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Cancer ResearchCancer ResearchGeorge WeinerGeorge Weiner
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American Associationfor Cancer Research
Cancer Progress Report 2013
Making Research Count for Patients: A
Continual Pursuit
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Prevention
Early Detection
Therapy
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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 presentationOther types of research are equally important
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Labo
rato
ry
Resea
rch
Clinica
l
Research
Bench toBedside
Bedside to
Bench
New ApproachesPrevention
Early DetectionTreatment
BasicResearch
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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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Over active“Grow” signals
Grow Die
Under active
“Die” (or change) signals
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It’sComplicated
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Mutations Associated with CancerOncogenes
Tumor suppressor genesDNA repair genesCell cycle genes
Cell cycle checkpoint genesCell death genes
Cell signaling genesCellular differentiating genes
Cellular senescence genesMetastasis 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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Gerlinger et alNEJM 2012
GeneticHeterogeneity
Within aSingle Tumor
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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
• Treatment based on specific molecular abnormality
New Paradigm
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Pillars of Cancer Therapy
Surgery Radiation ImmunoChemoTargeted
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Cancer develops when…
Cell “Grow” signal is stuck in the “on” position
(Oncogenes)
Cell “Stop” signal is stuck in the “off” position (Tumor Suppressor
Genes)
X
Often, multiple abnormalities combine to result in uncontrolled growth of cancer cell
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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
Oncogene
Tumor Suppressor
Transposon
Tumor
Insertional Mutagenesis
Transposon
Turns on gene that causescell to grow abnormally
Turns off gene that normallystops cell from growing
Find genes mutated bySleeping Beauty
Genes found in mouse model of cancerhave been found to be important in human cancer
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Detection System (HTS and HCS)
High Throughput Screening Facility
Objectives: Scalable high throughput screening platform for UI investigators and beyond For hits/leads of the drug discovery hits/leads of the drug discovery of clinically significant targets For probes for biological functions probes for biological functions (mechanism of actions) of novel targets
Capability:
Automatic Robotic Systems Screening Libraries
Hamilton MicroLab PE Cell:Explorer
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)
Plate ReadersPE EnVision
Plate ImagerPE Operetta
Multimodal readero Abs, Flu, Lumo FRET, BRET,
TRFo Alpha-Screen
Monochrometer-based detection
Fluorescent imaging based system o Epi-fluorescenceo Con-focal
Live-cell imaging (HTS & HCS)
Small Molecule Libraries
Other Libraries(biologics)
Commercial librariesoMicroSource Spectrum
of 2300 compoundsoChemBridge Diversity
Set of 50,000 compounds
UI Legacy collectionoNatural ProductsoFocused libraries
Peptide Librarieso Focused peptide
libraries for gene transfer
siRNA librarieso In pursue
Antibody collections
o In discussion
Plate qPCRRoche LightCycler
qPCR in 96 and 384 well formato Multiplex
detection
qPCR for small molecule effects
o Target gene and house-keeping gene
Contact: Meng Wu, Ph.D.Director, UIHTS Facility, The University of IowaPhone: (319) 335-8828; E-mail: [email protected]: http://pharmacy.uiowa.edu/high-throughput-screening-facility
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Cancer Immunotherapy
Monoclonal Antibody TherapyCancer Vaccines
Cellular Immunotherapy
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AntibodyTherapy
CellularT-Cell
Response
VaccinesInduce Patients
Immune Response
To ProduceT Cells
T-Cell Therapy
Modify T-Cells to Attack Tumor
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Production of Monoclonal Antibodies
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Murine AntibodyChimeric AntibodyHuman Antibody
Poor interaction with human immune system
Immunogenic
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Monoclonal Antibody-InducedCancer Cell Lysis Mediated by
Immune System
Complement C
AntibodyDependent
Cellular CytotoxicityADCC
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Therapeutic Effects of mAbNot Mediated by the Immune System
Signaling Induced
Apoptosis
Blocking Activation Signal
Blocking Angiogenesisor Other Vital Factors
in Stroma
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Antibody Drug Conjugates
• Monoclonal antibody
• Linker
• Drug
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Steps Necessary for Antibody-Drug Conjugate to be Effective
ADCReceptor-Mediated
Endocytosis
LysosomeTarget
Antigen
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Select ADCs Approved or in Development
Hematologic MalignaciesTarget Cancer ADCCD33 AML Gemtuzumab ozogamacinCD30 Hodgkin, ALCL Brentuximab vedotinCD22 ALL, B Cell Lymphoma CMC544CD19 ALL, B Cell Lymphoma SAR3419CD74 Myeloma hLL1-DOXCD138 Myeloma BT-062CD56 Myeloma, Solid Tumors IMGN901CD70 Lymphoma, Renal Cell SGN-75
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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
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Antibody Drug Conjugate in Lymphoma
Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 56; Palanca-Wessels ICML12 Lugano 2013
Monoclonal antibody against CD79bFirst in human trial
N=60
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Checkpoint Blockade
Where Monoclonal Antibody TherapyT-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 AgeTopalian, Weiner and PardollJournal of Clinical Oncology 2012
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Monoclonal antibodies block the checkpointAnti-cancer T cells remain active
Checkpoint BlockadeProceed to fight cancer
No TreatmentTurn off here
YY
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At this time of greatest potential, federal funding for biomedical research including
cancer research is being cut
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Is cancer too complicated to address?Should we give up because finding is so difficult to obtain?
Half Empty or Half Full?
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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
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ReduceBurden
ofCancer
Basic Clinical PopulationMolecule/Cell Patient Community
PreventionDetectionTherapy
Quality of Life
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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
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Commitment and Persistence
Example of new initiative
Molecular Epidemiology Resources(MERs)
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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
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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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• 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
Cancer Research 2013
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Thank you !!!Thank you !!!