Methods for predicting drug responsiveness
The present invention provides drug response predictors and biomarkers useful for assessing the responsiveness of a subject to treatment with one or more target drugs of interest, such as 5-fluorouracil (5-FU), irinotecan, and/or oxaliplatin. In particular, the invention provides methods useful in determining whether a subject is sensitive or resistant to a target drug by, e.g., measuring the expression level of one or more biomarkers of sensitivity and/or resistance to the drug in a biological sample obtained from the subject. The invention further features devices and kits for assessing target drug responsiveness in a subject, for example, by determining the expression level of such biomarkers.
1. A method of treating cancer in a subject in need thereof comprising administering 5-FU to said subject, wherein the subject has been determined to be responsive to 5-FU according to a method comprising:
(a) contacting a tumor sample from the subject comprising a plurality of nucleic acid molecules with a device comprising:
(i) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of biomarkers of resistance to 5-FU, wherein the biomarkers of resistance are NTSE, CNN3, ACTN1, FLNA, ATP2B4, CYR61, LGALS1, RHOC, RAB32, and TMEM158;
(ii) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of biomarkers of sensitivity to 5-FU wherein the biomarkers of sensitivity comprise APRT, GSR, TUFM, MRPS2, MTHFD2, WDR59, ANP32B, PMM2, STOML2, and NDUFAB1;
(b) detecting a level of expression of the biomarkers of resistance and the biomarkers of sensitivity by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR); and
(c) calculating a difference score for the subject by subtracting the mean expression levels of the plurality of biomarkers of resistance from the mean expression levels of the plurality of biomarkers of sensitivity, wherein the difference score is above a cutoff value.
2. The method of claim 1 , further comprising administering one or more additional therapies to said subject, wherein said one or more additional therapies is administered:
(a) concurrently with said administration of 5-FU; or
(b) separately from said administration of 5-FU; or
(c) prior to said administration of 5-FU; or
(d) after said administration of 5-FU.
3. The method of claim 2 , wherein said one or more additional therapies is administered within 1 week of said administration of 5-FU.
4. The method of claim 2 , wherein said one or more additional therapies comprises one or more additional therapeutic agents, surgery, or radiation therapy.
5. The method of claim 4 , wherein said one or more additional therapies comprises one or more additional therapeutic agents, wherein said 5-FU is administered alone or in admixture with said one or more additional therapeutic agents.
6. The method of claim 5 wherein said one or more additional therapeutic agents is selected from:
(a) the group consisting of: irinotecan, oxaliplatin, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, carboplatin, bortezomib, erlotinib, gemcitabine, mitoxantrone, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, vincristine, fulvestrant, teniposide, adriamycin, decitabine, and estramustine; or
(b) everolimus, temsirolimus, bleomycin, or lomustine; or
(c) leucovorin and at least one of irinotecan or oxaliplatin.
7. The method of claim 1 , wherein said 5-FU is administered to said subject intravenously, orally, intraperitoneally, intramuscularly, topically, rectally, cutaneously, subcutaneously, nasally, intracerebroventricularly, intraparenchymally, intrathecally, intracranially, ocularly, via inhalation, or through the skin.
8. The method of claim 7 , wherein said 5-FU is administered to said subject:
(a) once daily; and/or
(b) once daily, for up to four years; and/or
(c) once weekly, once every other week, or once every three weeks; and/or
(d) in six week cycles; and/or
(c) repeated 30 days after the completion of the previous administration; and/or
(d) repeated for at least 12 to 60 months.
9. The method of claim 1 , wherein said 5-FU is administered to the subject once daily at a dose of up to 800 mg.
10. The method of claim 1 , further comprising determining the expression level of one or more additional biomarkers, wherein said one or more additional biomarkers is selected from the group consisting of: carcinoembryonic antigen (CEA), BRAF, KRAS, Fas-ligand, p53, Ki-67, thymidylate-synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability (MIS), and 18q allelic loss of heterozygosity (LOH18q).
11. A method of treating cancer in a subject in need thereof comprising administering 5-FU to the subject with a difference score above a cutoff value, wherein the difference score is the difference between a mean of a level of expression of biomarkers of sensitivity and a mean of a level of expression of biomarkers of resistance determined in a tumor sample from the subject, wherein the biomarkers of sensitivity are APRT, GSR, TUFM, MRPS2, MTHFD2, WDR59, ANP32B, PMM2, STOML2, and NDUFAB1 and the biomarkers of resistance are NT5E, CNN3, ACTN1, FLNA, ATP2B4, CYR61, LGALS1, RHOC, RAB32, and TMEM158.
12. The method of claim 11 , wherein the cutoff value is a 50th percentile of the difference score in a reference population with the same diagnosis as the subject, or greater.
13. The method of claim 12 , wherein the cutoff value is a 60th percentile of the difference score in a reference population with the same diagnosis as the subject, or greater.
14. The method of claim 13 , wherein the cutoff value is a 70th percentile of the difference score in a reference population with the same diagnosis as the subject, or greater.
15. The method of claim 14 , wherein the cutoff value is an 80th percentile of the difference score in a reference population with the same diagnosis as the subject, or greater.