Lecture 4 - Preclinical Cancer Models Flashcards
How many % of new cancer drugs entering clinical trial are approved?
5%
What is COMPARE analysis?
compare data on new agents with known compounds in database
What does COMPARE give info on? 3
Degree of similarity
Possible molecular mechanism
Molecular pathology
What are limitation of drug screens?
Fail to pick up on drugs needing metabolic activation
Drugs that activate through the immune system
Drugs acting on tissue components like stroma
5 parameters of anti-tumour activity:
Tumour volume Optimal % T/C Tumour growth delay Net log cell kill Tumour regression
2 parameters of toxicity
Drug related deaths
Max % relative mean weight loss
4 limitations of subcutaneous CDX models
Cell lines selected for rapid growth
Not in specified organ (site of origin)
Non-metastatic
Immunocompromised mice
Subcutaneous CDX is valuable in
Identifying non-targeted cytotoxic agents
Primary assessment of drug toxicity
Analysing drug resistance mechanism
Triaging potentially effective targetted therapies
What are orthotopic models?
Put into organ (site of origin)
Characteristics of orthotopic models:
Metastatic patterns are injection site dependent
Orthotopic models maintain tumour microenvironment characteristics
More technically challenging and difficult to monitor
Human patient derived xenograft (PDX) models
surgically remove tumour from patient and engraft it into mice, then treat
3 advantages of subcutaneous PDX models
Intact tissue – preserves tumour architecture,
stromal composition, histology and molecular heterogeneity
Not compromised by in vitro adaptation
Patient-specific studies
4 disadvantages of subcutaneous PDX
. Transplantable take rates vary
• Time to establish varies
• Change with passage
• Immunocompromised host
