Final on W afternoon

• Review: M 6:00 here

• Covers section 9->

• All cases

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:

1.5 million cases per year in U.S; nearly half that # die!

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

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!

FIVE major classes of genes involved in cancer

• DNA repair genes

• [Proto]Oncogenes• TS genes

– Apoptosis genes

• Telomerase

• Angiogenesis genes

• 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

• Protein kinase oncogenes most common.

• Target proteins regulate cell cycle.

Receptor example: [protooncogene]• Herceptin: Antibody that Blocks an EGF receptor

that’s overexpressed in 30% of breast cancers.

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

Iressa & lung cancer: 10% of patients with a particular EGF

mutation• Being taken off market except for patients

who have already shown a response.

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.

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

• 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.

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

TUMOR-SPECIFIC ANTIGENS [TSAs]

Unique to tumor; “nonself”

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.

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?

Monoclonal antibody therapyTSA must be identified first.

Cancer VaccinesIn vitro DC maturation; or

HSP Adjuvant; or

Engineer tumor cells to express cytokines to make them more immunogenic.

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