MOLECULAR TARGETED THERAPIES IN ONCOLOGY
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1 Hacettepe University Institute of Oncology MOLECULAR TARGETED THERAPIES IN ONCOLOGY Emin Kansu, M.D.,FACP
2 PRESENTATION Biology of Cancer Molecular Targets in Cancer Cell Cancer Therapy Targeted Therapies in Oncology Nanocarriers as an emerging platform Nanomedicine in Cancer Therapy Types of Targeting Agents Future Prospects
3 CANCER NORMAL CELL Transformation VIRUSES ENVIROMENTAL FACTORS CHEMICALS GENES-ONCOGENES CANCER CELL
4 CANCER : CLONAL EVOLUTION CANCER
5 KANSER
6 CANCER CELLS Polimorphism..
7 RECEPTORS EGF-R VEGF-R HETEROGENEITY LUNG CANCER CELLS Scanning E/M
8 HETEROGENEITY OF CANCER CELLS
9 CANCER and METASTASIS 2004 Genentech, Inc. All rights reserved.
10 STAR WARS EPISODE : II DARK SIDE OF STEM CELLS
11 TREATMENT OF CANCER q SURGERY q CHEMOTHERAPY RADIOTHERAPY q
12 CHEMOTHERAPY Cancer cells Chemotherapy drugs target cancer cells because they are rapidly dividing DRUG Chemotherapy drug Cells destroyed Chemotherapy drugs enter the nucleus where they interfere with the DNA **CANCER CELLS may survive chemotherapy and resist further doses of Drugs. This is known as being refractory to chemotherapy!
13 BASIC QUESTIONS ASKED... IN CANCER THERAPY : CAN WE DEVELOP LESS TOXIC AGENTS THAN THE CURRENTLY AVAILABLE DRUGS,SPARING NORMAL CELLS and TISSUES? IS IT POSSIBLE TO DEVELOP NOVEL AGENTS BASED UPON CANCER CELL BIOLOGY?
14 TREATMENT OF CANCER q SURGERY q CHEMOTHERAPY RADIOTHERAPY q q BIOTHERAPY** Molecular Targeted Therapy
15 TARGETED THERAPIES IN ONCOLOGY SMART BOMBS
16 EINSTEIN and OPPENHEIMER
17 HIROSHIMA ve NAGASAKI ATOMIC BOMB August 1945
18 FOR HUMAN MANKIND...
19 WHICH CELL TO TARGET? WHICH STRUCTURE TO TARGET? WHICH MOLECULE TO TARGET?
20 CANCER
21 BASIC CELLULAR COMPONENTS
22 CELL BIOLOGY GENES mrnas PROTEINS CELL FATE
23 TARGET MOLECULES IN CANCER CELL
24 SMART TARGETS FOR TARGETED THERAPIES CELL MEMBRANE RECEPTORS CELL MEBRANE ANTIGENS SIGNALLING MOLECULES MOLECULES INVOLVED IN APOPTOSIS MOLECULES INVOLVED IN ANGIOGENESIS CELL CYCLE MOLECULES MICROENVIRONMENT
25 CELL MEMBRANE RECEPTOR SIGNAL DNA NUCLEUS
26 KANSER HÜCRESİNDE HEDEF MOLEKÜLLER Hücre Membranı TİROZİN KİNAZ SİNYAL MOLEKÜLLERİ TF Nukleus PROTEOZOM
27 ACTIVATION OF INTRACELLULAR SIGNALS LIGAND RECEPTOR SIGNALLING PATHWAYS
28 CELL WALL LIGAND RECEPTOR ONCOGENIC SIGNALLING*** * Protein Kinases *Jak-Stat Pathways
29 PROTEIN KINASES TYROSINE KINASE * THREONIN KINASE SERINE KINASE
30 CML THERAPY : GLIVEC Blocks Tyrosine Kinase Activity of Bcr-Abl
31 IMATINIB : MECHANISM OF ACTION IMATINIB INHIBITION OF PHOSPHORYLATION Bcr-Abl STOPS SIGNALLING CELL PROLIFERATION CELL SURVIVAL GLIVEC P ATP P P SIGNAL P Savage and Antman. NEJM 2002.
32 LEUKEMIC (CML) STEM CELLS WHERE and HOW DO THEY RESIDE? or HIDE? LEUKEMIC CELLS EARLY PROGENITORS Goldman J 2006, Weissman I 2007 LEUKEMIC STEM CELL COMPARTMENT DORMANT STATE + SELF-RENEWAL + NOT IN CELL CYCLE
33 LEUKEMIC (CML) STEM CELLS DO THEY HIDE?YES.. HOW? Don t Know AFTER CHEMOTHERAPY (TKIs) STEM CELL COMPARTMENT LEUKEMIC (CML) STEM CELLS *** DORMANT SELF-RENEWAL+ NOT IN CELL CYCLE
34 KEMOTERAPİ SONRASINDA KANSER KÖK HÜCRELERİ
35 MOLECULES OF SELF-RENEWAL IN STEM CELLS : Potential Targets in the Future WNT NOTCH SONIC HEDGEHOG
36 MULTI KINASE INHIBITORS ERLOTINIB SUNITIB SORAFENIB
37 * TUMOR ANTIGENS * * New Targets : CELL MEMBRANE ANTIGENS AND RECEPTORS Ligand TUMOR CELL RECEPTORS
38 CANCER CELL RECEPTORS
39 MONOCLONAL ANTIBODIES TO CELL MEMBRANE ANTIGENS AND RECEPTORS L H H L Fab-Region Antigen Binding region IgG IgA IgM IgD IgE H H Fc-Region STRUCTURE OF A MONOCLONAL ANTIBODY SYNTHESIZED BY HYBRIDOMAS
40 NANOMEDICINE Nanocarriers are nanosized structures (diameter nm) that can carry multiple drugs and/or imaging agents Nano : 2 Atom size
41 NANOCARRIERS FOR TARGETED DRUG DELIVERY (ANTIBODY) ANTI-CANCER DRUG
42 NANOCARRIERS : TYPES OF TARGETING AGENTS I. PROTEINS - ANTIBODIES***** -ANTIBODY FRAGMENTS II. NUCLEIC ACIDS -APTAMERS III. RECEPTOR LIGANDS -PEPTIDES -VITAMINS -CARBOHYDRATES
43 NANOMEDICINE & CANCER Nanoparticle Anti-Cancer Monoclonal Antibody Antibody + Nano Carrier CANCER CELL Ab Nano carrier Binding to Cancer Antigen CANCER CELL CELL DEATH
44 CANCER CELL 2004 Genentech, Inc. All rights reserved.
45 B-LYMPHOCYTE SURFACE ANTIBODIES IN THERAPY OF LYMPHOMAS sig CD 19 B LYMPHOCYTE CD 20 ANTI - CD20 (RITUXIMAB) 1997
46 HER-2 SIGNALLING - HERCEPTIN 1998 HER Receptors TK SIGNAL HER-2 RECEPTORS 2004 Genentech, Inc. All rights reserved.
47 Epidermal Growth Factor (EGFR) AS A TARGET : ERBITUX Baselga. Eur J Cancer 2002: 37 Suppl 4:S16-S22
48 MONOCLONAL ANTIBODY INDUCES Programmed Cell Death (APOPTOSIS ) Cytochrome c Caspase Activation APOPTOSIS
49 ANTI-CANCER MONOCLONAL ANTIBODIES MONOCLONAL TRADE ANTIBODY NAME INDICATIONS RITUXIMAB MABTHERA NHL - KLL TRASTUZUMAB HERCEPTIN BREAST CA ALEMTUZUMAB CAMPATH-1 NHL - CLL CETUXIMAB ERBITUX COLON CA ANTI-VEGF AVASTIN COLON CA
50 ALTUZAN : Anti-Angiogenic BEVACİZUMAB TUMOR NORMAL 2004 AFTER ALTUZAN
51 LABELLING OF MONOCLONAL ANTIBODIES DRUG (DAUNOMYCIN) * ISOTOPE * 131 Iodine, 90 Yttrium
52 CONJUGATED FORMS OF ANTI-CANCER MONOCLONAL ANTIBODIES RADIOIMMUNOCONJUGATE 3 IODINE TOSITUMOMAB :BEXXAR 90 YTTRIUM IBRITUMOMAB:ZEVALIN CHEMOTHERAPEUTIC CONJUGATE Calicheamycin + Anti-CD33 MYELOTARG
53 Iodine 131- TOSITUMOMAB BEXXAR ANTİ-CD20 IODINE 131* Slide 7
54 TOSITUMOMAB (BEXXAR) : Crossfire Action of Iodine-131 COLD ANTIBODY RADIOISOTOPE LABELLED MoAb Courtesy of Andrew Zelenetz, MD.
55 NANOMEDICINE DRUGS USED FOR CONJUGATION WITH POLYMERS DOXORUBICIN CAMPTOTHECIN PACLITAXEL PLATINATE
56 CANCER THERAPY : NEW TARGETS 4 7 Growth Factor Signaling Gene Transcription 2 RNA Translation 5 11 Plasma Membrane 7 17 Nuclear Membrane 12 DNA Replication and Repair Microtubule Dynamics 1. Growth factors 2. Growth factor receptors 3. Adaptor proteins 4. Docking proteins/ binding proteins 5. Guanine nucleotide exchange factors 6. Phosphatases and phospholipases 7. Signaling kinases 8. Ribosomes 9. Transcription factors 10. Histones 11. Molecular chaperones 12. DNA 13. Microtubules 14. Cyclins 15. Cyclin-dependent kinases 16. Cell death receptors 17. Apoptosis-effector caspases 18. Caspase inhibitors 19. CD40-CD40L Cell Growth Motility Survival Proliferation Angiogenesis
57 2006 in Physiology and Medicine ANDREW FIRE Carnegie Inst of Washington, USA CRAIG MELLO Univ Massachusets Cancer Ctr,USA Fundamental mechanisms by which gene expression and silencing is controlled with Process of RNA Interference - RNAi microrna (mirna)
58 NOBEL PRIZE IN MEDICINE 2009 Jack W. Szostak Professor of Genetics Harvard Medical School and MGH Carol W.Greider * Department of Molecular Biology Johns Hopkins University Medical School Ph.D. Supervisor : Elizabeth H.Blackburn (1987) Elizabeth H.Blackburn Professor of Biology & Physiology University of California at San Francisco
59 BENCH MOLECULAR TARGETING IN CANCER THERAPY
60 FUTURE OF NANOMEDICINE... IN VIVO NANODEVICES?
61 More expectations.. Future... We need more Basic and Clinical Research
62
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