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<ul><li><p>1</p><p>Dabur Research FoundationNew Delhi, INDIA</p><p>www.daburresearch.in</p><p>ONCOLOGY SERVICES</p><p>Provided in Europe by the Exclusive Distributor </p><p>Kinase Logistics ApSStationsvej 805792 AarslevDenmark</p></li><li><p>2</p><p>Dabur Research Foundation (DRF)</p><p> Parent company was established in 1884, Dabur India Ltd is among the oldest and largest </p><p>healthcare companies in India, has over 5000 employees working in more than 20 countries</p><p> Contract Research Organization focused on Preclinical drug discovery &amp; Development</p><p> Positioned as an Oncology specialist CRO with services in several other therapeutic areas</p><p> Strength of 70 scientists with close to 40 % being PhDs recruited from the top 5 </p><p>Universities of India</p><p> Over 20 years of experience in preclinical development of Cytotoxics, biologically targeted </p><p>molecules, Phytochemicals, generics &amp; differentiated formulations in multiple therapeutic </p><p>areas</p><p> Comprehensive Services in Cell Biology, Pharmacology, Toxicology, DMPK, Bioanalytical, </p><p>Analytical &amp; formulation development to enable lead identification as well as lead </p><p>development</p><p> Availability of stand alone service modules &amp; complete service packages to meet various </p><p>client requirements</p><p> Availability of guideline-driven services as well customized services for the clients</p><p> GLP compliant studies managed by Project coordinators, Technical Coordinators &amp; QAU </p><p>teams</p></li><li><p>3</p><p>Phase I Phase II Phase IIIClinical</p><p>Support</p><p>Drug</p><p>Discovery </p><p>Early </p><p>Preclinical</p><p>Advanced</p><p>Preclinical</p><p>APISynthesis </p><p>&amp; Form. Dev </p><p>Drug </p><p>Manufacture</p><p>CLINICALCLINICAL</p><p>Biochemical &amp; Cell based </p><p>screens</p><p>Target basedscreens</p><p>Signal transduction</p><p>Molecularmodeling</p><p>in silico</p><p>Computational designing</p><p>Chemistry</p><p> Medicinal</p><p> Combichem</p><p> Computational</p><p> Natural Product</p><p> Analytical</p><p>Efficacy</p><p> Oncology</p><p> Diabetes </p><p> Pain</p><p> Inflammation</p><p> Dermatology</p><p> Hair</p><p>ADME</p><p>Bioanalytical</p><p>Characterization</p><p>Pharmacokinetics</p><p>Toxicology</p><p>Special Toxicity</p><p>Safety Pharmacology</p><p>Process Development</p><p>Scale up</p><p>Characterization</p><p>GMP Synthesis</p><p>GMP</p><p> Manufacture</p><p> Solid oral</p><p> Injectible</p><p>Bioavailability</p><p>Bioequivalence</p><p>Tissue banking</p><p> Data Management Plan </p><p> Database Design </p><p> CRF Management </p><p> Double Data Entry</p><p> Central Lab Data Import</p><p> Medical / AE Coding</p><p> Query Management</p><p> Manual Data Quality Control </p><p>Our Focus Areas</p><p>CRAMCRAMDRUG DISCOVERY &amp; PRECLINICALDRUG DISCOVERY &amp; PRECLINICAL</p></li><li><p>4</p><p>Cell Biology &amp; Pharmacology</p></li><li><p>5</p><p>in vitro Screens Cancer</p><p> Cell Lines</p><p> Indias largest tumor bank repository with human cancer cell linesrepresenting 15 20 different cancer types</p><p> Authenticated sources (ATCC / ECACC)</p><p> Screens validated with client defined reference drugs</p><p> Cell lines include -</p><p> Human Cancer lines</p><p> Epidermal cells</p><p> Hepatocytes</p><p> Cardiomyocytes</p><p> Endothelial cells</p><p> Assays</p><p> Validated cell based assays</p><p> Drug resistant cell lines available</p><p> Primary cultures for colon cancers available</p><p> Combination index method for evaluation of synergy</p><p>P-II tissue culture facility capable of screening up to 1000 compounds/month using the 96-well-plate format</p></li><li><p>6</p><p>Cancer cell lines</p><p>Name of cell line Tumor type Species</p><p>BRAIN</p><p>U-87 MG Glioblastoma, astrocytoma Human</p><p>SK-N-SH Neuroblastoma Human</p><p>SK-N-MC Neuroepithelioma Human</p><p>U373 MG Glioblastoma, astrocytoma Human</p><p>D283 Brain,cerebellum Human</p><p>BREAST</p><p>MCF-7 Breast Adenocarcinoma Human</p><p>T-47D Ductal carcinoma Human</p><p>MDA-MB-453 Mammary gland,Metastatic carcinoma Human</p><p>SK-BR-3 Mammary gland Human</p><p>ZR-75-1 Ductal carcinoma Human</p><p>HBL100 Mammary gland Human</p><p>COLON</p><p>SW620 Colorectal adenocarcinoma Human</p><p>Colo 205 Adenocarcinoma Human</p><p>HT-29 Colon Adenocarcinoma Human</p><p>HCT-15 Colorectal carcinoma Human</p><p>CACO-2 Human Caucasian Colon Adenocarcinomas Human</p><p>MELANOMA</p><p>B16-F10 Melanoma Mouse</p><p>SK-MEL-28 Melanoma, malignant Human</p><p>SK-MEL-2 Malignant melanoma Human</p><p>SK-MEL-5 Melanoma Human</p><p>LEUKEMIA</p><p>HL-60 Leukemia, acute promyelocytic Human</p><p>RAW 264 Leukemic monocyte-macrophage Mouse</p><p>K-562 Leukemia Human</p><p>MOLT-4 Human acute lymphoblastic leukemia Human</p><p>JurgatE6.1 leukemia Human</p><p>KIDNEY</p><p>COS 7 Kidney fibroblast Monkey</p><p>RAG Adenocarcinoma,Kidney Mouse</p><p>293 Kidney Human</p><p>MDCK canine kidney Dog</p><p>LUNG</p><p>DMS 114 Small Cell Lung Cancer Human</p><p>NCI-H460 Lung Carcinoma Human</p></li><li><p>7</p><p>Cancer cell lines</p><p>A-549 Lung Carcinoma Human</p><p>NCI-H345 Small Cell Lung Carcinoma Human</p><p>NCI-H522 Adenocarcinoma; non-small cell lung cancer Human</p><p>L-132 Embryonic lung tissue (HeLa contaminant) Human</p><p>PROSTATE</p><p>PC-3 Adenocarcinoma, Prostate Human</p><p>DU-145 Prostate, Carcinoma Human</p><p>LNCaP Prostate, Carcinoma Human</p><p>ENDOTHELIAL</p><p>HUVEC Primary human umbilical vein endothelial cells Human</p><p>EAHY 926 Endothelial Human</p><p>ECV304 Umbilical cord, endothelial Carcinoma Human</p><p>OVARY</p><p>PA1 Teratocarcinoma Human</p><p>SK-OV-3 Adenocarcinoma Human</p><p>NIH:OVCAR-3 Adenocarcinoma,Ovary Human</p><p>ORAL</p><p>KB Oral (HeLa contaminant) Human</p><p>SCC-25 Tongue Carcinoma Human</p><p>CAL 27 Tongue Carcinoma Human</p><p>HEART</p><p>H9C2 Heart myocardium Rat</p><p>GASTRO-Intestinal</p><p>INT 407 Intestine Human</p><p>FHs 74 Int Small Intestine Human</p><p>SNU-5 Gastric Carcinoma Human</p><p>HuTu 80 Duodenum,Adenocarcinoma Human</p><p>BONE</p><p>KHOS Osteosarcoma Human</p><p>MG-63 Osteosarcoma Human</p><p>HOS Osteogenic Sarcoma Human</p><p>PANCREAS</p><p>MIA PaCa-2 Pancreas Carcinoma Human</p><p>Capan-2 Pancreatic Carcinoma Human</p><p>HPAC Human Pancreas Human</p><p>LIVER</p><p>HepG2 Carcinoma, hepatocellular Human</p><p>SKIN</p><p>A-431 Carcinoma, epidermoid Human</p><p>HFF-1 Human foreskin, fibroblast Human</p><p>+ many more</p></li><li><p>8</p><p> Test System</p><p> Cancer cell lines</p><p> Method</p><p> Determination of % cytotoxicity &amp; IC50 of individual drugs</p><p> Selection of concentrations around IC50 for</p><p>combination studies</p><p> Testing all possible combinations of drugs for</p><p>combined cytotoxicities</p><p> Calculation of Combination Index (CI)</p><p> CI1 - Antagonism</p><p> End points</p><p> Categorization of drug combinations as</p><p>synergistic/additive/antagonistic for each combination</p><p>tested.</p><p>Evaluation of drug interactions in combination cancer chemotherapy by combination index method</p><p>Drug Combination Studies</p><p>Drug 1</p><p>Drug 2</p></li><li><p>9</p><p>Xenograft Models1</p><p>Strains</p><p> FoxN1 or NMRI strain athymic nude mice SCID mice C57BL/6 mice</p><p>Xenograft Models</p><p> Ovary Oral Lung Colon Melanoma + other solid cancers incl. Adenocarcinomas &amp; squamous cell carcinomas</p><p>End points Body weight Change Median Tumor Volume % Tumor Growth Inhibition Log Cell Kill %T/C Relative Tumor Volume Tumor Growth Delay Regression Chart</p><p>All studies carried out in a welfare regulations approved rodent animal facility equipped with state-of-the-art barrier facility. We have performed efficacy studies for more than 100 NCEs </p><p>including plant-based, synthetics, biologicals &amp; differentiated products</p></li><li><p>10</p><p>Xenograft Models..2</p><p>0</p><p>250</p><p>500</p><p>750</p><p>1000</p><p>1250</p><p>1500</p><p>1750</p><p>2000</p><p>18 20 22 24 26 28 30 32 34 36 38</p><p>Days Post inoclulation</p><p>Med</p><p>ian </p><p>Tum</p><p>or V</p><p>olum</p><p>e (m</p><p>m3 ) Vehicle Control</p><p>Tamoxifen Citrate, 10mg/kg, s.c.</p><p>In-vivo anticancer activity of Tamoxifen citrate on nude mice bearing MCF-7 tumor</p><p>Time to Reach 500mm3</p><p>24</p><p>&gt;38</p><p>0 10 20 30 40</p><p>VehicleControl</p><p>TamoxifenCitrate,</p><p>10mg/kg, s.c.</p><p>Days</p><p>Median %T/C</p><p>0</p><p>25</p><p>50</p><p>75</p><p>100</p><p>125</p><p>18 20 22 24 26 28 30 32 34 36 38Days</p><p>Med</p><p>ian </p><p>%T/</p><p>C Tamoxifen Citrate, 10mg/kg, s.c.</p><p>Treatment Partial </p><p>Regression</p><p>Complete </p><p>Regression</p><p>Cure</p><p>XXX, 50mg/kg,p.o. </p><p>Late stage model0 1 0</p><p>XXX, 30mg/kg,p.o. </p><p>Early stage model1 1 2</p></li><li><p>11</p><p>Xenograft Models3</p><p>Median Tumor Volume</p><p>0</p><p>250</p><p>500</p><p>750</p><p>1000</p><p>1250</p><p>1500</p><p>1 3 5 7 9 11 13 15 17 19 21 23 25 27 29Days</p><p>Med</p><p>ian </p><p>Tum</p><p>or V</p><p>olum</p><p>e (m</p><p>m3)</p><p>Vehicle Control</p><p>Erlotinib, 90mpk,po</p><p>In-vivo anticancer activity of Erlotinib on nude mice bearing A549 tumor</p><p>Time to Reach 500mm3</p><p>30.2</p><p>45.5</p><p>0 10 20 30 40 50</p><p>VehicleControl</p><p>Erlotinib,90mpk,po</p><p>Days</p><p>Median %T/C</p><p>0</p><p>25</p><p>50</p><p>75</p><p>100</p><p>125</p><p>1 3 5 7 9 11 13 15 17 19 21 23 25 27 29</p><p>Days</p><p>Med</p><p>ian </p><p>%T/</p><p>C Erlotinib, 90mpk,po</p></li><li><p>12</p><p>Xenograft Models..4</p><p>Antitumor activity of DRFXXX on HT-29 (colon) xenograft. </p><p>Antitumor activity of DRFXXX on HuTtu-80 (duodenum) xenograft. </p><p>0</p><p>1000</p><p>2000</p><p>3000</p><p>4000</p><p>5000</p><p>6000</p><p>0 5 10 15 20 25 30</p><p>Days post inoculum</p><p>Tum</p><p>or v</p><p>olum</p><p>e (c</p><p>u.m</p><p>m)</p><p>Untreated</p><p>DRF7295</p><p>T/C% = 19.1%</p><p>0</p><p>1000</p><p>2000</p><p>3000</p><p>4000</p><p>5000</p><p>0 10 20 30</p><p>Days post inoculum</p><p>Tum</p><p>or v</p><p>olum</p><p>e (c</p><p>u.m</p><p>m)</p><p>UntreatedDRF7295 T/C% = 2.8%</p></li><li><p>13</p><p>in vivo Models Syngeneic..1</p><p> Animals C57BL/6 mice BALB/c</p><p> Syngeneic Models Lung Colon</p><p> Metastasis Model</p><p> Mouse melanoma - lung nodule- I.V Injection of melanoma cells in C57BL/6 mice- Estimation of Number of Lung nodule, Melanin content, etc</p><p> Colon SQ Model ( CT-26 - Colon )- SQ injection of CT-26 in BALB/c mice- Development of Solid tumor &amp; Metastatic tumor at</p><p>colon, pancreas, lung, etc- Tumor growth, Histopathology etc..</p><p>Relative Melanin Content</p><p>0</p><p>25</p><p>50</p><p>75</p><p>100</p><p>G1, SWFI, 10ml/kg,p.o. S1P ReceptorModulator,60mg/kg,p.o.</p><p>in vivo model for assessment of anti-cancer potential of Compounds using syngeneic model</p></li><li><p>14</p><p>Median Tumor Volume</p><p>0</p><p>1000</p><p>2000</p><p>3000</p><p>4000</p><p>5000</p><p>1 3 5 7 9 11 13 15</p><p>Days</p><p>Med</p><p>ian </p><p>Tum</p><p>or V</p><p>olum</p><p>e (m</p><p>m3 )</p><p>Vehicle Control</p><p>Paclitaxel, 5mg/kg, i.v.</p><p>Median %T/C</p><p>0</p><p>25</p><p>50</p><p>75</p><p>100</p><p>1 3 5 7 9 11 13 15Days</p><p>Med</p><p>ian </p><p>%T/</p><p>C</p><p>Paclitaxel, 5mg/kg, i.v.</p><p>In-vivo anticncer activity of Paclitaxel on BALB/c bearing CT-26 colon tumor</p><p>Time to Reach 500mm3</p><p>14</p><p>0</p><p>0 5 10 15</p><p>VehicleControl</p><p>Paclitaxel,5mg/kg, i.v.</p><p>Days</p><p>Syngeneic Models2</p></li><li><p>15</p><p>Syngeneic Models3</p><p>Median Tumor Volume Chart</p><p>0</p><p>500</p><p>1000</p><p>1500</p><p>2000</p><p>2500</p><p>3000</p><p>3500</p><p>1 3 5 7 9 11 13 15Days</p><p>Med</p><p>ian </p><p>Tum</p><p>or V</p><p>olum</p><p>e (m</p><p>m^3</p><p>)</p><p>Vehicle Control</p><p>5-FU, 12mg/kg, i.p.</p><p>Median %T/C</p><p>0</p><p>20</p><p>40</p><p>60</p><p>80</p><p>100</p><p>1 3 5 7 9 11 13 15Days</p><p>Med</p><p>ian </p><p>% T</p><p>/C 5-FU, 12mg/kg, i.p.</p><p>In-vivo anticancer activity of 5-FU on BALB/c bearing CT-26 colon tumor</p><p>Median Tumor Volume Chart</p><p>0</p><p>500</p><p>1000</p><p>1500</p><p>2000</p><p>2500</p><p>3000</p><p>3500</p><p>1 3 5 7 9 11 13 15Days</p><p>Med</p><p>ian </p><p>Tum</p><p>or V</p><p>olum</p><p>e (m</p><p>m^3</p><p>)</p><p>Vehicle Control</p><p>Herbal Formulation,500mg/kg</p><p>Herbal Formulation, 500mg/kg</p><p>0</p><p>10</p><p>20</p><p>30</p><p>40</p><p>50</p><p>60</p><p>70</p><p>80</p><p>90</p><p>100</p><p>1 3 5 7 9 11 13 15Days</p><p>Med</p><p>ian </p><p>% T</p><p>/C</p><p>Anticancer activity of Herbal formulation on BALB/c bearing CT-26 colon tumor</p></li><li><p>16</p><p>in vivo Models leukemia</p><p>in vivo model for assessment of anti-Leukemic potential of Compounds </p><p>Model Assessment of anti-leukemic activity of the compounds in SCID mice</p><p>Test system SCID mice</p><p>Method</p><p> Intravenous inoculation of leukemic cell line Administration of test item and reference item at predetermined </p><p>time Observation of animals for defined time period Observation of animals in satellite group for occurrence of </p><p>chloroma Percentage Change in body weight Survival rate of animals Clinical signs &amp; symptoms Quantification by flow cytometry analysis in bone marrow &amp; </p><p>peripheral blood</p><p>End points Standard surface specific antigen staining - CD45</p><p> Lineage specific antigen staining Histopathology</p></li><li><p>17</p><p>in vivo Models Angiogenesis</p><p>in vivo &amp; In-vivo model for assessment of anti-angiogenesis potential of Compounds</p><p> Currently available Angiogenesis Model</p><p> In-vivo SQ Model in C57BL/6- SQ injection of Matrigel with growth factors</p><p>(FGF &amp; VEGF)- Histopathology, Hb content etc..</p><p> In-vitro Tube formation assay- Culture of HUVEC on Matrigel plate- Estimation of branch point, Tube area and tube length</p><p> In-vitro cell migration Assay- HUVEC Cell- No. of cells migrated towards wound area</p><p> In-vitro VEGF estimation- Incubation of Test compound with various cells (HUVEC etc..)- Estimation of endogenous VEGF production using ELISA</p></li><li><p>18</p><p> Test Principle</p><p> The in-vitro studies are not fully predictive of the metastatic behavior of tumor cells due to</p><p>its lack of interaction with the host. B16F10, a murine melanoma selectively colonize the</p><p>lung after intravenous administration.</p><p> Test System</p><p> C57BL/6 Mice; 6-8week</p><p> Method</p><p> B16F10 cells cultured and injected into the lateral tail vein at the conc. of 5-10X104 in 0.2ml.</p><p> The test animals grouped as per experimental design</p><p> Treatment as per recommended dose &amp; regimen</p><p> Humane sacrifice on 3-4weeks and lung will be weighed &amp; fixed in Bouins solution</p><p> End points</p><p> Lung weight</p><p> Lung Nodule</p><p> Relative melanin content</p><p>Lung Metastasis Model</p><p>Evaluation of Anti metastatic potential by lung colonization assay using murine syngenic Melanoma model</p></li><li><p>19</p><p>Lung Metastasis Model2</p><p>0</p><p>10</p><p>20</p><p>30</p><p>G1, SWFI, 10ml/kg,p.o. S1P ReceptorModulator,60mg/kg,p.o.</p><p>No.</p><p> of l</p><p>ung </p><p>nodu</p><p>les</p><p>Relative Melanin Content</p><p>0</p><p>25</p><p>50</p><p>75</p><p>100</p><p>G1, SWFI, 10ml/kg,p.o. S1P ReceptorModulator,60mg/kg,p.o.</p><p> Weight of Lung</p><p>0</p><p>0.1</p><p>0.2</p><p>0.3</p><p>0.4</p><p>0.5</p><p>0.6</p><p>0.7</p><p>0.8</p><p>0.9</p><p>Untreated XXX, 5mg/kg, i.v Normal lungs</p><p>Wei</p><p>ght o</p><p>f lun</p><p>g (g</p><p>ram</p><p>s)</p><p>*</p><p>*Control</p><p>XXX Receptor </p><p>Modulator, 60mg/kg</p><p>Model under Validation</p><p>Spontaneous Meatstasis Model B16F10 cell injection into the foot pad of C57BL6 Mouse</p></li><li><p>20</p><p>in vivo Models Orthotopic</p><p> Animals Nude and SCID Mice</p><p> Models Colon Liver Breast Spleen Renal</p><p> Currently available Orthotopic Model</p><p> Colon Model- Development of Solid tumor &amp; Metastatic tumor at</p><p>colon, pancreas, lung etc- Tumor growth, Histopathology etc..</p><p>in vivo model for assessment of anti-cancer potential of Compounds using orthotopic model</p></li><li><p>21</p><p>Mechanistic Studies</p></li><li><p>22</p><p>Sorting Endosomes</p><p>ACTIVE TARGETING IN CYTOPLASM</p><p>Early Endosomes</p><p>Free Paclitaxel</p><p>6 Tubulin Stabilization</p><p>Nanoparticle micelles containing Paclitaxel</p><p>1</p><p>NIPAM based Micellar polymers with LCST of 52-60 C in plasma</p><p>2Targeting through EPR effect</p><p>3Polymer aided higher cellular </p><p>uptake</p><p>4</p><p>Intracellular trafficking through endosomal lysosomal compartment</p><p>5 Drug Release from micelles at low pH conditions in Endo-</p><p>lysosomal compartment</p><p>Early Endosomes</p><p>7 Apoptosis</p><p>MECHANISTIC PROFILING STRATEGIES</p><p>Nanoxel - A novel Nanopolymer based tumor targeted delivery system for Paclitaxel - ASCO 2008</p></li><li><p>23</p><p>Complete repertoire of Screens for PCD to enable selection of Proapoptotic molecules</p><p> Apoptotic pathways</p><p> Death receptor and mitochondrial pathway</p><p> Parameters</p><p> Transmembrane Mitochondrial permeability</p><p> Cell Cycle</p><p> Reactive oxygen species (ROS) quantitation</p><p> Levels of pro-apoptotic and anti-apoptotic proteins</p><p> Ras-ERK kinases</p><p> Caspase 3 activation</p><p> PARP cleavage</p><p> DNA fragmentation</p><p> Micronuclei staining</p><p>Apoptosis Screens</p></li><li><p>24</p><p>Models for Clinical Toxicities</p></li><li><p>25</p><p>in vivo Model for Cardiotoxicity</p><p>Preclinical Models to compare lead molecules/ formulations to assess cardiac safety</p><p> Model</p><p> Wistar rat/ FVB mice</p><p> Parameters</p><p> Serum markers</p><p> CK-MB </p><p> LDH </p><p> Validated with Dex.</p><p> Myocardial markers</p><p> SOD enzyme </p><p> Catalase enzyme </p><p> Reduced Glutathione</p><p> Glutathione peroxidase</p><p> Lipid Peroxidation</p><p> Histopathology</p><p> Light microscopy</p><p> Electron microscopy</p><p> Heart wt &amp; Body wt. ratio.</p><p>Discrete markers of toxicity in cardiac biopsies</p><p>CK-MB</p><p>Wistar rat</p><p>Biochemical analysis &amp; Histopathology</p></li><li><p>26</p><p>in vivo Model for Gastrointestinal Safety</p><p>Preclinical in vivo models to compare lead molecules / formulations for their potential to cause Gastrointestinal toxicity during Clinical development</p><p> Validated Screens</p><p> in vivo:</p><p> Adult Wistar rat FOLFOX induced models</p><p> Parameters</p><p> External analysis of scores</p><p> Oral Mucositis Index (OMI)</p><p> Erythema</p><p> Ulceration</p><p> Internal analysis of scores</p><p> Number of ulcers in tongue</p><p> % Ulcerative area in tongue</p><p> Histopathological evaluation</p><p> Loss of keratinized filliform papillae</p><p> Decrease in mucosal thickness </p><p> Necrotic fibrinoid material</p><p> Inflammatory cells </p><p> Active granulation tissue</p><p>External Stomatitis</p><p>Ulcer scoring</p><p>Tongue Histology</p></li><li><p>27</p><p> Validated Screens in vitro:</p><p> Murine model - Hematopoeitic progenitor cellsfrom Bone marrow of C57/BL6 mice</p><p> Human model - Cord Blood cells </p><p> Parameters</p><p> Scoring of CFU-GM colonies</p><p> Determination of IC 50 values Inhibition of cell p...</p></li></ul>