Methods and systems for determination of an effective therapeutic regimen and drug discovery
The present invention relates to the discovery of a method for identifying a treatment regimen for a patient diagnosed with cancer, predicting patient resistance to therapeutic agents and identifying new therapeutic agents. Specifically, the present invention relates to the use of an algorithm to identify a mutation in a kinase, determine if the mutation is an activation or resistance mutation and then to suggest an appropriate therapeutic regimen. The invention also relates to the use of a pattern matching algorithm and a crystal structure library to predict the functionality of a gene mutation, predict the specificity of small molecule kinase inhibitors and for the identification of new therapeutic agents.
1. A method of determining risk for developing resistance or monitoring the further development of resistance to a first therapeutic agent in an ER+ breast cancer patient comprising:
a) obtaining a biological sample and a tumor sample from the patient;
b) contacting the biological sample and the tumor sample from the patient with a probe that binds to a region of a sequence in a gene associated with kinase phosphorylation to identify at least one mutation,
wherein binding of the probe with the biological sample but not the tumor sample is indicative of a tumor that is at risk for developing resistance to a therapeutic agent;
c) using a pattern matching algorithm to determine if the at least one mutation is an activation mutation or a resistance mutation; and
d) using the pattern matching algorithm and a crystal structure library to identify therapeutic agents to target the activation mutation or resistance mutation, thereby identifying the risk for developing resistance or monitoring the further development of resistance to the first therapeutic agent optionally administering the first therapeutic agent to the patient and optionally repeating steps a) and b) at different time points in the patient's treatment.
2. The method of claim 1 , wherein the mutation is a deletion or a point mutation.
3. The method of claim 1 , wherein the gene sequence is an ESR1 or ESR2 receptor gene sequence.
4. The method of claim 3 , wherein the ESR1 receptor has a point mutation at Y537, E380, L536 or D538.
5. The method of claim 4 , wherein the point mutation is Y537S, Y537A, Y537E or Y537K.
6. The method of claim 3 , wherein the ESR2 receptor has a point mutation at V497.
7. The method of claim 6 , wherein the point mutation is V497M.
8. The method of claim 1 , wherein the first therapeutic agent is selected from the group consisting of an aromatase inhibitor, tamoxifen, Raloxifene and a competitor of estrogen in its ER binding site.
9. The method of claim 1 , further comprising predicting a response to a second therapeutic agent.
10. The method of claim 9 , wherein the first therapeutic agent is an aromatase inhibitor and the second therapeutic agent is a non-aromatase inhibitor chemotherapeutic drug.
11. The method of claim 1 , wherein the biological sample is selected from the group consisting of a blood, saliva, urine, bone marrow, serum, lymph, cerebrospinal fluid, sputum, stool, organ tissue and ejaculate sample.