lecture 5 - leukaemias Flashcards
what are the aims of targeted cancer therapies?
To identify ‘critical mutation’
To limit growth and invasion/spread
To increase specificity of effects and limit side effects
To prolong ‘quality of life’
What are the approaches for targeted therapies?
Identification of molecules/pathways dysregulated in cancer
requires genetic profiling of the cancer
easier to target over expression/over activation than LoF
What is leukaemia and how can it be characterised?
Unregulated proliferation of a clone of immature white blood cells - squeeze normal cells out of the bone marrow
Blood appears milky - loss of function of tissue is what causes the problem, not the cancer cells
Patient succumbs to infections as the white blood cells cannot carry out phagocytic and immune function
What are the classifications of leukaemia?
Acute or chronic, myeloid or lymphoid
What are the features of chronic myeloid leukaemia?
Fatigue, anemia, splenomegaly, hepatomegaly
Clinical phase 1 - initial chronic phase, fairly mild - initial mutation destabilises the DNA and makes it more susceptible to getting more mutations
phase 2 - accelerated phase develops after 4 years
3 - acute leukaemia phase
What is the molecular basis of CML?
Chromosome 22q is diagnostic
Translocations seem to be a common feature - different translocations cause development of different leukaemias
C-terminus of c-abl (kinase domain) is spliced onto the N-terminus of BCR - member of the src family
Gets recruited to active signalling complexes and will signal in the cytoplasm for active cell growth
What are the implications of c-abl and BCR-abl?
C-abl normally has cytoplasmic localisation in resting cells, but this changes when it undergoes stress
It is activated by ionising radiation/DNA damage, translocates to the nucleus - engages with tumour suppressor proteins
Nuclear c-Abl complexes with p53 to induce cell cycle arrest and DNA repair
Complexes with p73 to induce apoptosis
When it becomes a fusion protein with BCR, it becomes ‘locked’ in the cytoplasm and cannot help activate repair mechanisms by other processes
What are three inhibitors of BCR-Abl?
Imatinib, dasatinib and nilotinib
How does Gleevec/imatinib work?
Small synthetic molecule, not an antibody
Selectively inhibits proliferation of human CML-derived cell lines
BCR-Abl is not present in WT cells, making it a good target
It has a different structure so can be targeted without affecting WT cells
How can resistance to Glivec occur?
BCR-Abl gene could have been amplified - more protein produced
Point mutation in BCR-Abl - prevents Glivec from binding
Activation of additional transforming pathways - this is likely the main cause
Imatinib unregulated Wnt pathway, increasing activation of pro-tumourigenic TCF7 TF, which confers resistance
What is an example of a next generation inhibitor and how does it work?
Dasatinib binds the active conformation of BCR-Abl and can therefore be effective in imatinib-resistant patients
Constitutively active conformation, so this molecule should be more effective
Tozasertib was promising, but withdrawn from trials due to cardio toxicity
What are the implications of TEL-PDGFB fusion?
This is associated with chronic myelomonocytic leukaemia (CMML)
Translocation between chromosomes 5 and 12 - amino terminal region of TEL (TF), and tyrosine kinase domain of the PDGF receptor
Kinase always active, helix-loop-helix region of TEL induces oligomerisation
Fusion can transform cells in culture, similar to BCR-Abl
This kinase activity is also inhibited by Glivec, so can use same agent - but will still get resistance over time
What is the relationship between Glivec and GIST
GIST = gastro-intestinal stromal tumours
driven by constitutive c-kit activity
receptor blocked by Glivec - this tends to drive GIST
Overlap between different cancers - can look at which therapies to use in combination
How can personalised therapy be used to treat leukaemia patients?
Iressa - more effective in patients carrying mutation leading to hyperactive EGFR
TPMT - can lead to chemo toxicity
profiling is key
