Cancer Biology Course
Tuesdays, 12 noon, Farrell Teacher Center, Holden Auditorium, All students,
Postdocs, faculty, staff welcome
WebSite:http://www.siteman.wustl.edu/physician/prof_education/courses_online.shtml
Format: 45 min didactic/30 min discussion
Schedule for 2010 Course
Jan 19 - Lee Ratner – Intro
Jan 26 – Len Maggi - Translational Regulation of Cancer
Feb 2 - Laura Beirut - Genetics of Lung Cancer Prevention
Feb 9 - Dennis Hallahan – Radiosensitizers
Feb 16 – Tom Ellenberger - Molecular Logic of DNA Repair
Feb 23 – David Linehan - Immune Dysregulation of Pancreatic Ca
Mar2 – Will Gilanders - Breast Ca Vaccine
Mar 9 –Elaine Mardis – Genomics of Breast Ca
Mar 16 – To be scheduled
Mar 23 - You - ATM, DNA Damage Signaling and Cancer
*Mar 30 - Lihong Wang - Photoacoustic Imaging
*Apr 6 – Fehniger - microRNAs and hematologic malignancies
Apr 13 - Mills - Metaplasia and the Mists of change: the molecular basis of gastric cancer
Apr 20 - ? Visiting Speaker
Apr 27 - ? Visiting Speaker
Attendance of all sessions & active discussion esp during presentation classic paper
Introduction
• History
• Epidemiology
• Biology
• Diagnosis
• Treatment
• Prevention
• Social Issues
See Perspectives in Nature Reviews in Cancer
JCO Dec 10 2009, Advances 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.
Acquired
Capabilities
of Cancer
Genetic and epigenetic
instability
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
Multiple Steps to Cancer
Reversibility?
Cancer Genome Atlas - Glioblastoma
Mardis
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
2009 – EML4-ALK in Lung Cancer
Cancer Stem Cells
Stem cells in adult somatic tissues, Scenarios involving cancer stem cells
Metastasis
Paget, 1889 “seed and soil”
Bevacizmab slows disease
progression of metastatic renal cell
carcinoma
Signal
Transduction by
HER
family
Trastuzumab improves survival for
patients with HER2+ gastric cancer
Fig. 1. Her-2 IHC (A) and HE (B) in
intestinal-type gastric cancer
(magnification ×100). FISH analysis
shows homogenous amplification of
HER-2 (C) and TOP2A (D) in gastric
carcinoma (clusters of red signals).
Green signals represent centromere
17. Cell nuclei are counterstained with
blue dye.
International, phase III trail
found 26% reduction in deaths
with addition of trastuzumab to
standard chemo
Mills
Platinum-Based Chemotherapy
plus Cetuximab in Head and Neck
Cancer
NEJM Sep 08
Improved survival with cetuximab
The
molecular
circuitry
of cancer.
*
*
*
Maggi
Hallahan, Ellenberger, You
Fostamatinib, Syk inhibitor, shrinks
CLL
Fehniger
Old, 1996
Lancet. 2009 Jun.
Safety, immunogenicity, and efficacy of
quadrivalent human papillomavirus (types 6,
11, 16, 18) recombinant vaccine in women aged
24-45 years: a randomised, double-blind trial.
New Linkages in Imaging
XRT
Surgery
Molecular
Biology
Radiology
Molecular
Imaging
Nanotechnology; BLI
Wong
Phase I, II, III
CR, PR,
stable,
progressive
QoL, DFS,
OS, surrogate
markers –
cancer Ag,
PET
NCI, FDA,
IRB
Oncotype Dx for stage II colon cancer
4 studies (total n=1,851; 761 candidate genes) identified 48 genes associated with recurrence
risk and 66 genes predictive of 5FU/LV benefit
Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status,
yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate
prognostic recurrence score (RS) and predictive treatment score (TS) algorithms.
In validation study, tumor blocks of 1,490 pts with blocks had stage II colon cancer and RTPCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV)
Median FU=6.6 yrs.
In the primary analysis pts following Sx, the RS predicted recurrence risk (HR/25
units=1.58, 95% CI 1.15-2.15; p=0.004).
The RS also predicted DFS (p=0.01) and OS (p=0.04).
Recurrence risk increased monotonically with increasing RS.
In multivariate analyses, RS retained prognostic significance (p=0.008) independent of
mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion.
MMR deficiency (HR=0.31, 95% CI 0.15-0.63; p<0.001) and T4 stage (HR=1.94, 95% CI
1.35-2.79; p=0.005), together ~25% of pts, also were independently prognostic.
5FU/LV benefit was significant (p<0.001).
However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19).
J Natl Cancer Inst. 2009 January;
Meta-analysis of Risk Reduction Estimates
Associated With Risk-Reducing Salpingooophorectomy in BRCA1 or BRCA2 Mutation
Carriers
RRSO was also associated with a statistically
significant reduction in the risk of BRCA1/2associated ovarian or fallopian tube cancer (HR =
0.21; 95% CI = 0.12 to 0.39).
Animal
models
&
safety
Quality of Life & Prevention
Advances
US cancer screening rates are low or declining
PSA screening has limited benefit
Survivors of childhood cancer are not receiving
recommended cancer screening tests
Androgen receptor inhibitor reduces prostate cancer
risk
Supplements (vit E, minerals) ineffective
False positive screening tests increase number of f/u
tests
Studies identify determinants of and effects of end-oflife care
ASCO Recommendations
Strengthen nation’s clinical research
funding, support, insurers, regulatory barriers
High quality cancer care for all
Acquired
Capabilities
of Cancer
Genetic &
epigenetic
instability
Hanahan &
Weinberg
Cell 100:57-70,
2000
Discussion Paper