Transcript The Importance of Prioritizing Cancer Prevention at Major Academic

UNIVERSITY OF PITTSBURGH CANCER INSTITUTE
A National Cancer Institute (NCI)-designated Comprehensive Cancer Center
The Importance of Prioritizing
Cancer Prevention at
Major Academic Cancer Centers
Ronald B. Herberman, MD
University of Pittsburgh Cancer Institute
http://www.upmccancercenters.com
March 2009
Current Research Paradigm at Most
Academic Cancer Centers
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Main focus on
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Developing & improving cancer therapies
Carcinogenesis
Early detection
Little attention on cancer prevention or risk
reduction
Traditional Cancer Prevention Activities at
Academic Cancer Centers (1)
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Research on healthy lifestyles
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Strategies to reduce unhealthy behaviors
Smoking prevention; exercise; better nutrition;
calorie reduction
Molecular carcinogenesis research (geneenvironment interactions)
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Identification of genes contributing to risk
Identification of environmental risk factors
Traditional Cancer Prevention Activities at
Academic Cancer Centers (2)
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Screening of populations for genetic risk
factors & genetic counseling of individuals with
genetic risk
Research to develop new, more sensitive and
specific biomarkers for early detection of
cancer
Screening of populations for early detection of
certain cancers
Prevention Provides Greatest Impact on Wide
Variety of Diseases
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Greatest public health advance of 19th and 20th
century was prevention of infectious diseases
Greatest impact on heart disease was the wide
implementation of statins to reduce risk
Key impact of seat belts and helmets on
reduction of traumatic injuries
Preventive and risk-reducing strategies also
will most likely have the greatest impact on
reducing burden of cancer
Heart disease provides an excellent example
of successful prevention
Over the last 30 years heart disease
has decreased significantly.
50% of this decrease is attributed to
drug prevention strategies.
Pharmacologic intervention using
cholesterol and blood pressure
lowering drugs has been used to
prevent atherogenesis.
UPCI and UPMC Cancer Centers: Integrates Across
The Cancer Continuum To Improve Patient Care
[Source: The Pennsylvania Comprehensive Cancer Control Plan, December, 2003]
Epidemiology Describes Four Levels For
Cancer Prevention
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Primordial or Societal Prevention
– Avoids the emergence and establishment of social, economic,
and cultural patterns of living that are known to contribute to
elevated risk of disease
Primary Prevention
– Controlling causes and risk factors
 Condoms, needle exchange or vaccine to prevent spread of
HIV, HBV or HPV
Secondary Prevention (from onset of disease to normal diagnosis)
– Develop safe accurate methods of detection (at early curable
stage) and development of preventive drugs, vaccines
Tertiary Prevention
– Reducing ongoing morbidity or mortality once cancer is
diagnosed
• Monitoring for early detection of second primary cancers
Modified from Basic Epidemiology, R. Beaglehole, et al, 1993
Inherited Gene Defects Do Not Explain All
Cancer Risk
Fewer than 1 in 10 cases of
breast cancer arises in women
born with genetic defects
-National Cancer Institute
Academic Cancer Centers Can Develop More
Effective Cancer Prevention Strategies (1)
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Research on Environmental Risk Factors
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Evaluation of geographic areas with probable exposures to
identify risk factors and health impacts
Basic research to establish links between exposures and
cancer including mechanism of action
Development of biomarkers to identify people at increased risk
Research to develop strategies to reduce or
eliminate risk factors from the environment
Identification of effective ways to block
carcinogenic effects of environmental carcinogens
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Discovery and development of radioprotective agents
Discovery and development of free radical scavengers to
prevent DNA damage and approaches to improve DNA repair
Academic Cancer Centers Can Develop More
Effective Cancer Prevention Strategies (2)
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Identify effective ways to change the social,
economic, and cultural patterns of living that are
known to contribute to elevated risk of disease
Provide state-of-the-art, cancer center-based,
interdisciplinary approaches to identify
controllable or avoidable environmentally linked
causes of cancer and strategies to reduce risk
Develop and validate interventions that inform,
educate and change individual and institutional
behaviors associated with increased risk
Academic Cancer Centers Can Develop More
Effective Cancer Prevention Strategies (3)
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Development of Effective Interventions to
Prevent Cancer
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Discovery & development of chemopreventive
agents for individuals at increased risk for cancer
Nutraceutical research
Discovery & development of preventive vaccines
Development and validation of improved
strategies for Early Detection
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Develop improved and convenient biomarkers (e.g.
blood or urine) for screening and early detection
Cancer Prevention at UPCI
•Center for Environmental Oncology
•Biochemoprevention Program
•Biomarkers of exposure, increased risk,
and early stage cancers
What is ‘Environmental Oncology?’
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Clinical oncology detects and
treats disease
‘Environmental Oncology’ seeks
to identify causes of disease in
order to predict and prevent
cancer
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Identifies, develops, and
measures biomarkers of
exposure, susceptibility
Identifies windows of susceptibility
Develops and implements
interventions to reduce risk in
people exposed and at high risk
Center for Environmental Oncology (CEO)
Started July, 2004 at the University of
Pittsburgh Cancer Institute
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Focus on Environmental Risks, Exposures, Health
Effects Research and Community Education
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Provide a state-of-the-art, medical center-based, cross-disciplinary
approach to identify controllable or avoidable environmentally
linked causes of cancer
Develop and promote key changes in environmental policies to
reduce risk factors
Create and validate interventions that inform, educate and change
individual and institutional behaviors, or that have potential to
reduce cancer in individuals at increased risk
Four Divisions of the
Center for Environmental Oncology
Basic Research
Outreach,
Education,
and
Public
Policy
Molecular,
Environmental,
and
Clinical
Epidemiology
Environmental Assessment and Control
CEO Areas of Emphasis
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Basic Research
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Molecular, Environmental and Clinical Epidemiology
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Behavioral modification
Biochemoprevention
Environmental Assessment, Monitoring, and Control
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Perform community and clinical research to identify patterns and
trends of disease tied to environmental exposures
Preventive interventions based on epidemiologic
evidence for individuals at increased risk
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Provide scientific evidence on environmental carcinogens, geneenvronment interactions, & biomarkers of environmental
carcinogenesis
Develop institutional protocols for monitoring and control of pollutants
for the hospital and the community
Community and Professional Education and Public Policy
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Communicate links between the environment and cancer and develop
policies to reduce cancer risk for individuals and institutions
Evidence Supporting Environmental Exposure
as a Cause of Cancer
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Experimental
Epidemiological
Case control studies
Cancer Incidence Trends
Jobs With Increased Risk
of Breast Cancer
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Solvent workers
Chemists
Nurses and
Physicians
Dentists
Painters
Hair Dressers
Exposure Risk Assessment and Precaution
Pediatric Head CT Scans-2008
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Exposure
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Pediatric CT Scans are tool of choice in ER
ER Physicians are not aware of level of radiation exposure in
CT
Pediatric CT scans can be 200 to 6,000 chest x-ray
equivalents
Workshop held UPCI-March 26, 2008 with national
experts
White paper drafted outlining risks, benefits, and
better options for ER treatment with reduced
cancer risk with recommendations to reduce
exposures
Long-term Cell Phone Use and Brain Tumor
Risk Suggestive but not Definitive Data
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Case-control study ((Hardell et al Int. J of Oncology. 28:509-518, 2006)
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Acoustic neuroma: OR=2.9 (CI 2.0-4.3; analogue cell phone), OR=1.5
(CI1.1-2.1; digital cell phone); OR=1.5-fold (CI 1.04-2.0, cordless phone)
Acoustic neuroma > 15 years: OR=3.8 (CI 1.4-10; analogue cell phone)
Review of 11 case-control published studies with > 10 years wireless cell
phone use (Hardell et al. Occ Env Med. 64:626-632, 2007.
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Increase in acoustic neuroma (4 studies statistically significant)
Increase in glioma (all gave increased odds ratios, 4 statistically significant)
Meta-analysis
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Meta-analysis (Hardell et al. Int J of Oncology, 32:1097-1103, 2008)
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6 studies glioma: latency > 10 years, 4 studies ipsilateral OR=2.0 (CI 1.2-3.4)
4 studies acoustic neuroma: latency > 10 years, ipsilateral OR=2.4 (CI 1.15.3)
Meta-analysis (Kan et al. J Neurooncol 86:71-78, 2008, UTAH study)
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Acoustic neuroma (ipsilateral) OR=2.4 (CI 1.1- 5.3)
Glioma (ipsilateral) ) OR 2.0 (CI 1.2-3.4)
5 case control studies with cell phone use > 10 years: brain tumor OR=1.25
(CI 1.01-1.54)
INTERPHONE (2008 update)
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Glioma, ipsilateral OR=1.39 (CI 1.01-1.92); Nordic study (Lahkola et al, 2007)
Cell Phone Radiation is Absorbed More
Deeply Into the Brains of Children
Estimation of the absorption of electromagnetic radiation from
a cell phone based on age (Frequency GSM 900 Mhz) (On
the right, color scale showing the Specific Absorption Rate in W/kg)
Gandhi, O.P.G. Lazzi, and C.M. Furse, Electromagnetic Absorption in the Human
Head and Neck for Cell Telephones at 835 and 1900 MHz. IEEE Transactions
on Microwave Theory and Techniques, 1996. 44(10): p. 1884-1897
Hypothesis: If the long term use cell phone
studies are correct in pointing to increased
risk for brain tumors, the incidence of brain
tumors should be increasing, particularly in
children and young adults
SLER Registries for GLIOMAS
age-specific incidence, 0-39 years of age
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Incidence (per 100,000)
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0-9
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10-19
20-29
30-39
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1980
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1995
Year of Diagnosis
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2005
Exposure Risk Assessment and Precaution
0n Cell Phones; Follow up
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July, 2008: Ronald Herberman, after consultation with UPCI and
international experts including epidemiologists and neurosurgeons,
issued e mail with precautions for safer use of cell phones, and calls
for studies to more definitely determine cell phone risks
Media learns about the precautionary e mail and news travels around
the globe, mainly correct, but with some inaccuracies
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Other countries issue precautions (France, India, Israel, Canada)
October, 2008: Ronald Herberman asked to testify before Congress
on the science behind cell phone risk, the rationale for his
precautionary advisory, and the need for more studies
October, 2008: analysis of age-specific brain tumor data shows
increases in glioma rates especially for young adults-manuscript
submitted for publication
September, 2009: Planning in progress for an UPCI-led,
Congressionally sponsored workshop on cell phones and potential
risks for cancer
Plans being developed to further assess ability of radiofrequency
radiation to cause DNA damage, and determine underlying
mechanism(s)
Identification of Risks and Strategies for Reduction
selected examples
 Pediatric CT Scans
promoting awareness that CT radiation exposure for head scans in children can
be 200 to 6000 chest x-ray equivalents
– National workshop held at University of Pittsburgh, Spring 2008 and white paper
with recommendations for emergency room use of CT scans being developed
Cell phones and brain tumors
– Review literature and bring attention to multiple reports linking long-term cell
phone use with increased risk for glioma and acoustic neuroma
– Dissemination of precautionary use memo to UPCI and UPMC Cancer Center
faculty and staff
– Provide testimony at congressional hearing calling for needed studies to
determine safety of cell phones
Passive smoking in Allegheny County-promoting smoking ban in public buildings
including bars and restaurants
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Senior leadership testimony to Allegheny County political leaders
UPMC and University of Pittsburgh became smoke-free facilities in 2007
Allegheny County passed ban in 2007 on smoking in restaurants and bars that make a
significant percentage of profit from food
PA passed similar statewide ban in 2008
Fire retardants in bedding and computers-promote national and international
awareness of the lack of need for chemical fire retardants and awareness of
toxicities nationally and internationally
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Blocked passage of requirement for fire retardants nationally and world-wide
Biological Effects of Environmental
Xenoestrogens
• Assessment of the effect of growth of
estrogen-dependent breast cancer cell line
• Validation of an estrogen screening assays
that show competition for receptor binding
and cell growth effects
Talal El-Hefnawy
Estrogenic Pollutants Induce Breast
Cancer Cell Proliferation
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140
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20
Coum 2000
Coum 400
Coum 80
BaP 2000
BaP 400
BaP 80
DDE 2000
DDE 400
DDE 80
BPA 2000
BPA 400
BPA 80
endo 2000
endo 400
endo 80
E400
E 80
0
control
BrdU Value (absolute absorption)
Estrogenic compounds induce MCF7 breast cancer cell
proliferation
Quantitative BrdU assay, dark spots indicate high DNA synthesis
Talal El-Hefnawy
Biochemoprevention Program
University of Pittsburgh Cancer Institute
Ongoing Preclinical Cancer Prevention Research (1)
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Cancer prevention by garlic-derived organosulfur compounds
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Cancer prevention by cruciferous vegetable-derived isothiocyanates
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Prostate cancer (Singh)
Tobacco carcinogen-induced lung cancer (Singh)
Prostate cancer (Singh, Dhir, Nelson)
Breast cancer (Singh and Vogel)
Pancreatic cancer (Srivastava)
Head and neck cancer (Grandis and Singh)
Bladder (Singh)
Melanoma (Brown and Singh)
Angioprevention
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Resveratrol (red wine) plus statins (Li)
Isothiocyanates and organosulfides (Singh)
Ongoing Preclinical Cancer Prevention Research (2)
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Prevention of colon cancer with NSAIDs (Zhang)
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Cancer prevention by traditional Ayurvedic
remedies (Singh)
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Cancer prevention by vaccines or other
immunologic approaches (Finn, Gorelik)
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Cancer prevention by combination of small
molecules & biologics (Gorelik, Li)
Inhibition of PC-3 Xenograft Growth by
Garlic-derived Diallyl Trisulfide (DATS)
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B
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Control
DATS
450
300
150
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0
5
* 10*
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15
20
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29
600
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450
300
Weight (g)
Wet tumor weight (mg)
Tumor volume (mm 3)
750
600
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Control
DATS
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150
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Control
DATS
Days after tumor implantation
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0
5
10
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Days after tumor implanation
DATS (5 μmol) was given orally three times/week
*P < 0.05 by Student’s t-test.
Shivendra Singh
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Resveratrol is a chemoprevention agent
derived from natural sources
Natural sources:
Grapes (50-100 g/g)
Red wine (1-3 mg/L)
Peanuts
TCM Polygoum cuspidatum
Phytoalexin Resveratrol
Shivendra Singh
Resveratrol prevents experimental cancer
DMBA-induced skin
cancer model. 0, 1,
5, 10, or 25 µmol of
RSVL plus 5 µmol of
TPA
Copied from Jang et al,
Science, 1997
Shivendra Singh
Chemoprevention to Stop Progression of
Premalignant or Stage 0 Lesions
• UPCI Research Studies
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NSABP Polyp Prevention Trial
Evaluation of celecoxib as a breast cancer
chemopreventive agent with intracellular
biomarkers
Serial evaluation of ductal epithelium
NSABP STAR trial
Muc1 vaccine for prevention of colon polyps
Biomarkers Being Evaluated in Study of
Celecoxib for Prevention of Breast Cancer
• Changes in cytology
• Changes in biological markers COX-2,
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aromatase, and estradiol
Changes in the fractional mutation index
(defined as the number of mutated markers
divided by the sum of all informative markers
among 20 pre-selected genes)
MUC1-Poly ICLC (HiltonolTM)
Vaccine in Individuals with
Advanced Colorectal Adenoma
Robert Schoen & Olivera Finn
Rationale
• Chemoprevention of adenomas is an accepted
focus – ASA, COX2, vitamins
• Immunotherapy
• Non toxic
• Highly specific
• Boost or improve native immune surveillance →
prevent progression to malignant disease
• Vaccine potentially more effective before tumor
suppresses immune response
Meta-analysis: Muc 1
Immunotherapy in CRC
• 32 studies, 527 patients
• Toxicity mild – flu like symptoms, injection site
reactions
• Humoral immune response 59%, cellular
immunity – 44%
• Clinical response 10-14%
Nagorsen, Clin CA Res 2006;12:3064
Why Study Advanced Adenoma?
• “Target” for CRC screening
• Higher risk for subsequent cancer
• Higher adenoma recurrence rate: followed
with q3yr surveillance
• Intact immune system
• ↑ expression of Muc 1
• Prime candidate for vaccine administration
Objectives
Primary
• Evaluate immune response to MUC1-Poly ICLC
Secondary
• To monitor MUC1 isotypes: IgG, IgM
• To monitor adverse events
• To evaluate correlation between anti MUC1
response and adenoma recurrence (not powered
to this endpoint)
Serum and Tissue-based Biomarker
Discovery -- Needs
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Comparative/differential proteomics and metabolomics
– to identify and characterize protein patterns that distinguish exposed
individuals from healthy controls, using biological specimens
– to identify and characterize hormone or other metabolites that
distinguish exposed individuals from healthy controls
Comparative/differential genomics
– to identify and characterize changes in DNA and nuclear DNA and
protein methylation patterns that distinguish exposed individuals from
healthy controls, using biological specimens
Application: identification of biomarkers of exposure
including:
1. Cellular signatures indicative of toxic exposures
2. Epigenetic changes linked to altered gene expression
3. Hormone metabolites and cancer risk
Biomarker Discovery at UPCI
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Establishment of tissue and serum banks with high
quality specimens from healthy individuals and
cancer patients
Support for Bioinformatics both for tissue
annotation and high complexity data analysis
Development and support of integrated Cancer
Biomarkers Core for Specimen Analysis
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Platforms for genomic analysis including chip-based
array technology and multiplex genotyping
Platforms for high-throughput proteomic analysis
Platforms for comprehensive metabolomics analysis
SERUM vs. URINE IN OVARIAN CANCER
SERUM 4 biomarkers
SP=98%
URINE 3 biomarkers
SP=100%
Anna Lokshin
SN=90%
SN=100%
ROC curve for classification of endometrial
cancer
1.0
A
0.8
0.6
0.4
5 BIOMARKERS AUC=0.98
0.2
PROLACTIN
PROLACTIN
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6 BOMARKERS AUC=0.98
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AUC=0.94
AUC=0.94
0.8
1.0
SENSITIVITY
SENSITIVITY
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1-SPECIFICITY
SENSITIVITY = 98% SPECIFICITY = 94%
Prolactin, HE4, CA 72-4, MMP-3, and FasL
Anna Lokshin
6 BIOM
PROLA
0.2
0.4
1-SPECI
Expected Outcomes As Academic Cancer Centers
Focus on the 4 Levels of Cancer Prevention
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Rapid identification of environmental risk factors and
approaches to minimize exposures
Development of evidence-base to prioritize high impact
cancer control strategy
Improved strategies for early detection &
biochemoprevention
Establishment of regional and state-wide networks to
facilitate rapid implementation of effective education
and prevention-based interventions
Identification of resources and more effective use
through collaboration and cooperation will more
effectively disseminate prevention strategies