Cancer Research George Weiner

1. Cancer ResearchGeorge Weiner

2. American Association for Cancer Research Cancer Progress Report 2013 Making Research Count for Patients: A Continual Pursuit

6. Prevention Early Detection Therapy

7. Types of Cancer Research • Basic Research • Translational Research • T1 Basic Science to Humans • T2 Humans to Patients • T3 Patients to Clinical Practice • T4 Clinical Practice to Populations Will focus on Basic and T1 in this presentation Other types of research are equally important

8. Bench to Bedside New Approaches Prevention Early Detection Treatment Laboratory Research Basic Research Bedside to Bench Clinical Research

9. Cost of sequencing DNA is plummeting

10. Age of “Omics” Genomics, proteomics, etc • How DNA sequence impacts on gene expression • How gene expression impacts on production of proteins • How proteins impact on behavior of cells • How cells impacts on behavior of cancer • How cancer impact on patients • How cancer patients impact on society • How to leverage all of this information to reduce the burden of cancer

13. Grow Die Each of these steps is controlled by multiple genes In cancer, genes controlling these functions are abnormal

14. Over active “Grow” signals Grow Die Under active “Die” (or change) signals

15. It’sComplicated

16. Mutations Associated with Cancer Oncogenes Tumor suppressor genes DNA repair genes Cell cycle genes Cell cycle checkpoint genes Cell death genes Cell signaling genes Cellular differentiating genes Cellular senescence genes Metastasis and invasion genes Immune modulatory genes

17. What looks similar on the outside may actually be very different

18. Even things with the same name can be very, very different

19. Look beyond name and appearance • Tumors that look similar under the microscope have • Different genes misbehaving to cause the cancer • Each critical gene has hundreds of possible mutations • Each difference can impact on the behavior of cancer and its response to therapy

20. Example – Lung Cancer

21. Multiple mutations in a single tumor Some mutations are “Driver” mutations and are responsible for the malignant behavior of a cancer Some mutations are “Passenger” mutations and are just along for the ride Telling the difference can be difficult Cancers can “Change Drivers”

23. Genetic Heterogeneity Within a Single Tumor Gerlinger et al NEJM 2012

24. Every Tumor is Different

25. How can we be smarter in developing more precise approaches to cancer prevention, early detection and therapy?

26. Old Paradigm • All patients receive the same treatment New Paradigm • Treatment based on specific molecular abnormality

27. Pillars of Cancer Therapy Targeted Immuno Chemo Surgery Radiation

28. Cancer develops when… Cell “Grow” signal is stuck in the “on” position (Oncogenes) Often, multiple abnormalities combine to result in uncontrolled growth of cancer cell X Cell “Stop” signal is stuck in the “off” position (Tumor Suppressor Genes)

29. Adam Dupuy Todd Scheetz Fish gene that has been inserted into a mouse and randomly inserts itself into the mouse chromosomes and interupts other genes Cancer develops when mutations cause key genes to behave abnormally Sleeping Beauty Transposon and Gene Discovery

30. Find genes mutated by Sleeping Beauty Insertional Mutagenesis Oncogene Turns on gene that causes cell to grow abnormally Transposon Tumor Suppressor Tumor Turns off gene that normally stops cell from growing Transposon Genes found in mouse model of cancer have been found to be important in human cancer Sleeping Beauty Transposon and Gene Discovery

31. High Throughput Screening Facility • Objectives: Scalable high throughput screening platform for UI investigators and beyond • For hits/leads of the drug discovery of clinically significant targets • For probes for biological functions (mechanism of actions) of novel targets Capability: Detection System (HTS and HCS) Automatic Robotic Systems Screening Libraries Plate Readers PE EnVision Plate Imager PE Operetta Plate qPCR Roche LightCycler Hamilton MicroLab PE Cell:Explorer Small Molecule Libraries Other Libraries (biologics) • Handling screening libraries, library reformatting, cherry-picking, dose response building • Handling biochemical assays/screens • Handling large amount of plates • Handling cell-based assays/screens • Combing high throughput screening and high content screening (HTS & HCS) • Multimodal reader • Abs, Flu, Lum • FRET, BRET, TRF • Alpha-Screen • Monochrometer-based detection • Fluorescent imaging based system • Epi-fluorescence • Con-focal • Live-cell imaging (HTS & HCS) • qPCR in 96 and 384 well format • Multiplex detection • qPCR for small molecule effects • Target gene and house-keeping gene • Commercial libraries • MicroSource Spectrum of 2300 compounds • ChemBridge Diversity Set of 50,000 compounds • UI Legacy collection • Natural Products • Focused libraries • Peptide Libraries • Focused peptide libraries for gene transfer • siRNA libraries • In pursue • Antibody collections • In discussion Contact: Meng Wu, Ph.D. Director, UIHTS Facility, The University of Iowa Phone: (319) 335-8828; E-mail: meng-wu@uiowa.edu Website: http://pharmacy.uiowa.edu/high-throughput-screening-facility

33. Cancer Immunotherapy Monoclonal Antibody Therapy Cancer Vaccines Cellular Immunotherapy

34. AntibodyTherapy Cellular T-Cell Response Vaccines Induce Patients Immune Response To Produce T Cells T-Cell Therapy Modify T-Cells to Attack Tumor

35. Production of Monoclonal Antibodies

36. Human Antibody Chimeric Antibody Humanized Antibody Murine Antibody Poor interaction with human immune system Immunogenic

37. C Monoclonal Antibody-InducedCancer Cell Lysis Mediated by Immune System Complement Antibody Dependent Cellular Cytotoxicity ADCC

38. Therapeutic Effects of mAbNot Mediated by the Immune System Signaling Induced Apoptosis Blocking Angiogenesis or Other Vital Factors in Stroma Blocking Activation Signal

39. Antibody Drug Conjugates • Monoclonal antibody • Linker • Drug

40. Steps Necessary for Antibody-Drug Conjugate to be Effective ADC Receptor-Mediated Endocytosis Target Antigen Lysosome

41. Select ADCs Approved or in Development Hematologic Malignacies

42. Select ADCs Approved or in Development for Solid Tumors

43. Antibody Drug Conjugate in Lymphoma Monoclonal antibody against CD79b First in human trial N=60 Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 56; Palanca-Wessels ICML12 Lugano 2013

44. Checkpoint Blockade Where Monoclonal Antibody Therapy T-Cell Therapy Come Together

45. Grow Die With infection, immune response results in proliferation and activation of T cells When infection is controlled, T cells are programmed to die

46. Cancer Immunotherapy Comes of Age Topalian, Weiner and Pardoll Journal of Clinical Oncology 2012

48. Monoclonal antibodies block the checkpoint Anti-cancer T cells remain active Checkpoint Blockade Proceed to fight cancer No Treatment Turn off here Y Y

49. At this time of greatest potential, federal funding for biomedical research including cancer research is being cut