Cancer Biology CourseTuesdays, 12 noon, Southwest Tower 7th Floor Conference Room All students,Postdocs, faculty, staff welcome

Schedule for 2012 CourseJan 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 ApplicationsJan 31 – Denardo – Immune regulation of cancer preventionFeb 7 – Govindan – Lung cancerFeb 14-Ornitz – FGF Signaling in Non-Small Cell Lung CancerFeb 21 Oltz – Epigenomics in lymphomaFeb 28 Tran - GliomasMar 6 Dehdashti - PETMar 13 Tomasson –Biology & Treatment of Myeloma and Plasma Cell DyscrasiasMar 20 Schroeder – The Graft versus Tumor EffectMar 27 Yaseen - Molecular Pathogenesis of Acute Myeloid LeukemiaApr 3 Zighelboim – Ovarian CaApr 10 Kriesel – Genetics of DLBCL Apr 17 or 24 for Student Invited 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 Jan 1, 2012, Clinical Cancer Advances

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

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)

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

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

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

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

Govindan 90% stable or shrinkage with crizotinib

Phase 1screening

Zigelboim 8 vs 5 mos PFS

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 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% response65% dec pain46% off narcsAlso active in melanoma

Ruxolitinib effective at blocking Jak1 & 2 in Myelofibrosis

Yaseen,AML

50% mut

Old, 1996

Brentuximab approved for refractory Hodgkin’s lymphoma and ALCL

Kriesel, DLBCL

86% response in HLD and ALCL

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 2010Review 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