Methods for determining therapeutic index from gene expression profiles

A method for evaluating specificity of a drug comprising:

• a) measuring activity of said drug against its target pathway to obtain a target activity (Dtarget);
• b) measuring activity of said drug against at least one pathway other than said target pathway to obtain at least one off-target activity (Doff-target);
• and
• c) determining said specificity by comparing said target activity and said off-target activity.

A method of determining a therapeutic index of a drug in a biological sample comprising:

• a) applying a plurality of levels of said drug to said biological sample;
• b) determining a minimum effective concentration (Ctarget) needed to induce a threshold response in a target pathway, wherein said drug exerts its pharmacological activity through said target pathway;
• c) determining a minimum toxic concentration (Coff-target) needed to induce a threshold response in at least one off-target pathway;
• and
• d) determining said therapeutic index according to the formula:
• SI=Ctarget/Coff-target.

A method for monitoring a therapy for a patient comprising

• a) measuring a plurality of cellular constituents in said patient to obtain a drug response profile, wherein said patient is undergoing a treatment with a drug;
• b) perturbing said patient with a plurality of pathway perturbations to obtain a plurality of pathway perturbation profiles;
• c) decomposing said drug response profile into a plurality of pathway response profiles using said pathway perturbation profiles;
• and
• d) determining relative activity of said drug on its target pathway and at least one off-target pathway.

A method for determining an optimal dose of a drug for a patient comprising:

• a) applying a plurality of levels of a plurality of pathway perturbations to said patient;
• b) determining a plurality of cellular constituent responses in said patient to obtain perturbation profiles;
• b) applying a plurality of levels of said drug to said patient;
• c) determining a plurality of cellular constituent responses in said patient to obtain a drug response profile;
• d) decomposing said drug response profile to pathway responses using said plurality of perturbation profiles to obtain a drug activity on its target pathway and at least one off-target pathway;
• and
• c) determining an optimal dose, wherein said optimal dose has a relatively high activity on said target pathway and relatively low activity on said off-target pathway relative to other doses.