Targeted Therapies Flashcards
What are the approaches to targeted therapies?
Identification of molecules and pathways which are dysregulated in cancer.
Requires genetic profiling of the cancer
Easier to target overexpression / overactivation than LoF
What is the challenge of targeted therapies?
Endogenous molecules on ubiquitous pathways
What are leukaemias?
Cancers of white blood cells.
Unregulated proliferation of a clone of immature blood cells.
Leukaemic cells proliferate relentlessly, they squeeze normal cells out of the bone marrow and the blood of patients with leukaemia appears milky.
What are the classifications of leukaemias?
Acute or chronic
Divided depending on cell of origin
Myeloid or lymphoid.
What is chronic myeloid leukaemia?
Fatigue, anaemia, splenomegaly, hepatomegaly
Elevated number of white cells in blood count, all stages of granulocyte differentiation on blood smear.
Hypercellularity of bone marrow.
Increased ratio of myeloid to erythroid cells.
What are the features of chronic myeloid leukaemia?
Initial chronic phase
Accelerated phase develops after 4 years
Acute leukaemic phase – blast crisis.
There is reciprocal translocation between chromosomes 9 and 22 which generates a fusion between breakpoint cluster region and Abl tyrosine kinase
Where do leukaemia mutations arise?
In stem or progenitor cells
What is C-Abl?
A non receptor protein tyrosine kinase
Cytoplasmic and nuclear localisation
What is C-Abl activated by?
DNA damage
During S phase
Downstream of integrin signalling
What does nuclear c-Abl interact with?
Rb and p53 to regulate gene transcription.
Cytoplasmic c-Abl appears to play a role in cell growth.
What is the role of imatinib?
It is a small synthetic molecule which inhibits proliferation of human CML-derived cell lines.
It inhibits CML growth in mouse model.
It blocks ATP binding site of c-Abl kinase and also blocks PDGFbetaR and c-kit tyrosine kinases.
What is the resistance of imatinib?
There is a loss of sensitivity to imatinib in some patients where the BCR-ABL is amplified and there are point mutations in BCR-ABL which prevent imatinib binding.
What can be given to imatinib resistant patients?
Dasatinib and Nilotinib binds active conformation of BCR-Abl and can be effective in imatinib resistant patients. Neither are effective against T315l mutation.
What is TEL-PDGFbeta receptor fusion?
It is associated with chronic myelomonocytic leukaemia, where there are translocations between chromosomes 5 and 12. The amino terminal region of TEL and the tyrosine kinase domain of the PDGF receptor.
The kinase is always active and the helix-loop helix region of TEL induces oligomerisation.
What happens in TEL-PDGFbeta receptor fusion?
Cells transform in culture and myeloproliferative disorder in mice.
What is TEL-PDGFbeta receptor kinase activity inhibited by?
Glivec aka imatinib
How does imatinib stop gastrointestinal stromal tumours?
Gastrointestinal stromal tumours are driven by constitutive c-kit receptor activity and the receptor is blocked by imatinib.
What is the role of small molecule inhibitors eg Gefitinib/ erotinib, sorafenib?
They are often receptor tyrosine kinase inhibitors and block triggering of growth pathways
They are orally active and work on specific tissues
What is the role of monoclonal antibodies eg Herceptin, Avastin?
Can only target extracellular molecules
Highly specific but prone to mutation induced resistance
Require IV administration
They are cancer specific and expensive.
What is personalised therapy?
Patient and tumour variability leads to variation in treatment response.
Patients with mutations in K-Ras do not respond to EGFR inhibitors.
There are also variations in drug metabolising enzymes
What is reconstitution?
It is much more challenging to restore LoF.
The IV viral particle or nanodparticle mediated delivery egg Advexin where there is targeting but challenging delivery.
The alternative option is to target overactivity of the molecule which is no longer being suppressed.
