Targeted Cancer therapies and immunotherapies Flashcards
What are the two elements of personalized medicine?
Targeted therapeutic
Companion diagnostic
What enzyme breaks down 5-FU?
Dihydropyrimidine dehydrogenase
What is Chronic Myeloid Leukaemia?
Myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells
What is CML’s MoA?
Proto-oncogene activation by chromosomal translocation
3’ ABL fused to 5’ BCR -> chimeric oncogene
Retains ABL protein kinase activity
BCR alters expression
What is a protein-kinase inhibitor?
Imatinib mesylate (Gleevac)
Tyrosine-kinase inhibitor of BCR-ABL
What is Imatinib MoA?
Binds close to ATP binding site (blocks ATP)
Locking it in closed conformation
Prevents substrate tyrosine phosphorylation and signalling
What is Imatinib’s clinical uses?
GIT stromal tumours
What are the side effects of Imatinib?
GIT disturbances
fatigue
Headaches
Rashes
What are mechanisms of resistance to Imatinib?
Reactivation of BCR-ABL kinase activity
What are 2 examples of cancer immunotherapies?
IFN-a2 - hairy cell leukemia then advanced melanoma
IL-2 - mRCC and advanced melanoma
How are tumours invisible to the immune system?
Do not have co-stimulatory molecules
What is the target on engineered tumours?
B7 co-stimulatory molecules
What is a key immunotherapy ICT mechanism?
Blocking CTLA-4 which activates TCR
Remobilizes T cells
What is an example of a CTLA-4 inhibitor?
Ipilimumab
What are adverse effects of ipilimumab?
Colitis
hepatitis
some autoimmune diseases
fatal heart attack
What is the MoA of Programmed death 1 (PD1)?
Induced on tumour cells by interferon gamma
Exhausts tumour fighting T cells
What is a PD-1 inhibitor?
Nivolumab
What is Nivolumab’s MoA?
When bound by PD-L1 and PD-L2 a T cell response is triggered
Unlocks T cell
What is Nivolumab’s clinical uses?
Melanoma
Non-small-cell lung cancer
Renal cell carcinoma
cervical cancer
What are 4 big problems with immunotherapies?
Varying response rates
Resistance
Cost
health Inequalities
What is a key feature of a ‘cold’ tumour?
Not many immune cells present
What is the result of combining immunotherapies?
Improve survival
Greater inhibitory effects
