Cancer: The Basics (Steven Patierno, Ph.D.)

8/7/2019 Cancer: The Basics (Steven Patierno, Ph.D.)

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CANCER: THE BASICS and a little more too.

Dr. Steven R. PatiernoExecutive Director


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But not all these tragic consequences together are the worst evilwrought by cancer. For everybody that is killedby the factof

cancer, multiplied thousands of mindsare unnervedby the fearofcancer. What cancer, as an unsolved mystery, does to the moraleof millions who may never know its ravages is incalculable. Thereis an incidence of cancer that cannot be reached by the physiciansmedicaments, the surgeons knife, or any organized advice againstpanic. Nothing but the conquest of cancer itself will remove this

sword that today hangs over every head.

Glenn Frank, President, University of Wisconsin, 1936.


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The Top TenGoogle News

searches in 2006

ACCORDING TOUSA TODAY

AMERICA ISCONCERNEDABOUT CANCER


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CANCER: WHAT IS IT?

CANCER IS A DISESASE IN WHICH ONE CELL, OR A

GROUP OF CELLS, ACQUIRE THE CAPABILITY TOPROLIFERATE INDEFINATELY AND TO INVADE

DISTANT SITES AND ORGANS


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CANCER: IS IT NEW?

TUMORS HAVE BEEN FOUND ON DINASAUR BONES AND MUMMIES

Paleontologists Teach MedicalStudents About Fossil TumorsJune 1, 2006 Using medical-physicstools such as CT scans, medicalstudents can learn to recognize atumor even in a 150-million-year-old

dinosaur bone.

AN ANCIENT EGYPTIAN PAPYRUS

(1600BC) HAD A HEIROGLYPHICOF A TUMOR ON A PENIS ANDWRITING DESCRIBING THETREAMENT OF A BREASTGROWTH BY CAUTERIZATION BYA FIRE DRILL.


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CANCER: IS IT NEW?

Galen 200AD to 16th century:

Cancer caused by excess black bile.

Ramazzini 1700: breast cancer in nuns

Pott 1775: scrotal cancer in chimneysweeps

Bichat 1800s: cancer a tissue

Muller 1800s: cancer made of cells

Hippocrates, the great Greek physician (460-370

B.C), Hippocrates noticed that blood vessels arounda malignant tumor looked like the claws of crab. Henamed the disease karkinos (the Greek name forcrab). In English this term translates to carcinos orcarcinoma.
http://images.google.com/imgres?imgurl=http://www.nlm.nih.gov/hmd/greek/popup/images/galen_detail.jpg&imgrefurl=http://www.muslimheritage.com/topics/default.cfm%3FArticleID%3D1084&usg=__VkT_Mtm469IrAqhLY-gMHsgmBfA=&h=964&w=800&sz=106&hl=en&start=18&um=1&tbnid=7iiZIOiFCdmXVM:&tbnh=148&tbnw=123&prev=/images%3Fq%3Dgalen%2Bblack%2Bbile%26hl%3Den%26sig%3DyZdP_XZuvA5Pr-gBwl8bO5I_nFw%26um%3D1


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CANCER: WHERE DOES IT COMEFROM? HOW DOES IT BEGIN?

25% (1 in 4) of allhumans on theplanet will get or diefrom cancer

Up to 25% indevelopingcountries: HPV,HepB, HepC,H.Pylori

Environment:

oxygen,chemicals etc

Individual Life Risk:

Men 1:2, Women 1:3


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Smoking


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Living and Eating


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CANCER: WHERE DOES IT COME FROM?HOW DOES IT BEGIN?

SOME CONTEXTUAL BACKGROUND

The vast majority of genetic damage and mutations are the inevitable

consequences of life, for example:

Background Radiation and Oxidative Stress

Natural Chemicals in Food (cooked and uncooked)

Natural Chemicals in Bodily Waste Products

Non-anthropogenic hydrocarbons like volcanic eruptions


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SOME CONTEXTUAL BACKGROUND

The majority of DNA damage and mutations areprobably endogenous and/or stochastic

Estimated that the DNA in each of our cells get his with200,000 damaging events per day

Nearly a third of our total complement of genes isdedicated to DNA repair

This developed long before the Industrial Revolution


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CANCER: WHERE DOES IT COMEFROM? HOW DOES IT BEGIN?SOME MORE CONTEXTUAL BACKGROUND

At the population level cancer is a frequent disease:25% of all humans will either get cancer or die from it.

At the cellular level cancer is a very rare event,occurring in only 1/4 people with

100,000,000,000,000 (100 trillion) cellular targets perperson

Not everybody with similar chemical exposures getscancer

People exhibit hereditary susceptibility to specific

exposures


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SOME MORE CONTEXTUAL BACKGROUND

Tumors are monoclonal (from one cell) in origin andcancer requires accumulation of genetic changes

A background of cancer rates can be expected as astatistically pre-determined consequence of the

stochastic risks associated with aging

It is also influenced by personal and cultural behaviorsuperimposed on hereditary susceptibility

GENE-ENVIRONMENT INTERACTIONS


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A CRITICAL CONCEPT: RANGE OFPOTENCY


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THE TARGET

THE PROCESSOR


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THE RESULT: DNA MUTATIONS

AND PROTEINS WITH

ALTERED OR NO FUNCTION


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The Emergent Tumor: Progeny of One StubbornCell

In Normal Self-renewing tissues there is balance:

HOMEOSTASIS

Proliferation > Death


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In Cancer there is a loss of balance


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THE MULTI-STEP PROCESS


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CLONAL SELECTION/EXPANSION


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The Emergent Tumor: Progeny of One StubbornCell: From a Pathologists Viewpoint

Hyperplasia: Increase in CellNumber

Metaplasia: Replacement of

Cell Type

Dysplasia: Variation in Size,Shape, Organization

Anaplasia: Intracellular &Growth Changes

Neoplasia: New growth,Relatively Autonomous

Growth


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The Emergent Tumor: Progeny of One StubbornCell: From a Pathologists Viewpoint

Benign Growth: Encapsulated, non-invasive, lowmitoses, high differentiation, slow growth, littleanaplasia, not metastatic

Malignant Conversion: Non-encapsulated, locallyinvasive, variable differentiation, higher mitoticindex, more rapid growth, typical anaplasia,

metastatic


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The Main Themes of Cellular Dysregulation

Disruption of Cell Cycle Regulation: Failure ofArrest and Restraint

Escaping the Death Default: Resilience toApoptosis and Senescence

Cell Interrupted: Loss of Communication andIntegration

Genomic Instability: Acceleration towards

conversion


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The Emergent Tumor: Progeny of One StubbornCell:

CONVERSION

*Predominantly epigenetic*Up- and dis-regulation of transcriptional activity

*Gross Chromosome abnormalities

*Further disruption of cell cycle circuitry

*Activation and secretion of invasion-associatedcell surface molecules


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Progression Past Malignant ConversionEscaping Immune Recognition, Angiogenesis, Invasion, Metastasis


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HISTORICAL PERSPECTIVEPROTO-ONCOGENES AND ONCOGENES

Normal gene activated to become oncogenic bymutations, chromosomal rearrangement, or

amplification.

In order to be a proto-oncogene or becomean oncogene thenormal gene must be a

gene that controls acritical component ofcell growth/death.


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MOLECULAR CARCINOGENESIS


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HISTORICAL PERSPECTIVETUMOR SUPPRESSOR GENES

Normal genes that normally suppress growth orpromote death. Contribute to oncogenesis by

being inactivated by mutations or negativeepigenetic silencing (hypermethylation).


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MOLECULAR CARCINOGENESISGenes Defining the Emergent Tumor

A USEFUL MODEL PROPOSED BY KINZLER ANDVOGELSTEIN

GATEKEEPERS AND CARETAKERS

GATEKEEPERS: GENES WHICH RESTRAIN CELLGROWTH AND DIRECTLY SUPPRESS NEOPLASIA

CARETAKERS: GENES WHICH AFFECT SUSCEPTIBILITYAND INDIRECTLY SUPPRESS NEOPLASIA

O C C C OG S S


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GATEKEEPERS

INHIBIT CELL CYCLE

INDUCE APOPTOSIS

INDUCE SENESCENCE OR TERMINAL DIFFERENTIATION

CARETAKERS

DNA REPAIR: MAINTENANCE OF GENOMIC STABILITY

METABOLIC PHENOTYPE



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GATEKEEPERS GONE BAD

DYSREGULATED CELL CYCLE: p53, p21, RB1

INHIBIT or FAIL to INDUCE APOPTOSIS: Bcl-2

CARETAKERS

BROKEN DNA REPAIR:ATM (Ataxia Telangiectasia Mutated)

BRCA1, BRCA2

FA (Fanconi Anemia)


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ChromosomalDistribution ofsome Oncogenesand Tumor

SuppressorGenes.


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The New Biology of Cancer

How to Make A Cancer


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How to Make A Cancer

Cell 100; 57, 2000


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The forefront of a new wave in Oncology: Developing novel non-cytotoxic therapeutic strategies for controlling malignantprogression by inhibiting tumor cell growth and the spread ofcancer known as Metastasis.

a new, comprehensive molecular understanding of cancer will transformcancer from a death sentence into a chronic but manageable disease. U.S.News & World Report, June 24, 2002.

Whats in the future?

Molecularly TargetedCancer Therapeutics


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Science, 295, March 29, 2002

The Goal of Inhibiting Tumor Progression


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THE ULTIMATE GOAL?

By controlling tumor growth and metastasis, we aim tomanage it in the same way that diseases such as

hypertension and diabetes are managed.


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One of the first bullseyeMTDs


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Chronic Myelogenous Leukemia (CML)

Reciprocal translocation: Chromosome 9 & 22

(Philadelphia Chromosome)Creation of a unique fusion protein Bcr/Abl, a non-membrane bound

oncoprotein (p210)

This unique tyrosine kinase is capable as a sole-transforming event in

mice.

In human CML, activation of the Bcr/Abl oncogene leads to disease

progression through further phenotypic and genotypic instability

leading to mutations in p53, loss of p16, loss of INK41/caf exon 2,

and loss of the retinoblastoma (RB).


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Reciprocal translocation: Chromosome 9 & 22

(Philadelphia Chromosome)


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Prior to Gleevec

Allogeneic hematopoietic stem cell transplantation:

potentially curative but carries significant risk of mortality

and is restricted to young patients with a suitable donor.

Interferon alpha: high rates of cytogenetic and

hematological responses but 5 year survival rate of only

57%. Side effects nothing short of awful.

After Gleevec

Gleevec: at 5 years 98% still at Complete Hematologic

Response, and 87% at Complete Cytogenetic Response.


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F t t t t i ti ti l


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Future cancer treatment using antiparticles

from the exotic "antiworld"

Antiprotons do not belong to our world

An antiproton is a so-called antiparticle. It is thus part of the

mirror world that also consists of the positron the electrons

antiparticle as well as other exotic particles. A common

feature of them all is that they are not normally found in our

world.Unfortunately, the promising results will first

benefit the treatment system in ten years at the

earliest. This is partly because producing

antiprotons is expensive.


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Experiments indicate promising future for

nanotechnology in cancer treatment

Experiments on mice have shown promise for the futureof nanotechnology in treating cancer.

The research brings doctors one step closer to being able

to inject patients with nanoparticles that bore insidetumors and release powerful doses of cancer-killing drugs

while leaving the rest of the body unscathed.

Aft i h th i d f h t t


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After seeing how the mice were cured of human prostate

cancer with the technology, cancer specialists gathered at the

-------- on Tuesday praised the work as impressive and said

they had high hopes for its application to patients.


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But, genetically and medically speaking, noteverybody is the same


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. is it Personalized Medicine?

A major problem that needs to be at the heart of our efforts:


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A major problem that needs to be at the heart of our efforts:Eliminating Cancer Disparities

The District of Columbiahas some of the highestcancer mortality rates inthe United States.

Because of the highminority population, andextensive health carebarriers, cancerdisparities areparticularly severe.

DC is an acutemicrocosm of thenational challenge of the

unequal burden ofcancer.

An Important Lesson


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An Important Lesson

The same barriers that interferewith access to quality cancerTreatment, also interfere withCancer Prevention and Control,

utilization of available Screening,access to and utilization ofSupport Services (support groups,palliative care, end of life care),and long term Survivorship.

Disparities range across the health care continuum

A Novel Genomics Partnership


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A Novel Genomics Partnership

Genomics of Cancer Disparities

Gene profiles derived from prostate biopsy tissue:
http://crchd.cancer.gov/index.htmlhttp://www.med.howard.edu/hucc/default.htmhttp://www.jcvi.org/


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Gene profiles derived from prostate biopsy tissue:Hierarchical Clustering Analysis

comparing African American and Caucasian samples

Transcriptome Co E pression Mapping


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ProstateCancer

DifferentialGeneNetworks in

African

AmericanMen

Transcriptome Co-Expression Mapping

Genomics of Breast Cancer


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Genomics of Breast CancerDisparities

Gene network analysis reveals new targets:


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Gene network analysis reveals new targets:Uteroglobin (UG) expression in normal prostate

Loss of UG in PC Progression


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Cancer

BPH

Loss of UG in PC Progression

INHIBITION OF CELL GROWTH


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PC-3 ARE GROWTH ARRESTED BY CHRONIC

EXPOSURE TO rUG (daily, not cumulative)

Inhibition of PC-3 Cell Growthby Uteroglobin 8-6-02

100 101 102 103 1040

20

40

60

80

100

120

EC50= 0.66M

[Uteroglobin, M]

%C

ontrol

(Cell

Count)

Growth Curve: PC-3 and rUG

0100,000

200,000

300,000

400,000

Day

1

Day

2

Day

3

Day

4

Day

5

Day

CellCounts

Control mean

5 mcg/ml mean

10mcg/ml mean

20 mcg/ml mean

Rat AortaA i i


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Angiogenesis

Untreated

rUG 30ug/ml

Effect of rUG on PC-3 tumor nodule formation in CAM assay


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Control

rUG(30 ug/mlto CAM)


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Kaplan-Meier Survival Analysis: Overall Group Differences

SurvivalDist

ributionFunction

0.00

0.25

0.50

0.75

1.00

Days

0 10 20 30 40 50 60

20 mg/kg

Control

Model for Analysis of Population Health and Health Disparities


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Individual Risk FactorsAge, SES, Education, Obesity,Tobacco Use, Acculturation,

Diet, Race

Biologic/Genetic PathwaysAllostatic Load, Metabolic Processes,

Physiological Pathways, GeneticMechanisms

Warnecke e t al., AJPH 2008

Social andPhysicalContext

IndividualDemographicand Risk Factors

BiologicResponsesand Pathways

FundamentalCauses

Disparate HealthOutcomes

Social Conditions and PoliciesCulture, Norms, Racism, Sexism

Discrimination, Public Policies, Poverty

InstitutionsHealth Care System, Families, Churches,Community-based organizations, Legal

System, Media, Political System

Social RelationshipsSocial Networks, Social Support

Social Influences, Social Engagement

Social/Physical ContextCollective Efficacy, Social Capital,

Access to Resources, Social Cohesion,Segregation, Neighborhood Disadvantage,

Neighborhood Stability

UpstreamFactors

DownstreamFactors

The NewCancer

Economics


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Pharmacogenomics

Biopsy samplesand analysis

Racialdifferences

Social andPhysicalContext

The NewScience of

Cancer:

Cells to Society

SES

Exercise Diet

Epidemiology ofBreast Cancer

Risk Factors (ex-obesity)

Access toservices

Family stress

EnvironmentalGeography Unemployment

Biological Pathways& Responses

Genomics

Coverage

Discrimination

PovertyPrevention

PublicPolicy

Barriers

Mousemodels

Institutional Context &Social Conditions and

Policies

Psychology ofLow-income andurban

neighborhoods

Diseasemapping


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Man's inhumanity to man is not only

perpetrated by the vitriolicactions of those who are bad. It isalso perpetrated by the vitiatinginaction of those who are good.

--- Martin Luther King, Jr.

Documents

Cancer: The Basics (Steven Patierno, Ph.D.)