6 - Targeted Therapies – CRC and Lung Flashcards
What are two hallmarks that are targeted in lung cancer treatment
Avoiding immune destruction
Self-growth signals
What are two hallmarks targeted in CRC treatment
Self-growth signals
Inducing angiogenesis
What is EGFR
Membrane bound receptor
What does EGFR do in NSCLC
Regulate signalling pathways to increase cellular proliferation (RAF, PI3K, STAT3, NFKB, MAPK)
What is gefitinib
EGFR tyrosine kinase inhibitor
Where to TK inhibitors bind
Reversibly bind to ATP cleft in the EGRF TK domain
What were some of the mutations in the TK domain
Heterozygous mutations
In-frame delations that removed 4 amino acids
Leucine substitutions
Missense mutation
Will gefitinib or elortinib work in CRC
No
Why will gefitinib or elortininb work in CRC
TK mutations are not detected in the same rate as lung cancers
EGFR expression is upregulated in CRC
What are chimeric antibodies
Murine variable regions and human IgG1 constant regions
What is the target for cetuximab (Erbitux)
EGFR on normal and malignant cells
Overexpressed on a variety of cancer cells, including colorectal cancer cells
What are indications for cetuximab (2)
Metastatic colorectal cancer
Platinum resistant head and neck squamous cell cancer
What is the MOA of cetuximab (2)
Immunological - induces ADCC and CDCC to increase immune cell mediated cell death
Non-immunological - inhibiting EGFR signalling pathway to inhibit growth
What are non-immunological MOA of cetuximab (3)
Inhibits intracellular signalling required for cellular growth
Inhibits anti-apoptotic proteins
Reduces growth of cells or increases apoptosis
What is a side effect of cetuximab
Rash
What is a mutation that mainly causes non-response to cetuximab
K-ras
What is K-ras
GTP-ase
What to GAPs do
Inactivate GTP signalling by binding tightly to GTP
How to mutations impair the K-Ras intrinsic activity
Blocking or interfering with finger loop of GAP in GTP hydrolysis to GTP
What is the target of bevacizumab?
Soluble VEGF
What is the biological significance of VEGF
Growth factor for endothelial cells
Major cytokine that regulates angiogenesis
What are indications of bevacizumab
Colon cancer and NSCLC
What are some non-immunological actions of bevacizumab
Inhibiting VEGF signalling pathway
