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Cancer Research George Weiner

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Title: Holden Comprehensive Cancer Center Author: WeinerG Last modified by: Weiner, George Created Date: 10/6/2013 12:01:56 AM Document presentation format – PowerPoint PPT presentation

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Title: 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
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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
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Cost of sequencing DNA is plummeting
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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

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Grow
Die
Each of these steps is controlled by multiple
genes
In cancer, genes controlling these functions are
abnormal
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Grow
Die
  • Over active
  • Grow signals

Under active Die (or change) signals
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ItsComplicated
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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

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What looks similar on the outside may actually be
very different
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Even things with the same name can be very, very
different
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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

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Example Lung Cancer
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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
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Genetic Heterogeneity Within a Single Tumor
Gerlinger et al NEJM 2012
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Every Tumor is Different
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How can we be smarter in developing more precise
approaches to cancer prevention, early detection
and therapy?
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Old Paradigm
  • All patients receive the same treatment

New Paradigm
  • Treatment based on specific molecular abnormality

27
Pillars of Cancer Therapy
Surgery
Radiation
Chemo
28
Cancer develops when
Often, multiple abnormalities combine to result
in uncontrolled growth of cancer cell
29
  • Sleeping Beauty Transposon and Gene Discovery

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
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  • Sleeping Beauty Transposon and Gene Discovery

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
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 CellExplorer
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)
  • 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
  • qPCR in 96 and 384 well format
  • Multiplex detection
  • qPCR for small molecule effects
  • Target gene and house-keeping gene

Contact
Meng Wu, Ph.D. Director, UIHTS Facility, The
University of Iowa Phone (319) 335-8828 E-mail
meng-wu_at_uiowa.edu Website http//pharmacy.uiowa.e
du/high-throughput-screening-facility
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Cancer Immunotherapy
Monoclonal Antibody Therapy Cancer
Vaccines Cellular Immunotherapy
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AntibodyTherapy
Cellular T-Cell Response
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Production of Monoclonal Antibodies
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Murine Antibody
Poor interaction with human immune
system Immunogenic
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Monoclonal Antibody-InducedCancer Cell Lysis
Mediated by Immune System
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Therapeutic Effects of mAbNot Mediated by the
Immune System
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Antibody Drug Conjugates
  • Monoclonal antibody
  • Linker
  • Drug

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Steps Necessary for Antibody-Drug Conjugate to be
Effective
ADC
Receptor-Mediated Endocytosis
Target Antigen
Lysosome
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Select ADCs Approved or in Development
Hematologic Malignacies
Target Cancer ADC
CD33 AML Gemtuzumab ozogamacin
CD30 Hodgkin, ALCL Brentuximab vedotin
CD22 ALL, B Cell Lymphoma CMC544
CD19 ALL, B Cell Lymphoma SAR3419
CD74 Myeloma hLL1-DOX
CD138 Myeloma BT-062
CD56 Myeloma, Solid Tumors IMGN901
CD70 Lymphoma, Renal Cell SGN-75
42
Select ADCs Approved or in Development for Solid
Tumors
Target Cancer Type ADC
HER2 Breast Trastuzumab emtansine
GPNMB Breast, Melanoma CDX-011
PSMA Prostate PSMA-ADC
Ley Lung SGN-15
CA6 Various SAR566658
CanAng Various IMGN242
Av Integrin Various IMGN388
CEACAM5 Colorectal IMMU-130
Nectin-4 Various AGS-22M6E
AGS-16 Kidney, RCC AGS-16M8F
Anti-Cripto Various BIIB015
Carbonic Anhydrase Various BAY79-4620
Mesotheilin Various BAY94-9343
TENB2 Prostate Anti-TENB2 ADC
5T4 Lung A1mcMMAF

43
Antibody Drug Conjugate in Lymphoma
Monoclonal antibody against CD79b First in human
trial
N60
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
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Grow
Die
With infection, immune response results in
proliferation and activation of T cells
When infection is controlled, T cells are
programmed to die
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Cancer Immunotherapy Comes of Age Topalian,
Weiner and Pardoll Journal of Clinical Oncology
2012
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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
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Half Empty or Half Full?
  • Is cancer too complicated to address?
  • Should we give up because finding is so difficult
    to obtain?

52
Multidisciplinary Approach
  • In the laboratory
  • Geneticists, Immunologists, Pharmacologists,
    Biochemists, Cell biologists, Computational
    Biologists, Statisticians, Physicists, etc
  • In the clinic
  • Medical Oncologists, Surgical Oncologists,
    Radiation Oncologists, Pharmacists, Nurses,
    Physical Therapists, etc
  • In the community
  • Epidemiologists, Public Health Experts,
    Educators, Politicians, Philanthropists,
    Advocates, etc

The Holden Comprehensive Cancer Center has 190
Members with Each of These Backgrounds Working
Together on Cancer Research
53
Basic Clinical Population Molecule
/Cell Patient Community
Reduce Burden of Cancer
Prevention Detection Therapy Quality of Life
54
To address the complexity of cancerwe need
  • Basic Research Understand the complexity of
    cancer at the molecular and cellular level
  • Translational Research Use knowledge gained
    from basic research to design novel approaches to
    cancer prevention, early detection and therapy
  • Clinical Research Test novel approaches to
    cancer prevention, early detection and therapy
  • Population Research Evaluate what is happening
    in the real world and work to improve outcomes
  • Delivery of quality, state-of-the-art
    compassionate individualized care

55
Commitment and Persistence Example of new
initiative Molecular Epidemiology
Resources (MERs)
56
What is a MER?
  • Prospective Observational Database and
    Biorepository
  • Subjects
  • Cancer patients consented within 9 months of
    initial diagnosis
  • Clinical information
  • Staging, histology, lab, imaging, treatment
    modality, treatment response, events
    (progression, death)
  • Comorbidities
  • Update information 2x/year for 3 years, then
    annually
  • Psychosocial data at various time points
  • Biospecimens
  • Serum, plasma, buffy coat and peripheral blood
    DNA (some collected at multiple time points)
  • Tissue (tumor and normal) from resections and
    biopsies
  • Clinical data validated and ready to analyze

57
Molecular Epidemiology Resource Accrual
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Who uses the MERs?
  • Basic scientists interested in studying primary
    tissue
  • Population scientists interested in various
    aspects of outcomes research
  • Clinical investigators who need preliminary data
    on which to base a new clinical trial
  • Investigators interested in exploring new
    biomarkers
  • Host biomarkers
  • Tumor biomarkers

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Cancer Research 2013
  • We are in a moment of unique opportunity to make
    additional research advances and leverage recent
    research advances to reduce the burden of cancer
  • To take advantage of this unique opportunity, we
    need to work
  • More creatively
  • More efficiently
  • More collaboratively

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Thank you !!!
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