Cancer Biology CourseTuesdays, 12 noon, Farrell Teacher Center, Holden Auditorium, All students,Postdocs, faculty, staff welcome

Schedule for 2010 CourseJan 19 - Lee Ratner – IntroJan 26 – Len Maggi - Translational Regulation of CancerFeb 2 - Laura Beirut - Genetics of Lung Cancer PreventionFeb 9 - Dennis Hallahan – RadiosensitizersFeb 16 – Tom Ellenberger - Molecular Logic of DNA RepairFeb 23 – David Linehan - Immune Dysregulation of Pancreatic CaMar2 – Will Gilanders - Breast Ca VaccineMar 9 –Elaine Mardis – Genomics of Breast CaMar 16 – To be scheduledMar 23 - You - ATM, DNA Damage Signaling and Cancer*Mar 30 - Lihong Wang - Photoacoustic Imaging*Apr 6 – Fehniger - microRNAs and hematologic malignanciesApr 13 - Mills - Metaplasia and the Mists of change: the molecular basis of gastric cancerApr 20 - ? Visiting Speaker Apr 27 - ? Visiting SpeakerAttendance of all sessions & active discussion esp during presentation classic paper

WebSite:http://www.siteman.wustl.edu/physician/prof_education/courses_online.shtmlFormat: 45 min didactic/30 min discussion

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 Perspective1600 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 – 20th Century1903 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

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 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.

Boveri’s Predictions (1902)

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

ChromosomalTranslocations in CML and Solid

Tumors1961-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 Transduc-

tion 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

CancerNEJM 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 ImagingNew Linkages in Imaging

MolecularMolecularBiologyBiology

RadiologyRadiology

MolecularMolecularImagingImaging

XRT

Surgery

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 cancer4 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 RT-PCR 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 Salpingo-

oophorectomy in BRCA1 or BRCA2 Mutation Carriers

RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-

associated 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 decliningPSA screening has limited benefit

Survivors of childhood cancer are not receiving recommended cancer screening testsAndrogen receptor inhibitor reduces prostate cancer riskSupplements (vit E, minerals) ineffective False positive screening tests increase number of f/u testsStudies identify determinants of and effects of end-of-life 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