Cancer ResearchCancer ResearchGeorge WeinerGeorge Weiner

American Associationfor 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 presentationOther types of research are equally important

Labo

rato

ry

Resea

rch

Clinica

l

Research

Bench toBedside

Bedside to

Bench

New ApproachesPrevention

Early DetectionTreatment

BasicResearch

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 Die

Each of these steps is

controlled by multiple genes

In cancer, genes controlling these

functions are abnormal

Over active“Grow” signals

Grow Die

Under active

“Die” (or change) signals

It’sComplicated

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

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”

Gerlinger et alNEJM 2012

GeneticHeterogeneity

Within aSingle Tumor

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

• Treatment based on specific molecular abnormality

New Paradigm

Pillars of Cancer Therapy

Surgery Radiation ImmunoChemoTargeted

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

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

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: meng-wu@uiowa.eduWebsite: http://pharmacy.uiowa.edu/high-throughput-screening-facility

Cancer Immunotherapy

Monoclonal Antibody TherapyCancer Vaccines

Cellular Immunotherapy

AntibodyTherapy

CellularT-Cell

Response

VaccinesInduce Patients

Immune Response

To ProduceT Cells

T-Cell Therapy

Modify T-Cells to Attack Tumor

Production of Monoclonal Antibodies

Murine AntibodyChimeric AntibodyHuman Antibody

Poor interaction with human immune system

Immunogenic

Monoclonal Antibody-InducedCancer Cell Lysis Mediated by

Immune System

Complement C

AntibodyDependent

Cellular CytotoxicityADCC

Therapeutic Effects of mAbNot Mediated by the Immune System

Signaling Induced

Apoptosis

Blocking Activation Signal

Blocking Angiogenesisor Other Vital Factors

in Stroma

Antibody Drug Conjugates

• Monoclonal antibody

• Linker

• Drug

Steps Necessary for Antibody-Drug Conjugate to be Effective

ADCReceptor-Mediated

Endocytosis

LysosomeTarget

Antigen

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

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

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

Checkpoint Blockade

Where Monoclonal Antibody TherapyT-Cell Therapy Come Together

Grow Die

With infection, immune

response results in proliferation

and activation of T cells

When infection is controlled, T cells

are programmed to die

Cancer Immunotherapy Comes of AgeTopalian, Weiner and PardollJournal of Clinical Oncology 2012

Monoclonal antibodies block the checkpointAnti-cancer T cells remain active

Checkpoint BlockadeProceed to fight cancer

No TreatmentTurn off here

YY

At this time of greatest potential, federal funding for biomedical research including

cancer research is being cut

Is cancer too complicated to address?Should we give up because finding is so difficult to obtain?

Half Empty or Half Full?

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

ReduceBurden

ofCancer

Basic Clinical PopulationMolecule/Cell Patient Community

PreventionDetectionTherapy

Quality of Life

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

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

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

• 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

                  

Thank you !!!Thank you !!!