colon cancer Flashcards
What are the current options for colorectal cancer patients? (3)
- standard chemotherapy usually combined
- targeted therapy such as EGFR, VEGF or immune checkpoint therapies
- surgical intervention
How can EGFR be targeted in colon cancer?
- upregulates proliferation, survival and metastasis
- monoclonal antibodies can block receptors and reduce the size of tumours alongside DOXO treatment
- cetixumab
- increases overall survival when used together
How does EGFR overexpression affect coloreactal cancer?
can be predictive of and associated with poor survival - higher stage tumours tend to have EGFR+
What did studies looking at how EGFR inhibitors work between different people show?
- patients with K-ras mutation have no benefit from cetuximab treatment
- those without K-rad mutations had better survival
- therefore those being treated for metastasis need to be tested for K-rad mutations first
Why do K-ras mutations make EGFR inhibitors not work?
- RAS - RAF - MEK - ERK
- activating K-ras mutations mean the pathway is active regardless of EGFR binding
- blocking this therefore changes nothing
- b-raf + MEK inhibitors may help in disabling the pathway
What is VEGF?
- vasular endothelial growth factor
- induces angiogenesis and tumour progression through downstream signalling pathways such as MEK/ERK and PI3K
How can the VEGF family be targeted in cancer?
- monoclonal Abs
- small molecule inhibitors that bind the intracellular kinase domains
Why are studies of new cancers done on metastatic patients?
- start here and work backwards
- studies done on those with no other options after failing standard treatment
What is Aflibercept used in metastatic colorectal cancer?
- a VEGF trap
- protein that binds to VEGF protein extracellularly and stops it binding its receptor
- small survival increase but not routinely given
What are the two types of survival measured in cancer therapy?
- overall survival
- progression-free survival
What happens in treatment when both EGFR and VEGF pathways are blocked?
- worse outcome
- poorer survival and worse side effects
- not done
What is immune checkpoint therapy?
- aim to block the negative pathways that lead to tumour cells evading immune destruction
- especially used in MMR deficiency as theres lots of immune evasion in these tumours where they bind to immune cells and inhibit them
What is the process of MMR?
- primarily repairs base mismatches or insertion/deletion mispairs
- 4 genes acts as clamp proteins that bind DNA and signal for downstream DNA repair
- maintains genomic stability
- inherited dificncies leads to high rates of DNA damage and cancer
How is MMR deficiency important in colorectal cancer?
- 10-15% have MMR deficieny
- MLH1 + MLH2 are high risk genes
- mutations lead to truncated proteins and mutations in genes with microsatellite repeats that are especially susceptible to mismatch
How do cancer cells interact with T cells in colorectal cancer?q
- high infiltration of immune cells into the tumour microenvironment
- tumours produce B7 + PDL1 antigens that bind T cells and result in their anergy and sensence
- antibodies against these antigens can be used to target this process and increase survival
