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Almost Unimaginable Engineering Goals Can Become Reality
A Cure for Cancer
The Panama Canal
The Hoover Dam
The Moon
NASA
US Bureau of Reclamation
©
#1 Cancer is Defined by Proliferation
and Invasiveness*
All cancer cells engage in the pattern or combination of proliferation and invasiveness.
Normal cells do not engage in the pattern of proliferation and invasiveness.**
*In an abnormal context or setting within the body**Exceptions include wound healing, pregnancy and fetal development.
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#2 Drugs Targeted To Proliferation
are Highly Toxic
Conventional cancer drugs target proliferation, which is vital to life and therefore cause serious side effects and toxicity.
Toxicity often makes it impossible to give enough drugs to kill all cancer cells in the patient and cure the disease.
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#3 The Solution
Drugs that will kill cells, if and only if, the cells are engaged in the pattern of both proliferation and invasiveness.
Targeting the pattern will kill cancer cells without harming normal cells.
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#4 The Cure Cancer Project
Plans to make a set of drugs that will specifically kill all cells engaged in the pattern of proliferation and invasiveness.
Multiple drugs in combination will be required.*
*Cancer cells can develop resistance to any single drug.
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#5The Cure Cancer Project
We estimate that approximately 5 to 10 such drugs in combination will be required for the consistent cure of cancer --- without significant side effects.
The drugs should cure all types of solid cancers.*
* Breast, prostate, ovarian, pancreatic, lung, colon, melanoma, etc�
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Great Engineering Feats
Are based on understanding the requirements and implementing rational scientific plans
NASA
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The Cure of Cancer is Like Other Great Engineering Challenges
National Air and Space Museum, Smithsonian Institution
Wright brothers first flight
A number of inter-related requirements must be met
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Three Basic Requirements for the Specific Cure of Cancer
� Comprehensiveness� Specificity� Knowability
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Comprehensiveness
Refers to the ability to kill all cancer cells in the patient
One cancer cell that escapes destruction can One cancer cell that escapes destruction can multiply and cause progressive diseasemultiply and cause progressive disease
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Specificity
Refers to the ability to kill cancer cells without harming normal cells
Side effects and toxicity results when Side effects and toxicity results when cancer therapy lacks specificitycancer therapy lacks specificity
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Knowability
Comprehensiveness and specificity must be based on knowable properties of cancer
Many things are unknowable and totally Many things are unknowable and totally unpredictableunpredictable
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The Outcome of a Random Process is Unpredictable
We cannot know before hand the winning Powerball lottery number
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Cancer Cells Acquire Random Mutations
� This creates a genetically diverse population of cancer cells
� Cancer cells compete for survival� The most aggressive cancer cells
survive and multiply
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Cancer Cells Evolve that Can
� Escape destruction by any single anti-cancer drug
� Escape destruction by the immune system
� Cause progressive disease and treatment failures
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Random Processes Drive Tumor Cell Evolution
Cause genetic and epi-genetic alterations
Determine selection and cell survival
Produce a diversepopulation of cells
Chaotic
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The Specific Cure of Cancer Requires�
the destruction of an evolutionary population of cancer cells
Breast cancer cell populationPhoto NCI
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An almost unlimited numberAn almost unlimited numberof genetically different cancer of genetically different cancer cells can arise in the samecells can arise in the samepatientpatient
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Focus on Individual Cancer Focus on Individual Cancer Cells and Specific Genetic Cells and Specific Genetic Lesions Adds Little Clarity Lesions Adds Little Clarity to the Problemto the Problem
Photo Hubble TelescopePhoto Hubble Telescope
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We Must Focus on Sets of Cancer Cells and Their Properties
y
Knowability
Specificity
CureComprehensiveness
that satisfy the three joint requirements for cure
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Could Evolve in PatientCould Evolve in Patient
Too Improbable to Evolve in PatientToo Improbable to Evolve in Patient
Known by observation
Actually Present in Patient
Sets of Cells in the Universe of All Sets of Cells in the Universe of All Possible Cancer CellsPossible Cancer Cells
©
Could Evolve in PatientCould Evolve in Patient
Too Improbable to Evolve in PatientToo Improbable to Evolve in Patient
Known by observation
Actually Present in Patient
Sets of Cells in the Universe of All Sets of Cells in the Universe of All Possible Cancer CellsPossible Cancer Cells
©Probability = 0Probability = 0
Probability = 1
Actually Present in Patient
Could EvolveCould Evolve
Probability of EvolvingProbability of Evolving
Too Improbable to Too Improbable to Evolve in PatientEvolve in Patient
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Actually Present in Patient
that have particular known genetic alterations, that have particular known genetic alterations, tumor antigens, or other molecular targetstumor antigens, or other molecular targets
Sub-Set
Most Cancer Research has Focused onMost Cancer Research has Focused onSmall Small SubSub--SetsSets of of Cancer Cells
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Actually Present in Patient
and cannot cure or control cancerand cannot cure or control cancer
Therapy Targeted to these Therapy Targeted to these SubSub--SetsSetsof of Cancer Cells Lacks Comprehensiveness
Sub-Set
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Actually Present in Patient
Known by observation
The Set of Cancer Cells The Set of Cancer Cells Known by Known by ObservationObservation is Also Not Comprehensiveis Also Not Comprehensive
Unless every single cancer cell in the patient is Unless every single cancer cell in the patient is observed and characterized, at all points in timeobserved and characterized, at all points in time
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Billions of genetically different cancer cells can spread throughout the body of a patient�
Metastatic cancer in the mouse lungs Normal appearing lungPhoto NCI
and the cancer cells keep changing
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The only way to know all that has evolved is to examine and characterize every cancer cell in the patient�
which is generally not possible
Breast cancer cells in lung
© University of Alabama at Birmingham, Department of Pathology
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Actually Present in Patient
The Set of Cancer Cells The Set of Cancer Cells Actually Actually PresentPresent is Comprehensiveis Comprehensive
but is random and generally unknowablebut is random and generally unknowable
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Since evolution is a complex, random, unpredictable process
The Chaos HypertextbookThe Chaos Hypertextbook
Chaos
we cannot predict by theory what has evolved and what will evolve in a patient
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The Set of The Set of All Cancer CellsAll Cancer Cells that Could that Could EvolveEvolve is Comprehensiveis Comprehensive
non-random and �knowable� by means of a scientific theory
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The Set of All Cancer CellsThe Set of All Cancer Cellsthat Could Evolvethat Could Evolve
The Required Target for the Specific Cure of Cancer is�
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Targeting a lesser set, is like building Targeting a lesser set, is like building a dam that is too weak a dam that is too weak ------ it will failit will fail
Teton Dam Teton Dam in full flood.
US Bureau of Reclamation images
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Little Can be Known AboutThe Set of All Cancer Cells that
Could Evolve
What can be known sharply defines all possible solutions to the specific cure or control of cancer
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The Set of All Cancer CellsThe Set of All Cancer Cellsthat Could Evolvethat Could Evolve
We Cannot Observe or Experimentally Characterize
The set is abstract and has no real world existence
©
We Cannot Know
The probability that a given type of The probability that a given type of cancer cell could evolvecancer cell could evolve
??
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The Set of All Cancer CellsThe Set of All Cancer Cellsthat Could Evolvethat Could Evolve
The Only Knowledge We Can Have About
is in the form of a scientific theory
©
All Cancer Cells Engage in Malignant Behavior
This is true by definitionThis is true by definitionPhoto NCI
Breast cancer cells proliferating and invading in a lymph node
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Proliferation and invasiveness in an abnormal context
Malignant behavior is defined by�
The term The term ��abnormal contextabnormal context�� refers to a location or setting in the body refers to a location or setting in the body where the combination of proliferation and invasiveness does notwhere the combination of proliferation and invasiveness does notnormally occurnormally occur
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Invasiveness
Cancer cells penetrate into normal tissues and create new infrastructure and new blood vessels to support the metabolic needs of the tumor
Cancer cells also spread to distant sites of the body
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Only tumor cells that engage in Only tumor cells that engage in malignant behavior can sustain malignant behavior can sustain cancercancer
Killing all malignant cells will Killing all malignant cells will cure cancercure cancer
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All Malignant Cells that Could Evolve
Use normal cellular machinery to engage in proliferation and invasiveness
Normal cellular machinery is made of proteins, RNA, and other types of biomolecules
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An exception has never been observed
From Darwin�s Theory of Evolution we can be confident that an exception will not be observed
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Proliferation and Invasiveness Proliferation and Invasiveness are Complex Activitiesare Complex Activities
Requiring complex cellular machinery Requiring complex cellular machinery that took hundreds of millions of years that took hundreds of millions of years to evolveto evolve
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DarwinDarwin��s Theory of Evolutions Theory of Evolution
Implies that there is not time for the evolution of Implies that there is not time for the evolution of extensiveextensive new cellular machinery by cancer cellsnew cellular machinery by cancer cells
Charles Darwin© Smithsonian Institution
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This means that�
All malignant cells that could evolve must use normal cellular machinery to engage in proliferation and invasiveness
©
The normal cellular machinery that carries out proliferation and invasiveness is knowable and is largely already known
©
The machinery of proliferation and invasiveness is reflected in the biochemistry of:
�� DNA replicationDNA replication�� Cell divisionCell division�� Formation of the placentaFormation of the placenta�� Embryonic developmentEmbryonic development�� Wound healingWound healing
©
This means that all malignant cells that could evolve can be detected on the basis of�
Patterns of normal cellular machinery that effect or reflect proliferation and invasiveness in an abnormal context
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A Pattern is a Set of at Least Two Types of Biomolecules
Protein A Protein A ++ Protein BProtein B
A B
Both A and B must be present for the Pattern AB to be present
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Malignant Behavior, the Defining Property of Malignant Cells
No single type of biomolecule can enable the detection of malignant behavior
Can only be detected on the basis of patterns of normal cellular machinery related to proliferation and invasiveness
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Pathologists Diagnose Malignant Behavior on the Basis of Patterns
Pattern of cellular machinery reflecting breast cancer cells proliferating and invading the liver
Liver cells
We need cancer drugs that can to do the same
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A Pattern:
MCM + Urokinase
MCM proteins are characteristic of the potential for cell proliferation
Urokinase is a protein involved in invasiveness
©Urokinase photos: Harvey S.R., Gabor,M. et al., Am J Pathol 155: 1115 (1999) ©MCM photos:Freeman A, Morris et al., Clin Cancer Res. 5:2121 (1999) ©
Normal Colon
ProliferationMCM5
(Stained brown)
InvasivenessUrokinase
(Stained brown)
++ +
+_
Colon Cancer
Pattern
Pattern Absent Pattern Present
The Pattern of MCM5 and Urokinase in Colon Cancer
©1.) Scott IS, et al. Br J Cancer. 90:1583 (2004) © 2.) Laskey RA, et al. J Clin Oncol. 21:4306 (2003) ©
3.) Borgfeldt, c. et al. Int. J. Cancer 79,:588�595 (1998) © 4.) Dublin E., et al. Am J Pathol 157: 1219 (2000) ©
Ovarian Cancer
ProliferationMCM
(Stained brown or purple)
InvasivenessUrokinase
(Stained brown)
+ +
+_
Breast Cancer
Pattern
Pattern Present Pattern Present
The Pattern of MCM and Urokinase in Ovarian and Breast Cancer
1 2
43
+
©1.) Freeman, a. et al. Clin Cancer Res. 5:2121 © (1999) 2.) Dudderidge T.J. et al. Clin Cancer Res. 1(7):2510 (2005) ©
3.) Wagner SN, et al. Histochem Cell Biol. 105:53 (1996) Wagner SN, et al. Histochem Cell Biol. 105:53 (1996) © 4.) Ohaba, K. et al. J Urol. 174(2):461 (2005) ©
Normal Kidney
ProliferationMCM2
(Stained brown)
InvasivenessUrokinase
(Stained red or brown)
_ +
+_
Kidney Cancer
Pattern
Pattern Absent Pattern Present
The Pattern of MCM and Urokinase in Normal Kidney and Kidney Cancer
1 2
43
+
©1.) Freeman, a. et al. Clin Cancer Res. 5:2121 © (1999) 2.) Meng, M.V. et al. Clin Cancer Res.;7(9):271 (2001) ©3.) Shiomi, H. et al., Am J Pathol. 156(2):567 (2000) ) ) © 4.) Gavrilov, D., et al. Eur J Cancer. 37(8):1033 (2001) ©
Cancer of Esophagus
ProliferationMCM
(Stained black/gray)
InvasivenessUrokinase
(Stained brown)
+
+_
Prostate Cancer
Pattern
Pattern Present Pattern Present
The Pattern of MCM and Urokinase in Cancer
1 2
43
+
+
+MCM5MCM2
©1.) Shiomi, H. et al., Am J Pathol. 156(2):567 (2000) 2.) Meng, M.V. et al. Clin Cancer Res.;7(9):271 (2001) ©
3.) Shiomi, H. et al., Am J Pathol. 156(2):567 (2000) ) ) © 4.) Gavrilov, D., et al. Eur J Cancer. 37(8):1033 (2001) ©
Cancer of Esophagus
ProliferationMCM
(Stained black/gray)
InvasivenessUrokinase
(Stained brown)
+
+_
Prostate Cancer
Pattern
Pattern Present Pattern Present
The Pattern of MCM and Urokinase in Cancer
1 2
43
+
+
+MCM5MCM2
©
The normal cellular machinery that could carry out proliferation and invasiveness is the same�
for all for all types of cancers
The information for the machinery is encoded within normal sequences of human DNA in both cancer cells and normal cells present in the cancer cell environment that aid in tumor invasiveness
©
MCM proteins are required for proliferation and are present in all types of cancers and allmalignant cells
For example,
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This Means That Cancer is Essentially One Disease
and calls for a unified effortand calls for a unified effort
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With a Unified Effort
One set of drugs could be made for the cure of all types of solid cancers�
Breast, prostate, colon, lung, renal, ovarian, Breast, prostate, colon, lung, renal, ovarian, bladder, pancreatic cancer, melanoma, etcbladder, pancreatic cancer, melanoma, etc. .
©
What Can and Cannot be Known Cancer
Normal cellular machinery in tumor cells and their micro-environment
InvasivenessProliferation
Malignant Behavior
+
Knowable:
Unknowable:Comprehensive knowledge of the diverse, random, evolving, genetic alterations of cancer
Abnormal patterns of normal cellular machinery related to proliferation and invasiveness
©
There is Only One Way to Satisfy the Joint Requirements for The Specific Cure of
Cancer
Knowability
Specificity
CureComprehensiveness
©
To Detect and Destroy Cells that Express
Abnormal patterns of normal cellular machinery related to proliferation
and invasiveness
The requirements for the specific control of cancer are similar
©
Proliferation is Widely Distributed in the Normal body
Minimal Extensive
Bone MarrowSkinGI tractLungImmune systemReproductive organsWound repairBladderHair follicles
BrainHeartMuscleHeartBlood vesselsLiverKidneysPancreasAdrenal glandThyroid gland
Most current cancer drugs target proliferating cells and cause extensive toxicity and side effects
©
The Combination of Proliferation and Invasiveness is Highly Restricted in the
Normal Body
Present
Wound healingWound healingPlacental implantationPlacental implantationFetal developmentFetal developmentBlood vessel formationBlood vessel formationOvulationOvulationBreast developmentBreast development
Absent
Bone MarrowSkinGI tractLungImmune systemBladderHair folliclesBrainEyesNervesHeartMuscleHeartBlood vesselsLiverKidneysPancreasAdrenal glandThyroid gland
Present
But present in all malignant cells
©
If cancer therapy is avoided during pregnancy, infections and wound healing then�
Patterns of biomolecules characteristic of proliferation and invasiveness can provide a basis for the detection and destruction of the Set of All Cancer Cells that Could Evolve
Target Patterns and the Specific Cure of Cancer
©
To Detect The Set of All Cancer Cells that To Detect The Set of All Cancer Cells that Could Evolve Requires Multiple PatternsCould Evolve Requires Multiple Patterns
Since any protein or pattern could be lost during tumor cell evolution each pattern covers only a part of The Set
1 pattern 2 patterns 3 patterns n patterns
©
What is Both Knowable and Specific to All Cancer Cells
Normal cellular machinery in tumor cells and their micro-environment
InvasivenessProliferation
Malignant Behavior
+
Abnormal patterns of normal cellular machinery related to proliferation and invasiveness
Cancer Specific: NOCancer Specific: NO
Cancer Specific: YESCancer Specific: YES
©
The Number of Patterns Required for Comprehensiveness�
is related to the number of independent mechanisms of proliferation and invasiveness
Mechanisms are independent if they share no common cellular machinery characteristic of proliferation and invasiveness
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There is Only One Independent Mechanism of Cell Proliferation
All pathways of cell proliferation converge and use the same set of normal cellular machinery
©
Many Proteins are Required for Proliferation
Any protein in the set can be used for the detection of cell proliferation
The Set of Proteins Required for and Specific to Proliferation
proteins
©
Any Single Protein can be Lost by Mutation During Tumor Cell Evolution
However, the probability that 2 or 3 proteins will be jointly lost or mutated is vanishingly small
X
The Set of Proteins Required for and Specific to Proliferation
mutated protein
©
A comprehensive set of target patterns needs to include only 2 to 3 proteins related to proliferation
Therefore,
©
Invasiveness is a complex series of cooperative process involving tumor cells and non-tumor cells in the environment
Invasiveness is a property of both cancer cells and their environment
©
Cooperation of Non-Cancer Cells and Cancer Cells in Invasive Processes
Copyright ©2003 by the National Academy of Sciences
Yang, Meng et al. (2003) Proc. Natl. Acad. Sci. USA 100, 14259-14262
Cancer cells red, non-cancer cells green
New blood vessels
Melanoma in a Mouse
Copyright ©2003 by the National Academy of Sciences
©
While many proteins are involved in invasiveness�
no single protein appears to be absolutely required
©
However, invasiveness has well defined molecular signatures �
that reflect the underlying gene expression networks
©
For example,
Activation of C-MET by HGF triggers production of a cascade of proteins related to invasiveness
©
CC--MET/ HGFMET/ HGFuPARuPAR
UrokinaseUrokinase MMPsMMPs
VEGFVEGFPlasminPlasmin Osteopontin Osteopontin
Hyaluronic Acid
CD44CD44
MTMT--MMP1MMP1
©
The coordinated expression of multiple redundant mechanisms and proteins�
makes invasiveness easy to detect
©
In addition, the role played by genetically stable non-tumor cells confers�
a robustness to the molecular signatures of tumor invasiveness
©
There are a Number of Independent Mechanisms of Invasiveness
A set of target patterns is needed that can enable the detection of each of the independent mechanisms
The technology exists to identify these patterns
©
The Cure Cancer Project
Plans to identify and target a set of patterns that can comprehensively detect proliferation and invasiveness
©
The concept of targeting a protein pattern is simple
Specificity is for the patternnot the individual proteins that comprise the pattern
©
cellcell
For example,
A cancer drug targeted to the pattern of blue and green proteins would:
Spare Kill Spare
Protein
cell
Protein ProteinProtein
©
Components of Target Patterns can be
� On the tumor cell surface� In the microenvironment� Inside the tumor cell� Or combinations of the above
©
Pattern Recognition Tumor Targeting (PRTT)
PRTT is a technology designed to enable drugs to target patterns of proteins and other biomolecules
©
PRTT DrugsPRTT Drugs
Will kill Will kill cells if and only ifcells if and only if the the cells express the target cells express the target patternpattern
©
PRTT is Required to Satisfy the Joint Requirements for the Specific Cure of Cancer
Knowability
Specificity
CureComprehensiveness
©
The Cure Cancer Project Plans to Develop
A set of PRTT drugs that can A set of PRTT drugs that can detect and destroy all cells detect and destroy all cells engaged in the pattern of engaged in the pattern of proliferation and invasivenessproliferation and invasiveness
©
We estimate approximately 5 to 10 such drugs in combination will be required for the consistent and cure of cancer� without significant side effects
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