Carciongenesis III Flashcards
Discovery of oncogenes
- observing oncogenic retroviruses
- gag gene– internal virion protein
- env gene– virus membrane glycoporoteins
- pol gene– virus polymerase
- - harmless by themselves but replicate and transmitted in the host cell genome through somatic or sex cells - more oncogenes in retroviruses
- v-onc segment–> ability to rapidly transform infected cells to malignant phenotype
- v-src–> oncogene or Rous Sarcoma virus–> fibrosarcomas in birds
- v-erb–> oncogene of avian erythroblastosis virus–> erythrobalstosis in chickens
- v-abl–> oncogene in Abelson leukemia virus from mice
- v-myc–> fused with gag gene, capable of eliciting neoplastic transformations. - cellular transformation check
- assayed by tumor formation in animals after oncogenic virus
- transformation of cell morphology and growth regulation after infection of cultured cells in vitro
- foci of infected cells develop as clones can be counted
viral oncogenes proteins
- pp60v-src by v-src gene
- v-erb-B protein
- v-able protein
- v-able protein
- c-src protein
- c-myc protein
- c-ras
pp60v-src protein
membrane bound protein kinase phosphorylating the tyrosine residues in different proteins, affecting gene expression
v-erb-B protein
- similar structure to receptor for epidermal growth factor (EGFR)
- tyrosine specific protein kinase activity
- growth simulating protein
v-able protein
- protein kinase phosphorylating tyrosine residue on other proteins
- similar to c-ABL in BCR-ABL translocation in Philadelphia chromosome
- over-expressed in BCR-ABL CML(chronic myeloid leukemia)
c-src
- different carboxy terminal aa than v-src
- more introns
c-myc
- many introns more than v-myc, almost identical
substantial rearrangement
c-onc to v-onc
oncogenes as molecular markers in prognosis
oncogenes and tumor suppressors are good markers for cancer diagnosis and prognosis
- oncogene–> amplified
- tumor suppressor–> reduced
example of molecular marker for prognosis (c-ras gene)
detection of c-ras gene
- poor prognosis
- point mutation for human bladder cancer cell
- mutations in codon 12 or codon 61 of the ras gene
- detection of ras mutaiton–> poor diagnosis
- qualitative model (overactive protein)
example of molecular marker for prognosis (amplification of c-onc genes)
amplification of c-onc genes
- poor diagnosis
- n-myc amplification in neuroblastoma
- HER2/neu oncogene amplification about 20% in breast cancer
- quantitative model (too much protein)
- good because targeted drug can be designed
example of molecular marker for prognosis
translocations of c-onc
detection of translocations of c-onc gene
- poor diagnosis
- qualitative model (over expression)
- Burkitt lymphoma
- philadelphia chromosome (BCR-ABL translocation)
- good because targeted drug can be desgined
Def of oncogene
- normally stimulate cellular proliferation
- mutation activates oncogene
Def of tumor suppressor
- normally inhabit cellular proliferation
- mutation deactivates tumor suppressor
oncogene and tumor suppressor contribution to cancers
- both bush mutations
- loss of growth regulation
- increased mutation rate
- loss of apoptosis in colon cancer
molecular targeted therapy or rationally designed drug therapy
identify the defect in the tumor and target that specific defect to fix it
therapy for amplification of HER2/neu/erb2
monoclonal antibodies for HER2/neu/erbB2 protein
- Herceptin (the antibodies)
- reverse the cancer phenotype
- extend the life of breast cancer patients
therapy for RB negative small cell lung cancer
Injection of RB gene
- inhabit tumorigenesis
therapy for p53 cancer cell
E1B mutant adenoviruses
- kill p53 cancer cell selectively
- cannot inactivated p53 so cannot kill wild type cell
therapy for dominant negative p53 mutations
drug correcting mutant conformation
therapy for BCR-ABL translocation (Philadelphia chromosome)
Gleevac (ATP analog)
- inhabit the ABL tyrosine kinase
- no other ATPase inhabited
Bioinformatics
For targeted therapy and for “personalized medicine” in cancer
Heat map
- correlation of molecular data ( gene copy number, gene expression, mutations)
- relevant clinical info ( tumor grade, survival, age, tumor stage)
- red–> increase
- blue–> reduced
more examples of personalized medicine
- high erbB2 targeted with Herceptin (mentioned before)
- high estrogen receptor level treated with tamoxifen (estrogen antagonist)
the tool that made cancer therapy very personal design
Whole genome sequencing
- personal basis on type of mutations (ocogene vs tumor suppressor vs etc)
- decide the therapy based on case by case according to patient’s bioinformatics
