Parig Mallick, USC, "Developing Models of Therapeutic Response"

Therapeutic response: for many drugs, they only work in a small percentage of the population.

Components:

1. De novo resistance
• want to ID which patience likely to respond
• studying Oncogene addiction pathway
2. Acquired resitance
• How do we detect this?
• How do we overcome this?
• How does it develop and spread?
• Mechanical explanation:
• oncogene escape

Where does resistance come from?

• Environment or host
• drug never hits target, hypoxia or other mechanisms change interaction
• Target
• something about the target itself is "broken"
• Downstream of target
• cell's response circuitry is broken or something is compensating

Modeling:

• General cell/drug response model
• How does heterogeneity affect tumor drug response?

Acquired resistance:

• Chacterize the impact of resistance on cellular physiology
• environmental : not much 
• level of the target (cell addicted to a particular growth axis)

Studying EGFR resistance

• Developed multiple resistance strains of HCC827 to drug response
• Studied proteomics of these to try to understand the pathway
• Showed novel compensating pathways (example of oncogene escape)
• Magnitude of proteomic change between resistant strains of HCC827 and parent was much larger than the general proteomic change between any two random (cancer?) cell lines

Question: can we then look for proteomic changes in the blood stream

• Which cellular compartments do tumor-derived proteins in the circulation come from?
• Ans: cell surface and secreted proteins (15x more likely than intracellular proteins)