16_tumor.ppt
TRANSCRIPT
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Final on W afternoon
• Review: M 6:00 here
• Covers section 9->
• All cases
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CANCER: Definitions• Benign tumor
• Carcinogen
• “Familial” cancer
• Sporadic cancer
• Growth factor:
• Kinase:
• Malignant tumor
• Metastasis
• Neoplasm:
• Oncogene:
• Proto-oncogene:
• Somatic mutation, vs germ line
• [Oncogenic] Transformation:
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1.5 million cases per year in U.S; nearly half that # die!
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What causes cancer?
• Accumulation of genetic mutations– DNA replication– Viruses– Carcinogens– Radiation (UV rays)
http://people.bath.ac.uk/pr1cemb/Homepage.htm
7-10 mutations
in one single cell
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Pathogen related cancers• Estimated about 15% of human cancers.
– Virus can carry specific “oncogenes”; or promoter insertion.
– Chronic inflammation can contribute to cancerous mutations
– Killing of infected cells can require cell division to replace.
• Hepatitis B & C– HBV creates a protein that prevents normal apoptosis
• EBV: Lymphomas, mostly in Africa• Helicobacter pylori• HPV
– Manufactures proteins that interfere with cell cycle control.
• We can prevent these cancers with vaccination! Over a million deaths per year world wide!
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FIVE major classes of genes involved in cancer
• DNA repair genes
• [Proto]Oncogenes• TS genes
– Apoptosis genes
• Telomerase
• Angiogenesis genes
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• 1 single base different!
• About 100 oncogenes now found; fit into a small # of classes:– Protein Kinases
– Receptors
– Growth factors
– G proteins
– Nuclear protein gene regulators.
Oncogenes: First found in viruses.Non-viral oncogenes: Weinberg Expt
.mp3
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• Protein kinase oncogenes most common.
• Target proteins regulate cell cycle.
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Receptor example: [protooncogene]• Herceptin: Antibody that Blocks an EGF receptor
that’s overexpressed in 30% of breast cancers.
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MAb name Trade name Used to treat: Approved in:
rituximab Rituxan® non-Hodgkin lymphoma 1997
trastuzumab Herceptin® breast cancer 1998
gemtuzumab ozogamicin* Mylotarg® acute myelogenous leukemia (AML) 2000
alemtuzumab Campath® chronic lymphocytic leukemia (CLL) 2001
ibritumomab tiuxetan* Zevalin® non-Hodgkin lymphoma 2002
tositumomab* Bexxar® non-Hodgkin lymphoma 2003
cetuximab Erbitux® colorectal cancer head & neck cancers
20042006
bevacizumab Avastin® colorectal cancernon-small cell lung cancerbreast cancerglioblastomakidney cancer
20042006200820092009
panitumumab Vectibix® colorectal cancer 2006
ofatumumab Arzerra® chronic lymphocytic leukemia (CLL) 2009
ACS: http://www.cancer.org/docroot/ETO/content/ETO_1_4X_Monoclonal_Antibody_Therapy_Passive_Immunotherapy.asp
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Iressa & lung cancer: 10% of patients with a particular EGF
mutation• Being taken off market except for patients
who have already shown a response.
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Multi-step to carcinogenesis: Colon Cancer
• Study of 54 tumors of 20 different types, more than 1 oncogene in every tumor. – In most, fos, myc, ras were active.
• Can track addition of mutations over time.• Initial changes may be inherited; 5% of human cancers show strong genetic predisposition.
– Retinoblastoma– Familial Adenomatious Polyposis [FAP]: 1/5,000 Americans, defective AFP allele.
• Hundreds of polyps in colon– FAP gene located when 1 patient had FAP along with no gallbladder, incomplete liver,
mental retardation. Why so many defects?– Chr 5.– Breast, ovarian, colon, prostate less so.
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Burkitt’s Lymphoma• Childhood cancer in Africa; associated with EBV.
• T(8;14) fuses MYC oncogene to IgH; others to kappa or lambda light chain loci.
• Puts myc into euchromatin next to extremely active enhancer.
• Why are these translocations characteristic of blood cell cancers?
• Translocation may involve DNA recombination machinery normally present in lymphocytes.
• Similar T cell malignancies with myc to TCR genes.
• Follicular lymphomas often have translocation of Ig to bcl2
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• Mutations accumulate with age; cancer frequency low early in life.
• First change might induce increased DNA replication and cell division, increasing likelihood of later changes. Larger “target”.
• Early change makes hypermutable.
• Changes thereafter accelerate.
• Metastasis often latest changes.
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Tumor-Associated Antigens [TIAs]• Normal molecule, produced in
“wrong concentration, place, or time.”
• Her-2– About 50X overexpressed in
some breast cancers
• Wrong time: CarcinoEmbryonic Antigen [CEA], normally only in fetus.
• AFP, HCG
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TUMOR-SPECIFIC ANTIGENS [TSAs]
Unique to tumor; “nonself”
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Hurdles to Anti-Tumor Immunity
• Tolerance!
• Tumors “evolve” to actively evade or block immune response.
• Often immunosuppressed by presence of tumor;
• Immune system returns to normal after tumor removal.
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IMMUNOTHERAPY
• Monoclonal antibody therapy, tumor specific monoclonal administered to patient.
• “Adoptive T cell therapy”: Remove patient’s T cells, activate in vitro; reinject.
• Cancer “vaccine” injected into patient, to cause an immune response.– Two new ones you’ve learned about?
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Monoclonal antibody therapyTSA must be identified first.
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Cancer VaccinesIn vitro DC maturation; or
HSP Adjuvant; or
Engineer tumor cells to express cytokines to make them more immunogenic.
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Questions you should be able to answer
• A.I: #1-4• A.II-III: #1,2, 4, 7,8• B.INTRO: #1, 4• B.I: #1, 3• B.II: ALL• D: #2• E.I: ALL• E.II: #1, 3, 5-9• Bonus question