Transcript Schedule for 2008 Course

Cancer Biology Course
Courses started in 1999;
Tuesdays, 12 noon, Farrell Teacher Center, Holden Auditorium
All students, postdocs, faculty, staff welcome
Alternating years – D Wilson & L Ratner (emphasis on pediatric vs adult oncology
WebSite:http://www.siteman.wustl.edu/physician/prof_education/courses_online.shtml
Format: 45 min didactic/30 min discussion
Schedule for 2008 Course
Jan 22 Lee Ratner
Introduction
Jan 29 Rick Wilson
Cancer Genomics
Feb 5 Jason Weber
mTOR
Feb 12 Ron Bose
Her2/ErbB signaling
Feb 19 Greg Longmore Epithelial-mesenchymal transition
Feb 26 John Cooper
Cytoskeletal rearrangement in cancer
Mar 4 Graham Colditz Breast cancer prevention
Mar 12 DPiwnica-Worms Imaging protein-protein interactions
Mar 19 John DiPersio
Manipulating gvhd
Apr 8
Tim Ley
NK and T cell anti-tumor activity
To Be Scheduled (Mar 26, Apr 1, 15, 22):
Rafi Kopan
Notch signaling
Tej Pandita
ATM & DNA Repair
Jeff Arbeit
HIF-1 and Angiogenesis
Lee Ratner
NFkB activation in cancer
Student-Sponsored Speaker
Introduction
• History
• Epidemiology
• Biology
• Diagnosis
• Treatment
• Prevention
• Social Issues
See Perspectives in Nature Reviews in Cancer
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
1660 Mastectomy for breast cancer
1713 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
Cancer –
th
20
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 introduced
1966 NCI testing for cancer-causing chemicals
1970 DeVita develops MOPP for Hodgkin
Boveri’s 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-suppressor 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 growthstimulatory 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.
Chromosomal
Translocations in
CML and Solid
Tumors
1961-Nowell & Hungerford – Ph
chromosome
1972 Rowley t9;22 CML
t8;14 Burkitt, t15;17 APL,
t11;22 Ewings
1984 – BCR-ABL fusion
1988 – Huang – ATRA
1998 – Druker – Imatinib, Gleevec
Acquired
Capabilities
of Cancer
Genetic and epigenetic
instability
Genomic
Landscape
of Cancers
Estimated proportion of cancer in US that
could have been avoided by changes in
each category of non-genetic cancer causes
– Risk
– Structured-data
summaries
– Meta-analysis
– Pooled analysis
– Prospective studies
– Retrospective studies
– Bias
– Confounding
– Randomized controlled
trials
– Statistical power
Tobacco &
Cancer
Asbestos & Mesothelioma
Radiation & Thyroid Cancer
Chernobyl, 1986-10-20m exposed (3.7x1010 Bq = Ci)
1018 Bq 131I and 123I and 132Te->132I; 1017 Bq Cs
1000 vs 30 cases/10 yrs/ 50-90% RET-PTC
Atomic bomb – neutrons + gamma rays
Cancer Stem Cells
Stem cells in adult somatic tissues, Scenarios involving cancer stem cells
Multiple Steps to Cancer
Reversibility?
Epithelial-Mesenchymal Transition
Metastasis
Paget, 1889 “seed and soil”
Signal
Transduction by
HER
family
The
molecular
circuitry
of cancer.
*
*
*
Apoptosis & Cancer
Examples of genetically engineered mouse models that recapitulate
human solid cancers
Old, 1996
Histological Analysis
Grading: tubule formation, pleomorphism, mitoses
Clinical vs pathological staging (T, M, N)
Gene arrays, miRNA arrays, FISH, CGH, proteomics
Even within the same
organ, haematoxylin and
eosin (H&E) staining can
be used to identify
tumours with different
morphology and
prognosis. a | Classical
invasive ductal carcinoma
of the breast, exhibiting
focal glandular differentiation (arrow). b | Invasive 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.
New Linkages in Imaging
XRT
Surgery
Molecular
Biology
Radiology
Molecular
Imaging
Nanotechnology; BLI
Phase I, II, III
CR, PR,
stable,
progressive
QoL, DFS,
OS, surrogate
markers –
cancer Ag,
PET
NCI, FDA,
IRB
Natural Products
periwinkle
Pacific yew bark-taxol,
microbes – bleo,
mitomycin, anthracyclines
Marine sources –
bryostatin, cytosine
arabinoside
Enzymatic rxn, binding target, cell
killing, high throughput screens
Pharmacology
Antibodies (Her2, RIT),
Tyrosine kinase inhibitors (VEGFR,
ABL, KIT);
High dose therapy and BMT
Also
Antibodies –
Herceptin,
Rituximab
Other Tyr kin
inhibitors
e.g. imatinib
(gleevec)
High dose
therapy, gene
therapy, BMT
siRNAs
Animal
models
&
safety
Breast cancer
activism
Disease advocacy
organizations
Acquired
Capabilities
of Cancer
Genetic &
epigenetic
instability
Hanahan &
Weinberg
Cell 100:57-70,
2000
Discussion Paper