MD206 2023-24 Molecular Medicine Introduction PDF

MD206 2023-24 Molecular Medicine Introduction Prof. Corrado Santocanale Centre for Chromosome Biology CHROMOSOME REPLICATION AND CANCER THERAPEUTICS Corrado Santocanale BSc (1988) Milan Genetics PhD (1993) U of Milan (Advisor: Paolo Plevani) Post Doc (1994-1999) CRUK (ICRF), London Project leade...

MD206 2023-24 Molecular Medicine Introduction Prof. Corrado Santocanale Centre for Chromosome Biology CHROMOSOME REPLICATION AND CANCER THERAPEUTICS Corrado Santocanale BSc (1988) Milan Genetics PhD (1993) U of Milan (Advisor: Paolo Plevani) Post Doc (1994-1999) CRUK (ICRF), London Project leader (1999-2007) Pharmacia/Pfizer/NMS Oncology R&D, Italy Principal Investigator/Prof Molecular Medicine (2007-present) CCB, NUI Galway Cdc7: N-terminal Lobe I II Kinase Insert I10aa I I I C-terminal Lobe IV V VIA Hinge VIA VIII IX VII Kinase Insert II A-loop: 156aa X Kinase Insert III: 97aa XI 30aa 1. Roles of Cdc7 kinase in DNA replication 2. Cdc7 inhibitors in cancer therapy Cdt1 MCM ORC Cdc6 P P P Cdc7 Dbf4 Cdc7 Drf1 SFI funded research aimed at understanding the structure, functions and regulation of Cdc7 kinase using genetic and biochemical approaches • Cdc7 inhibitors have potent antitumor activity • Looking for genes that determine the potency of Cdc7 inhibitors www.santocanalelab.net • • • • • • Daniel Shamavu Bernard Stefanus Michael Rainey Anja Goder Corrado Santocanale Michael Rainey Molecular medicine – what is it? • A science that seeks to comprehend disease causes and mechanisms at the molecular level, and to apply this basic research to the prevention, diagnosis and treatment of diseases and disorders. National Library of Medicine, USA • A branch of medicine that develops ways to diagnose and treat disease by understanding the way genes, proteins, and other cellular molecules work. Molecular medicine is based on research that shows how certain genes, molecules, and cellular functions may become abnormal in diseases such as cancer. National Cancer Institute, USA Disease • Causes • Mechanisms • Genes, proteins and cellular processes • Functions • At a molecular level • Toward prevention, diagnosis, treatment, based on specific knowledge of molecular pathology Key features of MD206 • Requires of good understanding of structure and function of biomolecules: DNA, RNA and Proteins • And how they work together • A team of researchers contribute to the modules • Highly experts in the field • Organised in units • from basic concepts in biology to disease specific alterations, to rational treatments and techniques • Cell Cycle and DNA repair • Cell Signalling • Cell Biology of Cancer • Concepts of cancers and DDR • From Oncogenes and Tumour Suppressors to Drugs • Concepts of immuno-oncology • Apoptosis • Techniques and diagnostics Learning materials • Lecture notes will be uploaded in Canvas • Additional reading in Canvas • Scientific reviews • Suggested books: • Alberts et al Molecular Biology of THE CELL 6th ed. Garland Sciences • Weinberg R.A. (2013) The Biology of Cancer Garland Scientific • Final exam as MCQ covering the material of the all course Hemoglobin and the birth of molecular medicine • Sickle cell anemia is a genetic disorder of erythrocytes. It affects the shape of red blood cells • Anemia. Fatigue. Episodes of pain. Swelling of hands and feet. Frequent infections. Delayed growth or puberty. Vision problems • The major protein of erythrocytes is hemoglobin • Hemoglobin is a globular heterotetrameric protein of red blood cells that binds oxygen • In 1949 Linus Pauling and coworker’s asked – is sickle cell hemoglobin different to normal hemoglobin? Sickle-cell anemia hemoglobin is molecularly distinct from normal • Pauling used very early electrophoresis methods, separating protein by charge • He found an altered mobility for hemoglobin (Hb) in sickle cell anemia patients • He found both normal and altered Hb in people with sickle cell traits, asymptomatic carriers of the disease • He reasoned that • The cause of sickling was the presence of an abnormal Hb molecule with altered charge • The 50:50 mix of normal: sickle Hb was caused by genetic heterozygosity • That an alteration in the Hb gene caused an alteration in the corresponding protein • From this work Pauling coined the term ’molecular medicine’ Impact of molecular medicine on COVID-19 • Diagnosis based on symptoms • Hand washing • Face masks • Isolation and lockdowns • Forced ventilation • hydroxychloroquine and other antiviral drugs •… Impact of molecular medicine on COVID-19 Diagnosis based on symptoms Hand washing Face masks Isolation and lockdowns Forced ventilation hydroxychloroquine and other antiviral drugs • … • • • • • • • • • • • Biology of Coronaviruses SARS-CoV-2 sequenced PCR detection of viral RNA Antigen test Vaccine development • mRNA based • Viral based • Detection of SARS-CoV-2 variants • New antiviral drugs that specifically target SARS-Cov2 critical functions • …. MD206 focus on molecular medicine in cancer • Cancer is probably the disease that has most been touched by the revolution of molecular medicine • The areas of signal transduction and cancer biology will be presented in detail to illustrate how in-depth knowledge of molecular processes leads to new understanding and therapeutic strategies. • In addition, this module introduces some of the core technologies of contemporary molecular biology used in molecular medicine. Protein kinase inhibitors and the human kinome • Protein kinases are key regulatory enzymes that coordinate cell signaling processes • Mutations in protein kinases are associated with several cancers • Bcr/Abl in leukemia – Philadelphia chromosome • Src, EGFR, Akt in several cancers • Human kinome = the complete set of protein kinase genes in the genome = >500 Protein kinase inhibitors • Owing to the dysregulation of protein kinase activity in many diseases including cancer, the protein kinase enzyme family has become one of the most important drug targets in the 21st century. • There are 73 FDA-approved therapeutic agents that target about two dozen different protein kinases and eight of these were approved in 2020. • Major development in pharmaceutical industry Antibody based therapy to attack cancer cells Antibodies: • normally produced by B cells of immune system to fight infections • can be directed to recognise tumour cell surface antigens • Can be humanised • Can recruit other immune cells to fight cancer cells • Can be linked to highly potent cytotoxic drugs Rewiring the immune system to attack cancer: cell therapies Unit 1: Cell Cycle and DNA repair • • • • Understand and describe basic processes of the cell cycle Mechanisms and regulation of cell cycle transitions CDK regulation and activity DNA repair pathways • Value as drug target Corrado Santocanale Prof of Molecular Medicine PI DNA replication and cancer therapeutics group Centre for Chromosome Biology School of Biological and Chemical Sciences Unit 1 Cell signaling • Understand various methods used by cells to communicate • Know the features of different types of signaling • Have an understanding of the significance of signal transduction in health and disease Eva Szegezdi Principal investigator of the Cancer Niche Laboratory Head of the Blood Cancer Biobank in Ireland PI in the Genomics Data Sciences training centre Unit 3 Cell biology of Cancer • • • • • • Hallmarks of cancer Telomeres and cellular immortality Mechanisms of metastasis Angiogenesis and tumor formation Tumor associated inflammation Tumor as organ Kevin F. Sullivan Professor of Cell Biology Centre for Chromosome Biology School of Biological and Chemical Sciences Unit 4 General concepts of cancers • • • • • Definition of cancer Types of tumors Darwinian evolution of cancers Signaling pathways and gatekeepers in cancer DNA damage responses Noel Lowndes Professor of Biochemistry PI DNA damage response group Fellow of the Royal Irish Academy Centre for Chromosome Biology School of Biological and Chemical Sciences Unit 5 From genes to drugs • • • • • • Cancer mutations, oncogenes and tumor suppressors Definitions in chemotherapeutics Uses, activities, limitations of cancer drugs Strategies to target oncogenes and tumor suppressors Molecular targeted therapeutics Drug discovery process Corrado Santocanale Prof of Molecular Medicine PI DNA replication and cancer therapeutics group Centre for Chromosome Biology, School of Natural Sciences Unit 6 Apotosis, advanced therapies and concepts of immuno-oncology • Mechanisms of cell death • Key feature of the immune system • Cellular therapies Michael O'Dwyer Founder and Chief Scientific Officer ONK Therapeutics Professor of Haematology School of Medicine Consultant at UHG Unit 7 Techniques and Diagnostics • • • • Polymerase chain reaction – PCR DNA sequencing DNA microarrays Immunoassays Peter Creighton School of Natural Sciences Communication / information • Canvas announcements : MD206 and 2MB3 pages • For academic queries related to material presented in the lectures: lecturer • Others queries related to course: Corrado Santocanale • Administrator: Claudia Flaus Key features of MD206 • Requirement of good understanding of structure and function of biomolecules: DNA, RNA and Proteins • A team of researchers contribute to the modules • Highly experts in the field • Organised in units • from basic concepts in biology to disease specific alterations, to rational treatments and techniques • Lecture notes will be uploaded in Canvas • Suggested books and reading in Canvas • Final exam as MCQ covering the material of the all course 100% of marks • Very important to attend lectures and keep up with the studies Week 1 2 3 4 5 6 7 8 9 10 11 12 day/time 4 Sept Monday 2-3pm 8 Sept Friday 3-4pm 11 Sept Monday 2-3pm 15 Sept Friday 3-4pm 18 Sept Monday 2-3pm 22 Sept Friday 3-4pm 25 Sept Monday 2-3pm 29 Sept Friday 3-4pm 2 Oct Monday 2-3pm 6 Oct Friday 3-4pm 9 Oct Monday 2-3pm 13 Oct Friday 3-4pm 16 Oct Monday 2-3pm 20 Oct Friday 3-4pm 23 Oct Monday 2-3pm 27 Oct Friday 3-4pm 30 Oct Monday 2-3 pm 3 Nov Friday 3-4pm 6 Nov Monday 2-3pm 10 Nov Friday 3-4pm 13 Nov Monday 2-3 pm 17 Nov Friday 3-4pm 20 Nov Monday 2-3 pm 24 Nov Friday 3-4pm title Introduction to Molecular Medicine Cell Cycle and DNA repair Cell Cycle and DNA repair Cell Cycle and DNA repair Cell Signalling Cell Signalling Cell Signalling Cell Biology of Cancer Cell Biology of Cancer Cell Biology of Cancer Concepts of cancers and DDR Concepts of cancers and DDR Concepts of cancers and DDR Oncogenes and tumor suppressor genes Principles of Chemotherapeutics Drug development Bank Holiday no lecture/ mini test Apoptsis Concepts of immuno-oncology Immuno-oncology and therapy Techniques and diagnostics Techniques and diagnostics Techniques and diagnostics lecturer CS CS CS CS ES ES ES KS KS KS NL NL NL CS CS CS CS TBD MoD MoD PC PC PC