CML and Imatinib Flashcards
observational studies can only
identify patterns and suggest hypotheses
Imatinib ‘the wonder drug’
a type of biological therapy called a tyrosine kinase inhibitor. TK are proteins that cells use to signal to each other to grow (chemical messengers). Imatinib targets diff TK, depending on the types of cacncer
what has imatinib been used for
leukemia and rare stomach cancers
what does iamtinib target
tyrosine kinases- chemical messengers which cause growth
chronic myelogenous leukemia (CML)
a cancer of WBC. Characterised by and increase dan unrelated growth of myeloid cells in the bone marrow and accumulation of these in the blood
chronic phase of CML
3- years
chronic phase is followed by acute/blast phase which is
bad news
treatment of CML use to involve
arsenic
story starts in 1960
-genetic basis of cancer is not clear
-oncogenes are yet to be identified
-no such thing as TK
In 1960 investigators did not think that tumours were caused by genetic mutations
Nobel and Hungerford 1960
Noticed a small version of one of the small chromosomes, they thought it was props a Y. Only CML patients had it- cause or effect
Nowel and Hungerford ypothesis
a change in chromosomal structure causes CML
- The Philadelphia chromosome
the philadelphia chromosome
hypothesised to caused CML- when the ABL gene usually found on chr9 transacted to chr22
Janet Rowley 1973
- see in 9 CML patients
- not in other leukemias
- first specific cancer translocation
hypothesis: translation causes CML
Link between CML and Ableson
Human ABLE gene normally on Chr9. Several groups showed theABL is transacted to chr22 to make the philadelphia chromosome
how does a drug get approved
1) idea
2) basic research
3) clinical trials- phase 1/11/111- once a disease target is identified, drugs are designed and tested.
4) regulatory approval- human trials are completed. FDA approval
what continues after drug approval
safety and efficacy evaluation
process, simple
CML- observation- hypothesis- cure
the Imatinib legacy
- not all cancers are caused by transloacations- some are
- CML approached lucked out single kinase
- rational drug design can work
Nowell, 1976
most neoplasms arise form a single cel origin and tumour progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublimes.
tumour cell populations are
more genetically unstable than normal cells.
patients may require
individual therapy.
BCR-ABL codes for
a fusion protein - this is quite imprecise
how would you find out the exact sequence of the fusion prteins
identify cDNA and sequence it- about this time ABL shown to be a TK
what does the fusion protein do
insert plasmid containing BCR-ABL into cells
- check to see if the cells are actually making it
- see if it acts as a tyrosine kinase
what should be diff between the control cells and BCR-ABL cells
BCR-ABL should divide much more quickly
- then tested in animals e.g. mice
Dasatinib
Imatinib does not hit stem cells. If one stops imatinib CML comes back.
Dasatinib is active agains some resistant mutation- personalised medicine
Ciba-Geigy
worked on developing a range of TK inhibitors
Ciba-Geigy hypothesis
a TKI would cure CML
how can you tell that imatinib is clearing BCR-ABL +ve cells in
do a clinical trial
clinical trials- preclinical studies
-safety in primates
phase 1
- very small scale
- toxicity- tolerate does and pharmacokinetics
- can be healthy people or CML sufferers
- dose is evaluated slowly escalated
- side effects noted
phase 1 imatinib trial
showed compete hematologic response 53/54 patients treated daily with 300mg
phase 2
- small scale
- test for a biological response
- optimum dose evaluated
- someime an RCT- not alway
phase 2 imatinib trial
showed haematological response and cytogenetic response
phase 3
full RCT
- huge sample size
- lasting a long period of time
