Cancer Biology Course
Tuesdays, 12 noon, Southwest Tower 7th Floor Conference Room
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 2012 Course
Jan 17 – Ratner Intro (Paper: Hanahan & Weinberg, Cell 2011;144:646, Hallmarks of
cancer: the next generation)
Jan 24 – Curiel - Strategies to Adapt Adenoviruses for Cancer Therapy Applications
Jan 31 – Denardo – Immune regulation of cancer prevention
Feb 7 – Govindan – Lung cancer
Feb 14-Ornitz – FGF Signaling in Non-Small Cell Lung Cancer
Feb 21 Oltz – Epigenomics in lymphoma
Feb 28 Tran - Gliomas
Mar 6 Dehdashti - PET
Mar 13 Tomasson –Biology & Treatment of Myeloma and Plasma Cell Dyscrasias
Mar 20 Schroeder – The Graft versus Tumor Effect
Mar 27 Yaseen - Molecular Pathogenesis of Acute Myeloid Leukemia
Apr 3 Zighelboim – Ovarian Ca
Apr 10 Kriesel – Genetics of DLBCL
Apr 17 or 24 for Student Invited 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 Jan 1, 2012, Clinical Cancer Advances
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
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.
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
Therapeutic Targeting of the Hallmarks of Cancer
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
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
Multiple Steps to Cancer
Reversibility?
Cancer Genome Atlas - Glioblastoma
Tran
Intracellular Signaling Networks Regulate the Operations of
the Cancer Cell
NFKBIA Deletion in Glioblastoma
(NEJM 2011; 364: 627)
Tran
BRAF Inhibitor for Melanoma
Targeting Mutations in Lung Cancer
Phase 1
screening
Govindan
90% stable or shrinkage with crizotinib
Zigelboim
8 vs 5 mos PFS
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 trial
found 26% reduction in deaths
with addition of trastuzumab to
standard chemo
Dual HER2 inhibition improves survival in advanced breast cancer
Pertuzumab and
trastuzumab
Science 8 May 2009: Development of a Second-Generation Antiandrogen for Treatment of
Advanced Prostate Cancer
Sawyers and colleagues
Cabozantinib active in protstate
cancer, esp bone mets
86% response
65% dec pain
46% off narcs
Also active in
melanoma
Ruxolitinib effective at blocking
Jak1 & 2 in Myelofibrosis
50% mut
Yaseen,AML
Old, 1996
Brentuximab approved for refractory
Hodgkin’s lymphoma and ALCL
86% response in
HLD and ALCL
Kriesel, DLBCL
Ipilimumab doubles survival in melanoma
47% vs 36% OS
Signaling Interactions in the Tumor Microenvironment during Malignant Progression
Angiogenesis and other inhibitors
 Pazopanib has activity in several soft tissue
sarcomas
 Brivanib has activity in soft tissue sarcomas
(blocks VEGF and FGF)
 Axitinib sup to sorafenib in renal cell ca
 Bevacizumab for ovarian cancer
52% dec disease progression; 80% response; 36%
dec in deaths in advanced ovarian Ca
 Denosumab for bone metastases
Developments in Screening
 US panel recommended against routine use of
PSA for prostate screening
 Low dose CT scanning reduces lung cancer
deaths (20% vs CXR screen)
 Cervical cancer screening extended to 3 yrs,
HPV testing superior to Pap testing alone
Dehdashti
Exemestane reduces risk of invasive breast
cancer in high-risk, post menopausal women
65% reduction in invasive ca
Racial disparities in the use of hospice services according to geographic residence
and socioeconomic status in an elderly cohort with nonsmall cell lung cancer
Cancer117: 1506-1515, 8 NOV 2010
Review also indicates racial disparities in myeloma survival, ovarian cancer care, and
cancer death rates, which may be due to differences in education level
ASCO Recommendations
 Continued progress depends on access to clinical
trials and quality care
 Faster and smarter clinical trials utilizing information
technology
 Revitalize federal funding of clinical trials
 Examine potential impact of health care reform on
cancer disparities
 Assist FDA in addressing cancer drug shortages
 Improve advanced cancer care planning
 Highlight potential solutions for oncology workforce
shortages
 Assist UN in addressing cancer crisis in developing
counties