Cancer Biology Course Schedule for 2008 Course Jan 22Lee RatnerIntroduction Jan 29Rick WilsonCancer Genomics Feb 5Jason WebermTOR Feb 12Ron BoseHer2/ErbB signaling Feb 19Greg LongmoreEpithelial-mesenchymal transition Feb 26John CooperCytoskeletal rearrangement in cancer Mar 4Graham ColditzBreast cancer prevention Mar 12DPiwnica-WormsImaging protein-protein interactions Mar 19 John DiPersioManipulating gvhd Apr 8Tim Ley NK and T cell anti-tumor activity To Be Scheduled (Mar 26, Apr 1, 15, 22): Rafi KopanNotch signaling Tej Pandita ATM & DNA Repair Jeff ArbeitHIF-1 and Angiogenesis Lee RatnerNFkB activation in cancer Student-Sponsored Speaker 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: Format: 45 min didactic/30 min discussion

Introduction History Epidemiology Biology Diagnosis Treatment Prevention Social Issues See Perspectives in Nature Reviews in Cancer

Cancer – Historical Perspective 1600 BC Egyptian physician record 1 st 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 – 20 th 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

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. 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)

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, m exposed (3.7x10 10 Bq = Ci) Bq 131 I and 123I and 132Te->132I; 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 Transduc- tion 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 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 differen- tiation (arrow). b | Inva- sive 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. Grading: tubule formation, pleomorphism, mitoses Clinical vs pathological staging (T, M, N) Gene arrays, miRNA arrays, FISH, CGH, proteomics

New Linkages in Imaging MolecularBiology Radiology MolecularImaging XRT Surgery 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