Transcript Cancer - Genboree

Cancer Biology II
Computer-Aided Discovery Methods
Sean E. McGuire, MD.,Ph.D.
Assistant Professor
Department of Molecular and
Cellular Biology
Department of Radiation Oncology
UT MD Anderson Cancer Center
Cancer Statistics
• Cancer affects 1 in 3 people
• Worldwide incidence of 10M cases/year
• 555,500 Americans died from cancer in
2002
US Mortality, 2004
Rank
Cause of Death
No. of
deaths
% of all
deaths
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
33,373
1.4
10. Septicemia
Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control
and Prevention, 2006.
2007 Estimated US Cancer Deaths*
Lung & bronchus
31%
Men
289,550
Women
270,100
26%
Lung & bronchus
15%
Breast
Prostate
9%
Colon & rectum
9%
10%
Colon & rectum
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Liver & intrahepatic
bile duct
4%
4%
Leukemia
3%
Esophagus
4%
Non-Hodgkin
lymphoma
Urinary bladder
3%
3%
Uterine corpus
Non-Hodgkin
lymphoma
3%
2%
Brain/ONS
2%
Kidney
3%
Liver & intrahepatic
bile duct
All other sites
24%
ONS=Other nervous system.
Source: American Cancer Society, 2007.
23%
All other sites
Change in the US Death Rates* by Cause,
1950 & 2004
Rate Per 100,000
600
586.8
1950
500
2004
400
300
217.0
193.9
180.7
200
185.8
100
50.0
48.1
19.8
0
Heart
Diseases
Cerebrovascular
Diseases
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
Trends in the Number of Cancer Deaths
Among Men and Women, US, 1930-2004
290,000
Number of Cancer Deaths
300,000
Men
285,000
Men
280,000
250,000
Women
200,000
275,000
270,000
150,000
Women
265,000
2000 2001 2002 2003 2004
100,000
50,000
0
1930
1940
1950
1960
1970
1980
1990
2000
Source: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease
Control and Prevention, 2006.
Cancer Death Rates*, All Sites Combined,
All Races, US, 1975-2003
300
Rate Per 100,000
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.gov) SEER*Stat 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).
Age-Adjusted Female Cancer Death Rates
33%
28%
EBCTG. Lancet. 2005 May 14-20;365(9472):1687-717.
Decline in Breast Cancer Incidence Rates in 2003
Ravdin PM, N Engl J Med. 2007 Apr 19;356(16):1670-4.
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
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
Hannahan & Weinberg, 2000
Targets in Cancer
• Proliferation
• Apoptosis/survival
• Differentiation
Cell Proliferation & the Cell Cycle
Mutations & Proliferation
Numerous Oncogenes Control
Cell Growth
Growth factors (I)
Growth factor
receptors (II)
Intracellular
Transducers (III)
Transcription
factors (IV)
Intracellular
receptors (II)
Selected Oncogenes and the Proteins of Their
Proto-Oncogenes
Oncogene
Animal
Retrovirus
Nonviral
Tumor
Subcellular
Location of
Protein
Protein Encoded by
Proto-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
erbB
McDonough feline
sarcoma
Avian erythroblastosis
Neu (or erb2)
ros
Breast Cancer
Plasma
membrane
Plasma
membrane
Plasma
membrane
CSF-1 receptor
Nuclear
Thyroid hormone
receptor
UR II avian sarcoma
Epidermal growth factor
receptor
Related to epidermal
growth factor
receptor
B. Intracellular receptors
erbA
Avian erythroblastosis
Oncogene
Animal
Retrovirus
Nonviral
Tumor
Subcellular
Location of
Protein
Protein
Encoded by
ProtoOncogene
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
abl
Abelson murine
leukemia
Cytoplasm
and
nucleus
met
Chronic
myelogenous
leukemia
Murine
osteosarcoma
Protein kinases that
phosphorylate
tyrosine residues
Oncogene
Animal
Retrovirus
Nonviral
Tumor
Subcellular
Location of
Protein
Protein
Encoded by
ProtoOncogene
B. Protein-serine/threonine kinases
mos
Raf
(mil)
Moloney murine sarcoma
3611 murine
sarcoma
Melanoma
Cytoplasm
Cytoplasm
Protein kinases
specific for serine or
threonine
C. Ras proteins
Ha-ras
Ki-ras
Nras
Harvey murine
sarcoma
Kirsten
murine
sarcoma
Bladder, mammary,
and skin
carcinomas
Lung and colon
carcinomas
Neuroblastoma
and leukemias
Plasma
membrane
Plasma
membrane
Plasma
membrane
Guanine
nucleotidebinding proteins
with GTPase
activity
D. Adaptors
crk
Avian sarcoma
virus
Cytoplasm
Contains protein with
SH2 and SH3
domains but not
catalytic domain
Oncogene
Animal
Retrovirus
Nonviral
Tumor
Subcellular
Location of
Protein
Protein
Encoded by
ProtoOncogene
Class IV: Nuclear Transcription Factors:
jun
Avian sacroma virus
17
Nucleus
fos
FBJ osteosarcoma
Nucleus
myc
Avian MC29
Myelocytomatosis
Nucleus
N-myc
Neuroblastoama
Nucleus
Leukemia
Nucleus
myb
Avian myeloblastosis
ski
Avian SKV770
Nucleus
rel
Avian
reticuloendotheliosis
Nucleus
and
cytoplasm
Transcription factor
AP1
Protein that
regulate
transcription
Targeted Biologic Therapies – HER2
• 20-30% of primary invasive breast 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 response 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)
New Targeted Biologic Therapies
Baselga and Norton. Focus on Breast Cancer. Cancer Cell; 1; 319-322
Signaling is more complex than
you can possibly imagine
Bange et al. Molecular targets for
breast cancer therapy and
prevention. Nat Med 2001;7:548
Estrogen and Estrogen Receptor
as a Therapy for Breast Cancer
Benefit of Adjuvant Tamoxifen
Clustering of breast tumors associated with ER and coregulated genes
Stanford/Norway
West et al.
Van’t Veer et al.
data from Sorlie et al. PNAS, 100: 8418, 2003
cyclins, GFs
Rb, PP2A
IGFs, Bcl2
ER
ER
MMPs,
Cadherins
VEGF, Ets-1
Hanahan and Weinberg: The
hallmarks of cancer. Cell. 2000
telomerase
Estrogen Receptor as a ‘Signaling Node’
Estradiol
Kinases
ECM
Growth factors
ER
RNA
SP-1
STATs
ERE
AP-1
D1/CDKs
Co-regulators
Loss of Tumor Supressors: Loss of
regulation of the cell cycle
Retinoblastoma
Knudsen Two-Hit Hypothesis
DSB DNA repair complex
P53 Protein
Targeting P53
APOPTOSIS
DIFFERENTIATION
Parallels Between Normal and “Cancer” Stem Cells
Pardall et al. Nat Rev Cancer 3:895, 2003
Glinsky et al JCI, 115, 1507, 2005
A Model For “Cancer Stem Cells” In
Treatment Resistance and Disease
Recurrence
Mammary Stem Cell Regulation
Notch
family
Hedgehog
family
Wnt
family
GH/IGF
Estrogen
EGF
family
FGF
family
TGFβ
family
Progesterone
Self-renewal
Prolactin
Stem Cell
Modified from Clarke et al 2005
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
Hedgehog Network Antagonists
Cyclopamine (CYC)
• Plant derived – Corn lily
• Causes birth defects
• Binds and inactivates SMO
Veratrum
Californicum
C27H41NO2
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
Cyclopia
Breast Cancer Progression
Abba et al. Breast Cancer Res 2004 6:R499
Angiogenesis
Angiogenesis Inhibitors
Summary
Change in the US Death Rates* by Cause,
1950 & 2004
Rate Per 100,000
600
586.8
1950
500
2004
400
300
217.0
193.9
180.7
200
185.8
100
50.0
48.1
19.8
0
Heart
Diseases
Cerebrovascular
Diseases
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
Angiogenesis Inhibitors