Lecture 8 - targeted therapy 2 Flashcards
describe normal growth of a cell in signal transduction
For a normal cell to divide It needs a
signal from the body
i.e. a growth factor, which tutns on cell growth. If another growth factor binds it divides again
mutational events in cancer affect pathways in cells which control the normal growth, survival, division and death of the cell
If these signalling pathways get “broken” or mutated cells loose their normal control
Many of these proteins involved in signalling pathways are oncoproteins
descried bow signals cause change in the result go cells behaviour
- The receptor gets the torch (growth factor) first
- It passes this torch (growth signal) to a lot of “ people” along the route ( though the cell cytoplasm)
- The signal to grow then gets to the nucleus
- Once in the nucleus it directs proteins to transcribe certain bits of DNA to make proteins it needs
to respond to that signal i.e. for growth cell growth required proteins - Once these proteins are made the cell then does the action requested
phosphorylation of the protein by enzyme kinases turns on the protein whereas removal of phosphate groups by phosphatases Tuens off the protein signal
explain how tyrosine kinase works and its effect on cells pathway.
tyrosine kinase catalyses the transfer of a gamma phosphate from ATP to the hydroxyl groups of tyrosine.
tyrosine kinase phosphorylation is uncommon, but abundant in rapidly proliferating cell - therapeutic differential.
they can be hyperactive by increased expression of the tyrosine receptor or its ligand; mutational events causing autoregulation of tyrosine; and consistent activation of tyrosine by binding to a partner protein
aberrant tyrosine kinase may result in high cell survival and proliferation, and in drug resistance. in tumour cells increased angiogenesis and invasiveness may result.
Tyrosine kinase pathways mediate cell growth, division, differentiation, metabolic regulation etc
what are receptor tyrosine kinases as target routes for cancer therapy?
3 routes are extracellular, intracellular and nuclear
explain the extracellular pathway in cancer therapy targeting the tyrosine kinase receptor.
the extraceullaur pathway is by the growth factor binding to the tyrosine kinase receptor, which signals for cell to divide in two.
bevacumizab (Avastin) can be used to prevent angiogenesis,
Avastin inhibits VEGF extracellularly and therefore, may inhibit angiogenesis without disrupting targets outside of the VEGF pathway.
it is given via IV infusion, and used for cancers such as colorectal, breast, ovarian, NSCLC. some Adverse effects include GI perforations, wound healing issues and blood pressure. best use din combination.
explain how eGFR can be used as a target for GFRs
epidermal groth factor receptor is a cell surface receptor for the members of the epidermal growth factor family of extracellaulr protein ligands. the mutant version of cause consistent grow signals to the cell.
anti-egfr drugs; ligand competitive examples are cetuximab and panitumumab
explain the use of cetuximab
cetuximab is a monoclonal antibody directed against EGFR.
It is a IgG1 chimerised anti-EGFR mAb. it binds to EGFR with high affinity, prevents ligand binding and activation.
approved as a single agent or in combination with other therapies for patents with mestastatic colorectal cancer and shamus cell carcinoma of the head and neck
explain the use of panitumumab
panitumumab is a fully human antibody specific to the epidermal growth factor receptor.
bowel cancer are tested for mutations in KRAS Gene as panitumumab does not work for bowel cancer with KRAS mutations. testing is done from same cells of cancer at time of cancer diagnosis or previous cells from biopsies or surgery.
what are intracellular methods of cancer theory for the tyrosine kinase receptors?
intracellular -small molecules of the egfr that inhibit the trysien doamin, so are known as TKI eGFR.
mechanism of action: tyrosine kinase inhibitors inhibits the EGFR kinase activity and so no signalling - apoptosis and G arrest
what is gefitinib?
i
Gefitinib (trade name Iressa) -Treatment of locally advanced or metastatic non-small cell lung cancer with
activating mutations of epidermal growth factor receptor
EGFR inhibitor which interrupts signalling through the EGFR Therefore, it is only effective in cancers with mutated and overactive EGFR –same mechanism as Erlotinib
Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the
EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways
These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib
and erlotinib.
describe erlotinib
Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small cell lung cancer
Pancreatic cancer and several other types of cancer. It is a reversible EGFR TKI.
As with other ATP competitive small molecule tyrosine kinase patients rapidly develop resistance.
In the case of erlotinib this typically occurs 8–12 months from the start of treatment.
Over 50% of resistance is caused by mutation in the ATP binding pocket of the EGFR kinase domain
what tests are done before treatment with targeted tyrosine kinase receptor therapy?
tests the EGFR receptor for mutations
common EGFR analytical methodologies are
EGFR protein expression by immunohistochemcitry
EGFR gene copy number by fluorescence in situ hybridisation FISH
EGFR mutation status by gene sequencing
what is the use of targets therapies limitations?
development of resistance- overcome by monitoring for maintenance
of mutations in resistant disease
- 2nd mutations in EGFR can cause resistance
- combination therapy
lack of tumour response in the general population
- requires careful selection of patients
- initial trials non-selected patients - 10% response rate - those with mutations
Adverse effects
- generally mild – resolved after discontinuing drug
-diarrhoea, rash, acne, nausea, vomiting anorexia
-pulmonary toxicity- controversial
what TKIs are used when TKI resiatant develops
when TKIs resistance develops, use 2nd or 3rd generation TKIs.
1st geenration EGFR TKI; reversibly binds to EGF an inhibits binding to ATP therefore halts over expression of ECF
2nd geenration - altered structure of EGFR site makes 1st geenration EGFR TKI unable to bind so ATP can agin bind freely allowing over-expression of EGF
3rd geenration - irreversible covalent binding of EGFR to mutants preventing binding of ATP therefore halts over expression
TAGRISSO is the 1st approved therapy forT790M mediated EGFR TKI resistance
descried the MAP kinase pathway
- Ligand binds to RTK (egfr). Tyrosine kinase catalyses the transfer of gamma phosphate from ATP to the receptor tyrosine kinase.
- GRB2 attaches to the phosphorylated receptor and interacts with SOS
- SOS activates the membrane bound RAS exchange of GDP for GTP which activates RAF and phsphoayltes MEK and ERK.
- this translated in nuclear and leading to the regulation of gene expression.
