Adrian V. Lee, Ph.D.

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Cancer Biology II Computer-Aided Discovery Methods
Adrian V. Lee, Ph.D. Associate Professor Breast
Center Departments of Medicine and Molecular and
Cellular Biology
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Cancer Statistics

• Cancer affects 1 in 3 people
• Worldwide incidence of 10M cases/year
• 555,500 Americans died from cancer in 2002

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US Mortality, 2004
No. of deaths
of all deaths
Rank
Cause of Death

• 1. Heart Diseases 652,486 27.2
• 2. Cancer 553,888 23.1
• 3. Cerebrovascular diseases 150,074 6.3
• 4. Chronic lower respiratory diseases 121,987
  5.1
• 5. Accidents (Unintentional injuries) 112,012
  4.7
• 6. Diabetes mellitus 73,138 3.1
• 7. Alzheimer disease 65,965 2.8
• 8. Influenza pneumonia 59,664 2.5
• 9. Nephritis 42,480 1.8

Source US Mortality Public Use Data Tape 2004,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2006.
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2007 Estimated US Cancer Deaths
Men289,550
Women270,100
26 Lung bronchus 15 Breast 10 Colon
rectum 6 Pancreas 6 Ovary 4 Leukemia 3 Non
-Hodgkin lymphoma 3 Uterine
corpus 2 Brain/ONS 2 Liver
intrahepatic bile duct 23 All other sites
Lung bronchus 31 Prostate 9 Colon rectum
9 Pancreas 6 Leukemia 4 Liver
intrahepatic 4bile duct Esophagus 4 Urinary
bladder 3 Non-Hodgkin 3
lymphoma Kidney 3 All other sites
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ONSOther nervous system. Source American Cancer
Society, 2007.
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Change in the US Death Rates by Cause, 1950
2004
Rate Per 100,000
586.8
600
1950 2004
500
400
300
217.0
193.9
185.8
180.7
200
100
48.1
50.0
19.8
0
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
Age-adjusted to 2000 US standard
population. Sources 1950 Mortality Data -
CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality
Data US Mortality Public Use Data Tape, 2004,
NCHS, Centers for Disease Control and Prevention,
2006
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Trends in the Number of Cancer Deaths Among Men
and Women, US, 1930-2004
Men
Men
Women
Number of Cancer Deaths
Women
Source US Mortality Public Use Data Tape, 2004,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2006.
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Cancer Death Rates, All Sites Combined, All
Races, US, 1975-2003
Rate Per 100,000
300
Men
250
Both Sexes
200
Women
150
100
50
0
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
Age-adjusted to the 2000 US standard
population. Source Surveillance, Epidemiology,
and End Results (SEER) Program (www.seer.cancer.go
v) SEERStat Database Mortality - All COD,
Public-Use With State, Total U.S. (1969-2003),
National Cancer Institute, DCCPS, Surveillance
Research Program, Cancer Statistics Branch,
released April 2006. Underlying mortality data
provided by NCHS (www.cdc.gov/nchs).
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Age-Adjusted Female Cancer Death Rates
33
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EBCTG. Lancet. 2005 May 14-20365(9472)1687-717.

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Decline in Breast Cancer Incidence Rates in 2003
Ravdin PM, N Engl J Med. 2007 Apr
19356(16)1670-4.
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Why are we interested in the molecular biology of
cancer?

• Cancer is a genetic disease
• Agents that cause cancer cause genetic change
• Agents that cause genetic change cause cancer
• e.g. chemical carcinogens, ionizing radiation,
  viruses

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Why are we interested in the molecular biology of
cancer?

• If we can understand the molecular biology of
  cancer we may be able to
• Prevent cancer
• Better treat cancer

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Targets in Cancer

• Proliferation
• Apoptosis/survival
• Differentiation

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Numerous Oncogenes Control Cell Growth
Growth factors (I)
Growth factor receptors (II)
Intracellular Transducers (III)
Transcription factors (IV)
Intracellular receptors (II)
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Selected Oncogenes and the Proteins of Their
Proto-Oncogenes
Animal Retrovirus
Nonviral Tumor
Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Oncogene
Class I Growth Factors
Sis
Simian sarcoma
Secreted
Platelet-derived growth factor
Class II Receptors
A. Cell-surface receptors with protein-tyrosine
kinase activity
fms
McDonough feline sarcoma
Plasma membrane
CSF-1 receptor
erbB
Avian erythroblastosis
Plasma membrane
Epidermal growth factor receptor
Neu (or erb-2)
Breast Cancer
Plasma membrane
Related to epidermal growth factor receptor
ros
UR II avian sarcoma
B. Intracellular receptors
erbA
Avian erythroblastosis
Nuclear
Thyroid hormone receptor
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Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Nonviral Tumor
Animal Retrovirus
Oncogene
Class III Intracellular Transducers A
Protein-tyrosine kinase
src
Rous avian sarcoma
Cytoplasm
yes
Yamaguchi avian sarcoma
Cytoplasm
Fps (fes)
Fujinami avian sarcoma (and feline sarcoma)
Cytoplasm
Protein kinases that phosphorylate tyrosine
residues
abl
Abelson murine leukemia
Chronic myelogenous leukemia
Cytoplasm and nucleus
met
Murine osteosarcoma
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Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Nonviral Tumor
Animal Retrovirus
Oncogene
B. Protein-serine/threonine kinases
mos
Moloney murine sarcoma
Cytoplasm
Protein kinases specific for serine or threonine
Raf (mil)
3611 murine sarcoma
Cytoplasm
C. Ras proteins
Ha-ras
Harvey murine sarcoma
Bladder, mammary, and skin carcinomas
Plasma membrane
Guanine nucleotide-binding proteins with GTPase
activity
Ki-ras
Kirsten murine sarcoma
Plasma membrane
Lung and colon carcinomas
N-ras
Neuroblastoma and leukemias
Plasma membrane
D. Adaptors
crk
Avian sarcoma virus
Cytoplasm
Contains protein with SH2 and SH3 domains but not
catalytic domain
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Subcellular Location of Protein
Protein Encoded by Proto-Oncogene
Nonviral Tumor
Animal Retrovirus
Oncogene
Class IV Nuclear Transcription Factors
jun
Avian sacroma virus 17
Nucleus
Transcription factor AP1
fos
FBJ osteo-sarcoma
Nucleus
myc
Avian MC29 Myelocytomatosis
Nucleus
Neuroblastoama
N-myc
Nucleus
Protein that regulate transcription
myb
Avian myelo-blastosis
Leukemia
Nucleus
ski
Avian SKV770
Nucleus
rel
Avian reticuloendotheliosis
Nucleus and cytoplasm
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Targeted Biologic Therapies HER2

• 20-30 of primary invasive cancers overexpress
  HER-2 (90 of these are via gene amplification)
• Overexpression of HER-2 correlates with high
  mitotic rate and poor prognosis (node-positive
  patients)
• HER-2 overexpression is associated with a better
  patient resposne to doxorubicin, but a poor
  response to other drugs (methotrexate,
  5-fluorouracil, cyclophosphamide and tamoxifen)
• Auto-antibodies to HER-2 are found in patient
  serum and may be a marker for tumor burden
• HER-2 is a therapeutic target using a humanized
  antibody (trastuzumab Herceptin)

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New Targeted Biologic Therapies
Baselga and Norton. Focus on Breast Cancer.
Cancer Cell 1 319-322
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Signaling is more complex than you can possibly
imagine
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Estrogen and Estrogen Receptor as a Therapy for
Breast Cancer
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Benefit of Adjuvant Tamoxifen
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Clustering of breast tumors associated with ER
and coregulated genes
West et al.
Stanford/Norway
Vant Veer et al.
data from Sorlie et al. PNAS, 100 8418, 2003
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VEGF, Ets-1
Hanahan and Weinberg The hallmarks of cancer.
Cell. 2000
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Estrogen Receptor as a Signaling Node
Estradiol
ER
RNA
AP-1
SP-1
Co-regulators
ERE
D1/CDKs
STATs
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Loss of regulation of the cell cycle
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DSB DNA repair complex
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APOPTOSIS
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DIFFERENTIATION
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Parallels Between Normal and Cancer Stem Cells
Pardall et al. Nat Rev Cancer 3895, 2003
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Glinsky et al JCI, 115, 1507, 2005
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A Model For Cancer Stem Cells In Treatment
Resistance and Disease Recurrence
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Mammary Stem Cell Regulation
Hedgehog family
Notch family
TGFß family
Wnt family
GH/IGF
Estrogen
EGF family
Progesterone
Self-renewal
FGF family
Prolactin
Stem Cell
Modified from Clarke et al 2005
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Scientists Weigh Stem Cells Role as Cancer Cause
Within the next year, we will see medical
centers targeting stem cells in almost every
cancer, said Dr. Max S. Wicha, director of the
University of Michigan Comprehensive Cancer
Center, one of the sites for the preliminary
study that begins in the next few months (the
other participating institutions are Baylor
College of Medicine in Houston and the
Dana-Farber Cancer Institute in Boston).
By GINA KOLATA Published December 21, 2007
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Hedgehog Network Antagonists

• Cyclopamine (CYC)
• Plant derived Corn lily
• Causes birth defects
• Binds and inactivates SMO
• CUR0199691 (Curis Inc.)
• One of three chemical classes that inhibit SMO
• Binds and inactivates SMO
• Tomatidine (TOM)
• Structurally similar to CYC
• Does not inhibit Hedgehog

Veratrum Californicum
C27H41NO2
Cyclopia
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Breast Cancer Progression
Abba et al. Breast Cancer Res 2004 6R499
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Angiogenesis Inhibitors