Cancer Biology Course

1
Cancer Biology Course

• WebSitehttp//www.siteman.wustl.edu/physician/pro
  f_education/courses_online.shtml
• Format 45 min didactic/30 min discussion
• Cell Cycle Regulation
• Checkpoints (Piwnica-Worms) ARF (Weber)
• Rb (Harbour) Telomeres (Stewart)
• Viral Oncology
• Herpesviruses (Virgin) Papillomaviruses
  (Laimins)
• Retroviruses (Ratner) Hepatitis Viruses
  (Blight)
• Breast Cancer
• Biologic markers/targets (Ellis)
  Metastatic breast cancer (Weilbaecher)
• Genetics of progression (Polyak) Angiogenesis

2
Introduction

• History
• Epidemiology
• Biology
• Diagnosis
• Treatment
• Prevention
• Social Issues
• See Perspective in Nature Reviews in Cancer
• Hanahan Weinberg The hallmarks of cancer Cell
  10057, 2000

3
Cancer Historical Perspective

• 1600 BC Egyptian physician record 1st
  description of breast cancer
• 460 BC Hippocrates uses carcinos to describe
  tumors (Greek crab)
• 129 AD Galen attributes cancer to black bile
• Mastectomy for breast cancer
• Ramazzini notes absence of cervical but
  increased breast ca in nuns
• 1775 Pott describes scrotal cancer in chimney
  sweeps
• 1838 Muller describes cancer as abnormalities of
  cells
• 1896 Grubbe administers xrays to cancer patient

4
Cancer 20th Century
1903 Radium isolated by Curies used for tumor
treatment 1913 American Cancer Society
founded 1928 Papanicolau provides basis for PAP
smears 1937 Roosevelt creates NCI 1941 Huggins
used hormones to treat prostate Ca 1948 Hitchings
uses 6MP for childhood leukemia 1955 MTX used for
solid tumor 1957 IFN and FU introduces 1966 NCI
testing for cancer-causing chemicals 1970 DeVita
develops MOPP for Hodgkin
5
Boveris Predictions (1902)
Cell-cycle checkpoints (Hemmungseinrichtung
inhibitory mechanism) that would allow cell
division only when a specific external stimulus
is experienced by the cell. The clonal
origin of tumours. Genetic mosaicism. Tumour-sup
pressor genes (Teilungshemmende Chromosomen), the
effects of which can be overcome by external
signals, and which are physically lost in
progressively growing tumours. Oncogenes
(Teilungsfoerdernde Chromosomen) that become
amplified (im permanenten Übergewicht) during
tumour development. Tumour progression from
benign to malignant, involving sequential changes
of increased growth-stimulatory chromosomes and
loss of growth-inhibitory chromosomes. Cancer
predisposition through inheritance of chromosomes
(genes) that are less able to suppress
malignancy. Cancer predisposition through
inheritance of genes that cause aberrant
mitoses. Inheritance of the same 'weak
chromosome' from both parents leads to
homozygosity for the defective chromosome and,
consequently, to high-penetrance cancer syndromes
for example, xeroderma pigmentosum. The role of
wounding and inflammation in tumour
promotion. Loss of cell adhesion in
metastasis. Sensitivity of malignant cells to
radiation therapy.
6
(No Transcript)
7
ChromosomalTranslocations in CML and Solid Tumors
1961-Nowell Hungerford Ph chromosome 1972
Rowley t821 CML t814 Burkitt, t1517 PML,
t1122 Ewings 1984 BCR-ABL fusion 1988 Huang
ATRA 1998 Druker STI571
8
Acquired Capabilities of Cancer
Genetic and epigenetic instability
9
Tobacco Cancer
10
Asbestos Mesothelioma
11
(No Transcript)
12
Radiation Thyroid Cancer
Chernobyl, 1986-10-20m exposed 1018 Bq 131I and
123I and 132Te-gt132I 1017 Bq Cs 1000 vs 30
cases/10 yrs/ 50-90 RET-PTC Atomic bomb
neutrons gamma rays
13
Multiple Steps to Cancer
Reversibility?
14
Metastasis
Paget, 1889 seed and soil
15
The molecular circuitry of cancer.
16
APOPTOTIC SIGNALING PATHWAYS
Growth Factor Withdrawal Irradiation Loss of
Matrix Contact Glucocorticoids
?
Bax/Bak
FADD
Fas
Bcl-2 Bcl-X
Cytochrome c
??m
tBid
Procaspase 8
Apaf-1
Smac
IAPs
Procaspase 9
C-FLIP
Bid
Caspase 9
Caspase 8
Procaspase 3
iCAD
Procaspase 3
CAD
Caspase 3
Caspase 3
DNA Fragmentation
EXTRINSIC PATHWAY
INTRINSIC PATHWAY
17
Other Models Rat Monkey Worm Fly Zebrafish
18
Old, 1996
19
Histological Analysis
Even within the same organ, haematoxylin and
eosin (HE) staining can be used to identify
tumours with different morphology and prognosis.
a Classical invasive ductal carcinoma of the
breast, exhibiting focal glandular
differen-tiation (arrow). b Inva-sive and in
situ lobular carcinoma, in which the invasive
tumour grows in rows of single cells (short
arrow). Similar cells are seen within lobular
units (long arrow). c Invasive medullary
carcinoma, exhibiting solid sheets of tumour
cells (short arrow) and lymphocytic infiltrate at
the pushing edge of the tumour (long arrow). d
Invasive micropapillary carcinoma, a rare
aggressive type of breast cancer. The tumour is
composed entirely of cells that are arranged in
small papillary structures.
Grading tubule formation, pleomorphism,
mitoses Clinical vs pathological staging (T, M, N)
20
Gene Tissue Arrays
Proteomics, FISH, CGH
21
Annual cost estimate for universal colonoscopy at
age 50     Number of individuals in the United
States who will turn 50 during a 12-month period
3,000,000     Cost of screening colonoscopy
per person US 1,000     Annual cost of
universal population-based screening by
colonoscopy for 50-year olds, excluding costs
related to follow-up of abnormalities detected
US 3,000,000,000     Cost estimate in terms
of dollars needed to save 1 year of life US
10,00025,000 per year of life saved
PSA, mammograms, BRCA, virtual colonoscopy
Molecular markers
22
New Linkages in Imaging
XRT Surgery
Molecular Biology
Radiology
23
Phase I, II, III CR, PR, stable, progressive QoL,
DFS, OS, surrogate markers cancer Ag, PET NCI,
FDA, IRB
24
Natural Products
Figure 1  Two of the earliest plants to yield
natural products with anticancer activities.   a
Podophyllum peltatum (the mayapple), which
produces podophyllotoxin, and b Catharanthus
roseus (also known as Vinca rosea or the rosy
periwinkle), which produces the Vinca alkaloids
vinblastine and vincristine
Pacific yew bark-taxol, microbes bleo,
mitomycin, anthracylcines Marine sources
bryostatin, cytosine arabinoside
25
Identifying Active Agents
Structureactivity relationships for the
sarcodictyins.   This example shows how altering
the structure of a naturally occurring compound
with activity against cancer cells can markedly
change its activity. Altering the structure of
the highlighted side chains can lead to
differences in cytotoxic activity of gt1,000-fold
Enzymatic rxn, binding target, cell killing, high
throughput screens
26
Pharmacology
Antibodies (Her2, RIT), Tyrosine kinase
inhibitors (VEGFR, ABL, KIT) High dose therapy
and BMT
27
Hormonal Therapies
28
Also Antibodies Herceptin, Rituximab Other
Tyr kin inhibitors e.g. imatinib (gleevec) High
dose therapy, gene therapy, BMT
29
(No Transcript)
30
Animal models safety
31
(No Transcript)
32
(No Transcript)
33
Breast cancer activism Disease advocacy
organizations
34
(No Transcript)