Methods of treating cancer sensitive to anti-EGFR therapy and modifying treatment using peroxiredoxin 6 biomarker
The present disclosure provides methods of treating cancer and modifying a cancer treatment for a cancer with an anti-EGFR drug by creating PRDX6 expression profiles and using the profiles to evaluate and optionally modify treatment. The present disclosure also provides assays and systems for assessing sensitivity of a cancer to an anti-EGFR therapy.
1. A method of treating cancer in a subject, the method comprising:
determining a pre-treatment level of peroxiredoxin 6 (PRDX6) protein in a sample taken from a human subject having a cancer predicted to be sensitive to anti-epidermal growth factor receptor (EGFR) treatment, the cancer comprising cells with an EGFR mutation, wherein the pre-treatment sample is taken from the subject before or at the time of initiation of treatment with a tyrosine kinase inhibitor (TKI) anti-EGFR drug;
initiating a treatment regimen for the subject with a TKI anti-EGFR drug, wherein the subject receives one or more doses of the TKI anti-EGFR drug over a period of time;
determining a second level of PRDX6 in a second sample taken from the subject no later than about 4 weeks after the subject takes the initial dose of the TKI anti-EGFR drug;
creating a PRDX6 expression profile for the subject, wherein the PRDX6 expression profile compares the pre-treatment and second PRDX6 levels relative to the TKI anti-EGFR treatment regimen; and
continuing, modifying, or discontinuing the treatment regimen with the TKI anti-EGFR drug based on the PRDX6 expression profile, wherein:
treatment with the anti-EGFR drug is continued when the second level is at least 10% greater than the pre-treatment level of PRDX6 for the subject, indicating sensitivity to the anti-EGFR drug, or
treatment with the anti-EGFR drug is either discontinued or is continued by maintaining the dosage of the anti-EGFR drug or by increasing the amount of the drug subsequently administered to the subject when the second level is about the same as the pre-treatment level, about 10% less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject, indicating potential non-responsiveness or resistance, and
optionally determining one or more subsequent levels of PRDX6 in subsequent samples taken from the subject after the second sample, wherein the pre-treatment sample, second sample and any subsequent samples comprise a sample selected from the group consisting of: blood, plasma, and sera; and
updating the PRDX6 expression profile for the subject to include any subsequent PRDX6 levels for evaluation of efficacy of the TKI anti-EGRF drug in reducing tumor volume.
2. The method of claim 1 , wherein the second sample is taken from the subject between about 2 weeks and about 4 weeks after the initial treatment with the anti-EGFR drug.
3. The method of claim 1 , wherein the cancer is selected from a group of cancers sensitive to anti-EGFR therapy consisting of: non-small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer, breast cancer, and prostate cancer.
4. The method of claim 1 wherein the anti-EGFR drug comprises an anti-EGFR drug selected from the group consisting of: gefitinib, erlotinib, and icontinib.
5. The method of claim 1 , wherein determining a level of PRDX6 in a sample taken from the subject comprises performing an ELISA assay on the sample with a capture antibody specific for PRDX6 and a detection antibody capable of binding PRDX6.
6. The method of claim 5 , wherein the capture antibody comprises sc-59671 and the detection antibody comprises ab73350.
7. The method of claim 1 , comprising increasing the amount of the drug subsequently administered to the subject when the second PRDX6 level is about the same as the pre-treatment level, less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject.
8. The method of claim 1 , comprising continuing to treat the subject with the anti-EGFR drug when a third level of PRDX6, determined from a third sample taken from the subject about 2 weeks, or more, after the second sample, is about the same as the second level of PRDX for the subject or less than the second level of PRDX6 for the subject.
9. The method of claim 1 , indicating possible resistance of the cancer to the anti-EGFR drug when the PRDX6 expression profile shows at least two consecutive PRDX6 levels after the second level within about 10% or less of each other, or when, after a third level that was lower than the second level, one or more subsequent levels after the third level are more than about 10% greater than the third level.
10. The method of claim 9 , further comprising discontinuing the anti-EGFR drug when the PRDX6 expression profile indicates possible resistance to the anti-EGRF drug.
11. A method of treating cancer in a subject, the method comprising:
a) determining a pre-treatment level of peroxiredoxin 6 (PRDX6) protein in a sample taken from a human subject having a cancer predicted to be sensitive to anti-epidermal growth factor receptor (EGFR) treatment, the cancer comprising cells with an EGFR mutation, wherein the pre-treatment sample is taken from the subject before or at the time of initiation of treatment with a tyrosine kinase inhibitor (TKI) anti-EGFR drug;
b) initiating a treatment regimen for the subject with a TKI anti-EGFR drug, wherein the subject receives one or more doses of the TKI anti-EGFR drug over a period of time;
c) determining a second level of PRDX6 in a second sample taken from the subject no later than about 4 weeks after the subject takes the initial dose of the TKI anti-EGFR drug;
d) creating a PRDX6 expression profile for the subject, wherein the PRDX6 expression profile compares the pre-treatment and second PRDX6 levels relative to the TKI anti-EGFR treatment regimen; and
e) continuing, modifying, or discontinuing the treatment regimen with the TKI anti-EGFR drug based on the PRDX6 expression profile, wherein:
treatment with the anti-EGFR drug is continued when the second level is at least 10% greater than the pre-treatment level of PRDX6 for the subject, indicating sensitivity to the anti-EGFR drug, or
treatment with the anti-EGFR drug is either discontinued or is continued by maintaining the dosage of the anti-EGFR drug or by increasing the amount of the drug subsequently administered to the subject when the second level is about the same as the pre-treatment level, about 10% less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject, indicating potential non-responsiveness or resistance, and;
f) optionally determining one or more subsequent levels of PRDX6 in subsequent samples taken from the subject after the second sample, wherein the pre-treatment sample, second sample and any subsequent samples comprise a sample selected from the group consisting of: blood, plasma, and sera;
g) updating the PRDX6 expression profile for the subject to include any subsequent PRDX6 levels; and
h) continuing, modifying, or discontinuing the treatment regimen with the TKI anti-EGFR drug based on the PRDX6 expression profile, wherein:
when a third level of PRDX6, determined from a third sample taken from the subject about 2 weeks or more after the second sample, is about the same as the second level of PRDX6 for the subject or less than the second level of PRDX6 for the subject, sensitivity is indicated and treatment of the subject is continued with the anti-EGFR drug, or
when two consecutive PRDX6 levels after the second level are within about 10% of each other or less, or when, after a third level that was lower than the second level, one or more subsequent levels after the third level are more than about 10% greater than the third level, possible tumor re-growth and possible resistance of the cancer to the anti-EGFR drug is indicated and treatment with the drug is discontinued or resistance by other tests is confirmed.
12. A method of determining sensitivity or resistance of a cancer in a human subject to a tyrosine kinase inhibitor (TKI) anti-epidermal growth factor receptor (EGFR) drug, the method comprising:
determining a pre-treatment level of peroxiredoxin 6 (PRDX6) protein in a sample taken from a human subject having cancer comprising cells with an EGFR mutation, wherein the pre-treatment level is determined from a sample taken from the subject before or at the time of initiation of treatment with the TKI anti-EGFR drug;
providing one or more doses of the TKI anti-EGFR drug to the subject over a period of time;
determining a second level of PRDX6 in a second sample taken from the subject no later than about 4 weeks after the subject takes the initial dose of the TKI anti-EGFR drug, wherein the pre-treatment sample and second sample and any subsequent samples comprise a sample selected from the group consisting of: blood, plasma, and sera;
creating a PRDX6 expression profile for the subject comparing the pre-treatment level of PRDX6 with the second level of PRDX6, relative to the TKI anti-EGFR treatment regimen; and
determining sensitivity or potential non-responsiveness or resistance of the cancer to the anti-EGFR drug based on the PRDX6 expression profile, wherein:
when the second level of PRDX6 is at least 10% greater than the pre-treatment level of PRDX6 for the subject, indicating sensitivity and continuing to treat the subject with the anti-EGFR drug, and
when the second level is about the same as the pre-treatment level, about 10% less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject, indicating potential non-responsiveness or resistance, and either discontinuing treatment with the anti-EGFR drug or continuing to treat the subject with the anti-EGFR drug by maintaining the dosage of the anti-EGFR drug or increasing the amount of the drug subsequently administered to the subject and determining one or more subsequent PRDX6 levels from the subject to confirm sensitivity or resistance.
13. The method of claim 12 , comprising discontinuing treatment with the anti-EGFR drug when the second level is about the same as the pre-treatment level, about 10% less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject.
14. The method of claim 12 , comprising continuing to treat the subject with the anti-EGFR drug by maintaining the dosage of the anti-EGFR drug or increasing the amount of the drug subsequently administered to the subject to confirm sensitivity or resistance when the second level is about the same as the pre-treatment level, about 10% less than the pre-treatment level, or less than about 10% greater than the pre-treatment level of PRDX6 for the subject.
15. The method of claim 12 , further comprising:
determining one or more subsequent levels of PRDX6 in one or more subsequent samples taken from the subject, wherein the one or more subsequent samples are taken beginning about 6 weeks, or more, after the subject takes the initial dose of the TKI anti-EGFR drug;
updating the PRDX6 expression profile based on the PRDX6 levels of the one or more subsequent samples;
maintaining or increasing the amount of the anti-EGFR drug subsequently administered to the subject when the one or more subsequent levels of PRDX6 are about 10%, or more, less than the second level of PRDX6 for the subject; and
wherein potential acquired resistance to anti-EGFR therapy is indicated when the one or more subsequent levels are the same or greater than the second level of PRDX6 for the subject.