Oncogenes Flashcards
What are oncogenes?
They are proto-oncogenes which are converted to oncogenes by gain of function. They may be mutated by:
Point mutation – increased activity
Gene amplification – more protein
Chromosomal translocation
A gene which encodes a protein able to transform cells. The normal function of proto-oncogenes is to control cell growth.
What is the effect of the Src gene of cells?
The test for oncogenic function is the ability of transfected DNA to transform Src mutation often correlates with metastatic potential.
What are Src inhibitors?
Dasatinib, saracatinib, bosutinib.
What is the relationship between HPV and cancer?
Oncogenic DNA virus integrates viral DNA into host genome and permanently transform host cells which causes warts and other benign epithelial growth. This is the cause of cervical cancer. The E5 subunit causes prolonged activation of PDGFR, E6 and E7 inhibit pRb and p53.
How can HPV be prevented?
Mainly contracted through sexual infections. Most people are exposed to it in their lifetime but it is cleared by the immune system.
Gardasil 9 vaccine protects against 9 types of HPV which accounts for 95% of induced cervical cancer.
What are epidermal growth factor receptors?
They are important proto-oncogenes involved in many cancers. EGF is an important growth factor as it drives cell proliferation. Intrinsic kinase domain leading to activation of downstream signaling pathways – Ras/MAPk and PI3K-PKB. Mutations in the receptor can cause ligand independence where there is constitutive activation of the receptor and over expression where there is gene amplification and more receptors.
How can EGFR signalling be targeted therapeutically?
Block the intrinsic kinase domain of the receptor – a small molecule inhibitors that block ATP binding site.
Iressa and Afatinib/ Lapatinib and osmiertinib are examples of this.
The monoclonal antibodies block ligand binding eg Herceptin, Cetuximab, pertuzumab.
What is the correlation between HER2 and breast cancer?
The WT HER2 gene is amplified in metastatic breast cancers. Cells express 10 – 100x more HER2 receptor. HER2+ cells associated with more aggressive tumour phenotype and reduced survival rate. The cells grow faster and tumours are more likely to recur. This correlates with more serious prognosis.
How is HER2 status detected?
Immunohistochemistry starting with ab.
Fluorescent in situ hybridisation which is more sensitive than immunohistochemistry.
HER2-ECD ELISA – detects cleavage product in serum.
What is Herceptin?
Humanised monoclonal antibody which recognises HER2. It is a recombinant molecule which is constructed by inserting murine CDR into human IgG.
Herceptin binds HER2 and blocks its activity.
Phase I clinical trials showed that the tumours grew more slowly and some disappeared, there is significant survival benefit.
What is the mechanism of action of Herceptin?
It decreases the activation of signalling pathways. It may induce downregulation of the receptor and uncouples Src activation, increases PTEN activation and induces cell cycle arrest, increased p27. It may also increase apoptosis and decrease angiogenesis. It promotes antibody-dependent cellular cytotoxicity via FcR on NK cells.
What are therapeutics?
They are usually given with chemotherapy = doxorubicin and cyclophosphamide or paclitaxel. Patients are treated for 1 year but build up of resistance. There is potential cardiotoxicity as HER2 is important in ventricular development.
What are some future developments in cancer treatment?
Immunotherapy: Chimeric proteins; 2 antibody sites that cross link HER2 and immune cell.
HER2 vaccines – activate CD4+ T cell immunity.
What the link between Ras and cancer?
Activating mutations at positions 12 or 61 present in many human tumours. There are different mutations found in different cancers. The mutations generate Ras proteins which are always active.
Ras mutations of any amino acid from glycine causes constant activation.
How can Ras become an anticancer target?
Ras has a fatty acid modification that tethers it to the membrane. Inhibitors of this modification can be developed by peptidomimetics. These can be farnesyl transferase inhibitors.
There are good responses in the mouse breast tumour model and disappointing clinical trial results because the mode of action is unclear.
Antisense oligonucleotides eg Hras, c-Ras have made it to phase II trials but have little efficacy.
MEK inhibitors are orally active CI-1040 and have made it to phase I trials for colon cancer.
Ras inhibitors eg orally active kinase inhibitor Nexavar has been approved for renal carcinoma and also blocks VEGFR and PDGFR.
