition, limited stability and unacceptable pharmacokinetic properties of most existing drugs have made off target effects very difficult to ignore. However, advances in cancer biology and drug discovery research have led to the development of several different types of targeted therapies and each of these targets cancer through different mechanisms. Among these, PI3K-Akt-mTOR signaling is an important regulator of most of the cellular processes. At cellular level, PI3K signaling regulates many processes including cell migration, angiogenesis, cell cycle progression, cell growth, survival and vesicular transport. There are many PI3K inhibitors under clinical development that target PI3K signaling which is highly deregulated in cancer. In addition, epigenetic modifiers like DNA methyl transferases, histone methyl transferases and histone deacetylases have also emerged as clinically validated targets and are being explored.At CSIR-IIIM Jammu, the major focus of Cancer Pharmacology Division has been target specific novel small molecule modulator(s) from natural products, synthetic and semi-synthetic sources in an attempt to achieve the more potent preventive and chemotherapeutic effects. The goal in this effort is to maximize the therapeutic effects of inhibitors against deregulated isoforms specific to particular cancers under in vitro and in vivo conditions. Interest is growing in the posttranslational modifications that comprise mainly the evaluation of histone code and their relationship to cancer development and as therapeutic tool. The division has state of the art facilities for in vitro cytotoxicity studies against human cancer cell lines, in vivo anticancer studies against murine tumor models/human cancer xenograft/orthotropic models and target based in vitro mechanistic studies leading to the discovery of novel anti-cancer chemotherapeutics. Furthermore, human embryonic and cancer stem cell modulations by small molecule(s) are being explored lately for understanding regenerative and therapeutic aspects respectively.

Mission and Goals

  • Discovery and preclinical development of target based novel molecule(s) for anticancer therapeutics from natural/synthetic/semi-synthetic sources followed by elucidation of mechanism of action in in vitro and in vivo models
  • Evaluating the different signaling pathways like PI3K, Akt, mTOR, IGF-R, EGF-R, Wnt/β-Catenin, HDAC, HMT, DNMT in context with cancer biology and drug discovery using proteomic, biochemical and molecular biology approaches
  • Modulation of human embryonic stem cells for self renewal, pluripotency, differentiation for pathway elucidation and cancer stem cell for possible therapeutics
  • Identification of small molecule(s) having role in induced pluripotent stem cell (iPSC) formation
  • Conducting and supporting basic research, human resource development, imparting training and participation in related cancer research programs at national/international level
  • To represent the institution at global level in the area of Cancer Biology & Drug Discover

Competencies

  • Enzyme inhibition & kinetic constants determination including isoform specific PI3K, Akt, mTOR, IGF-R, EGF-R, HDAC, DNMT, CDK, MMP, HMT, Phosphodiesterase etc; Cytotoxicity assays (MTT, XTT, SRB) against human cancer cell lines representing various cancers
  • Cell Migration; Invasion; Clonogenic; Angiogenesis assays like Tube formation, Permeability, Wound Healing, Matrigel Plug assay, Air Sac model, Aortic Ring assay; Gelatin zymography; qPCR; Western; Northern; Luciferase Reporter Gene Assay; Chromatin Immunoprecipitation (ChIP); Bisulphite & Methylation; Gene Silencing and Transfection; Histopathology; Immunohistochemistry; Live Cell Imaging; Fluorescence and Immunofluorescence; Confocal Microscopic, Scanning and Transmission Electron Microscopic Studies etc.
  • Epigenetic and Posttranslational Modification assays; Development of Precancerous Models
  • In vitro assays for different modes of cell death (Apoptosis & Autophagy)
  • In vivo anticancer studies against murine cancer models such as Ehrlich Ascites Carcinoma; Ehrlich Tumor (Solid); Sarcoma-180 Ascites; Sarcoma-180 (Solid); Methyl Cholanthrere Induced Ascites; L1210 Lymphoid Leukemia; P388 Lymphocytic Leukemia and Human Cancer Xenograft models; In vivo Hollow Fiber Mouse Model; In vivo Preclinical Anticancer Mutagenicity/Anti-mutagenicity Models; Hepatoprotective Assays etc
  • Detection of apoptosis/autophagy/necrosis; Detection of nuclei condensation; Cell cycle analysis; ROS estimation; Nitric oxide estimation; Mitochondrial membrane potential; Tunnel assay; Intracellular calcium measurement; DNA fragmentation; Genotoxicity by COMET Assay; Apoptotic/Autophagy signaling cascades via TNF-R1, Fas, DR4, Bcl-2, Bcl-xL, Bax, Cyt C, Bid, NF-κB, IκB, Survivin, HSP70, HSP-90, STAT-3, Akt, PI3K, mTOR, Telomerase, iNOS , DRP-1, Smac/Diablo, AIF etc; Determination of caspases activity; Topoisomerase I & II; PARP etc

Area of research

  • Anti-cancer Drug Discovery; Cancer Biology & Target based Therapeutic Strategies; Stem Cell Biology

Facilities

  • Cell Culture Facilities including C02 Incubators and Laminars; Cytometers with Cell Sorter; Confocal & Electron Microscope; Gel Documentation System; Multiplate Detection Reader (UV-Visible/UV, Fluorescence, Luminescence); Robotic Liquid Handling System Aided MTS; Electroblotter; Real Time PCR, 2-D Gel Electrophoretic System; FPLC; Electron Microscope (JEOL-JEM-100CXII) and LSCM (Fluoview-FV-1000); Deep Freezers (-20°C,-80°C); Refrigerated Centrifuges; Protein, RNA & DNA Electrophoretic Apparatus; Magnetic Stirrer; Millipore Water Purification System; pH Meter; Water Bath; Sonicator; Preparative and Analytical Centrifuges including Ultracentrifuge; High Precision Weighing Balance; Inverted Microscope (Phase Contrast); Scanning and Transmission Electron Microscope; Live Cell Image Analyzer; Fluorescence and Immuno-fluorescence Microscope etc.
  • Individually Ventilated Caging Systems; NOD.SCID (Immuno-deficient) Inbred Mice; Luciferase Expressing Human Cancer Cell Lines; IVIS Kinetic In Vivo Optical Imaging System; Inverted Phase Contrast Microscope; UV/Visible Spectrophotometer etc
  • AERB/BARC approved Radioactive Facilities (Type-1); Facilities include β-Scintillation Counters, Contamination and Radiation Monitor, β-Waste Shield, Autobypass Fume Hood, Safety Tray, Radiation Safety Shields & Boxes/Bags, Remote Handling Tongs, Decontamination Pit for Waste Disposal etc

Current

  • Evaluation of PI3K, Akt, mTOR, EGF-R, IGF-R,Wnt/β-catenin signaling in anticancer drug discovery in in vitro and in vivo models of cancer using novel molecules from natural/synthetic/semi-synthetic sources
  • Exploring the mechanism of action of lead molecule(s) exploring advanced understanding of cancer biology
  • Employing different signaling pathways for human embryonic stem cell fate modulation and in cancer stem cells by novel molecule(s)
  • Studies of lead molecule(s) for pre-clinical development and mutagenic/anti-mutagenic potential
  • Development of precancerous and cancerous assays/models for studying cancer development and inhibition

Projects

» BSC-0205:- Nurturing a new Pan-CSIR drug pipe line: high Intensity preclinical, clinical studies on lead candidates.
» BSC-0108:- Medicinal chemistry for stem cell biology and regenerative medicine.

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