Cancer Research
George Weiner
American
Association
for Cancer
Research
Cancer Progress
Report 2013
Making Research
Count for Patients: A
Continual Pursuit
Prevention
Early Detection
Therapy
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
New Approaches
Prevention
Early Detection
Treatment
Basic
Research
Cost of sequencing DNA is plummeting
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
Grow
Each of these
steps is
controlled by
multiple genes
Die
In cancer, genes
controlling these
functions are
abnormal
Grow
Over active
“Grow” signals
Die
Under active
“Die” (or change)
signals
It’s
Complicated
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
What looks similar on the outside
may actually be very different
Even things with the same name
can be very, very different
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
Example – Lung Cancer
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”
Genetic
Heterogeneity
Within a
Single Tumor
Gerlinger et al
NEJM 2012
Every Tumor is Different
How can we be smarter in
developing more precise
approaches to cancer prevention,
early detection and therapy?
Old Paradigm
• All patients receive the same treatment
New Paradigm
• Treatment based on specific molecular
abnormality
Pillars of Cancer Therapy
Targeted
Chemo
Surgery
Radiation
Immuno
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
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
Sleeping Beauty Transposon and Gene Discovery
Insertional Mutagenesis
Find genes mutated by
Sleeping Beauty
Oncogene
Turns on gene that causes
cell to grow abnormally
Transposon
Tumor
Tumor Suppressor
Turns off gene that normally
Transposon
stops cell from growing
Genes found in mouse model of cancer
have been found to be important in human cancer
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
Hamilton MicroLab
PE Cell:Explorer
 Handling screening
libraries, library
reformatting, cherrypicking, dose
response building
 Handling large
amount of plates
 Handling cell-based
assays/screens
 Combing high
throughput
screening and high
content screening
(HTS & HCS)
 Handling
biochemical
assays/screens
Contact:
Plate Readers
PE EnVision
 Multimodal reader
o Abs, Flu, Lum
o FRET, BRET,
TRF
o Alpha-Screen
 Monochrometerbased detection
Plate Imager
PE Operetta
Screening Libraries
Plate qPCR
Roche LightCycler
 Fluorescent imaging  qPCR in 96 and 384
based system
well format
o Epi-fluorescence
o Multiplex
o Con-focal
detection
 Live-cell imaging
(HTS & HCS)
 qPCR for small
molecule effects
o Target gene and
house-keeping
gene
Small Molecule
Libraries
Other Libraries
(biologics)
Commercial libraries  Peptide Libraries
oMicroSource Spectrum
o Focused peptide
of 2300 compounds
libraries for
oChemBridge Diversity
gene transfer
Set of 50,000
 siRNA libraries
compounds
o In pursue
 UI Legacy collection
o Natural Products
 Antibody
o Focused libraries
collections
o In discussion
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
Cancer Immunotherapy
Monoclonal Antibody Therapy
Cancer Vaccines
Cellular Immunotherapy
Antibody
Therapy
Cellular
T-Cell
Response
Vaccines
T-Cell
Therapy
Induce Patients
Immune
Modify T-Cells
Response
to Attack
To Produce
Tumor
T Cells
Production of Monoclonal
Antibodies
Chimeric
Antibody
Murine
Antibody
Humanized
Antibody
Human Antibody
Poor interaction
with human
immune system
Immunogenic
Monoclonal Antibody-Induced
Cancer Cell Lysis Mediated by
Immune System
Complement
Antibody
Dependent
Cellular Cytotoxicity
ADCC
C
Therapeutic Effects of mAb
Not Mediated by the Immune System
Signaling
Induced
Apoptosis
Blocking Activation Signal
Blocking Angiogenesis
or Other Vital Factors
in Stroma
Antibody Drug Conjugates
• Monoclonal antibody
• Linker
• Drug
Steps Necessary for Antibody-Drug
Conjugate to be Effective
ADC
Target
Antigen
ReceptorMediated
Endocytosis
Lysosome
Select ADCs Approved or in
Development
Hematologic Malignacies
Target
Cancer
ADC
CD33
CD30
CD22
CD19
CD74
CD138
CD56
CD70
AML
Hodgkin, ALCL
ALL, B Cell Lymphoma
ALL, B Cell Lymphoma
Myeloma
Myeloma
Myeloma, Solid Tumors
Lymphoma, Renal Cell
Gemtuzumab ozogamacin
Brentuximab vedotin
CMC544
SAR3419
hLL1-DOX
BT-062
IMGN901
SGN-75
Target
Cancer Type
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
Breast ApprovedTrastuzumab
emtansine
Select
ADCs
or
in
GPNMB
Breast, Melanoma
CDX-011
PSMA Development
Prostate for Solid Tumors
PSMA-ADC
HER2
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
Checkpoint Blockade
Where Monoclonal Antibody Therapy
T-Cell Therapy Come Together
Grow
With infection,
immune
response results
in proliferation
and activation of
T cells
Die
When infection is
controlled, T cells
are programmed to
die
Cancer Immunotherapy Comes of Age
Topalian, Weiner and Pardoll
Journal of Clinical Oncology 2012
Monoclonal antibodies block the checkpoint
Anti-cancer T cells remain active
Checkpoint Blockade
Proceed to fight cancer
No Treatment
Turn off here
Y
Y
At this time of greatest potential, federal
funding for biomedical research including
cancer research is being cut
Half Empty or Half Full?
Is cancer too complicated to address?
Should we give up because finding is so
difficult to obtain?
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
Basic
Clinical Population
Molecule/Cell Patient Community
Prevention
Detection
Therapy
Quality of Life
Reduce
Burden
of
Cancer
To address the complexity of cancer
we 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
Commitment and Persistence
Example of new initiative
Molecular Epidemiology Resources
(MERs)
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
Molecular Epidemiology Resource Accrual
MER Accrual Overall
HCCC MER Accrual
1600
1
2003
1000
800
600
2005
127
121
2007
170
148
2009
87
152
244
144
400
2011
200
166
225
174
2013
0
-200 2002 2004 2006 2008 2010 2012
BEST
66
118
1200
Calendar Year
Consented Patients
1400
BMER
LMER
MAST
216
147
230
241
151
233
106 96 74 122
0
BEST
500
BMER
LMER
N= Consented Patients
1000
MAST
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
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
Thank you !!!