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Cancer Biology Course Tuesdays, 12 noon, Southwest Tower 7 th Floor Conference Room All students,Postdocs, faculty, staff welcome Schedule for 2012 Course.

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Presentation on theme: "Cancer Biology Course Tuesdays, 12 noon, Southwest Tower 7 th Floor Conference Room All students,Postdocs, faculty, staff welcome Schedule for 2012 Course."— Presentation transcript:

1 Cancer Biology Course Tuesdays, 12 noon, Southwest Tower 7 th Floor Conference Room All students,Postdocs, faculty, staff welcome 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 WebSite: Format: 45 min didactic/30 min discussion

2 Introduction History Epidemiology Biology Diagnosis Treatment Prevention Social Issues See Perspectives in Nature Reviews in Cancer JCO Jan 1, 2012, Clinical Cancer Advances

3 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

4 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)

5 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

6 Therapeutic Targeting of the Hallmarks of Cancer


8 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

9 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

10 Multiple Steps to Cancer Reversibility?

11 Cancer Genome Atlas - Glioblastoma Tran

12 Intracellular Signaling Networks Regulate the Operations of the Cancer Cell

13 NFKBIA Deletion in Glioblastoma (NEJM 2011; 364: 627) Tran

14 BRAF Inhibitor for Melanoma

15 Targeting Mutations in Lung Cancer Govindan 90% stable or shrinkage with crizotinib Phase 1 screening

16 Zigelboim8 vs 5 mos PFS

17 Signal Transduc- tion by HER family

18 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

19 Dual HER2 inhibition improves survival in advanced breast cancer Pertuzumab and trastuzumab

20 Science 8 May 2009: Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer Sawyers and colleagues

21 Cabozantinib active in protstate cancer, esp bone mets 86% response 65% dec pain 46% off narcs Also active in melanoma

22 Ruxolitinib effective at blocking Jak1 & 2 in Myelofibrosis Yaseen,AML 50% mut

23 Old, 1996 Linehan, Gillanders

24 Brentuximab approved for refractory Hodgkin’s lymphoma and ALCL Kriesel, DLBCL 86% response in HLD and ALCL

25 Ipilimumab doubles survival in melanoma 47% vs 36% OS

26 Signaling Interactions in the Tumor Microenvironment during Malignant Progression

27 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


29 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

30 Exemestane reduces risk of invasive breast cancer in high-risk, post menopausal women 65% reduction in invasive ca

31 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


33 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

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