Methods of stratifying patients for treatment with retinoic acid receptor-α agonists
Described herein are methods that define cellular populations that are sensitive to RARA agonists and identify patient populations that will benefit from treatment with RARA agonists. The methods may comprise administering RARA agonists to patient populations.
1. A method of treating a disease or condition selected from the group consisting of non-acute promyelocytic leukemia acute myelogenous leukemia (non-APL AML) and myelodysplastic syndrome (MDS) in a subject, the method comprising a step of:
administering tamibarotene to the subject, wherein a PBMC sample or an enriched PBMC sample from the subject is determined to have an elevated IRF8 mRNA level relative to a threshold level determined by IRF8 mRNA levels observed in comparable samples from a population of subjects having the same disease or condition.
2. The method of claim 1 , wherein the PBMC sample or an enriched PBMC sample from the subject is determined to have an elevated IRF8 mRNA level through detection of an IRF8 mRNA level equal to or above a pre-determined cutoff value.
3. The method of claim 1 , wherein the subject further has been demonstrated to show an elevated RARA mRNA level, wherein the RARA mRNA is transcribed from a RARA gene that encodes a functional retinoic acid receptor-α gene and specifically excludes gene fusions that comprise all or a portion of the RARA gene; and wherein the subject is determined to have an elevated RARA mRNA level relative to a threshold level determined by RARA mRNA levels observed in comparable samples from a population of subjects having the same disease or condition.
4. The method of claim 1 , wherein the subject has further been demonstrated not to show an elevated RARA mRNA level, wherein the RARA mRNA is transcribed from a RARA gene that encodes a functional retinoic acid receptor-α gene and specifically excludes gene fusions that comprise all or a portion of the RARA gene; and wherein the subject is determined to have an elevated RARA mRNA level relative to a threshold level determined by RARA mRNA levels observed in comparable samples from a population of subjects having the same disease or condition.
5. The method of claim 1 , wherein the disease or condition is non-APL AML.
6. A method of diagnosing, prognosing, or treating a subject suffering from non-APL AML or MDS comprising the steps of:
a. obtaining a PBMC sample or an enriched PBMC sample from the subject;
b. determining in the sample an IRF8 mRNA level; and
c. administering a therapeutic composition comprising tamibarotene if
the IRF8 mRNA level is equal to or above a threshold level, wherein the level is determined by IRF8 mRNA levels observed in comparable samples from a population of subjects having the same disease or condition.
7. A method comprising:
a. detecting a RARA mRNA level in a PBMC sample or an enriched PBMC sample obtained from a subject with non-acute promyelocytic leukemia acute myelogenous leukemia (non-APL AML) or myelodysplastic syndrome (MDS), wherein the RARA mRNA is transcribed from a RARA gene that encodes a functional retinoic acid receptor-α gene and specifically excludes gene fusions that comprise all or a portion of the RARA gene;
b. detecting an IRF8 mRNA level in the PBMC or enriched PBMC sample;
c. administering tamibarotene to the subject if the PBMC or enriched PBMC sample expresses either an elevated RARA mRNA level equal to or above a RARA mRNA threshold value or an elevated IRF8 mRNA level equal to or above an IRF8 threshold value, wherein:
the IRF8 threshold level is determined by IRF8 mRNA levels observed in comparable samples from a population of subjects having the same disease or condition; and
the RARA threshold level determined by RARA mRNA levels observed in comparable samples from a population of subjects having the same disease or condition.
8. The method of claim 7 , wherein the step of detecting the IRF8 mRNA level or the RARA mRNA level is performed using fluorescent hybridization, PCR, qPCR, qRT-PCR, RNA sequencing, RNA hybridization and signal amplification or northern blot.
9. The method of claim 1 , wherein the elevated IRF8 mRNA level is determined using fluorescent hybridization, PCR, qPCR, qRT-PCR, RNA sequencing, RNA hybridization and signal amplification or northern blot.
10. The method of claim 9 , wherein the elevated IRF8 mRNA level is determined using qPCR.
11. The method of claim 1 , wherein the cancer is MDS.
12. The method of claim 6 , wherein the subject has non-APL AML.
13. The method of claim 6 , wherein the subject has MDS.
14. The method of claim 6 , wherein the IRF8 mRNA level is determined using fluorescent hybridization, PCR, qPCR, qRT-PCR, RNA sequencing, RNA hybridization and signal amplification or northern blot.
15. The method of claim 14 , wherein the IRF8 mRNA level is determined using qPCR.
16. The method of claim 7 , wherein the subject has non-APL AML.
17. The method of claim 7 , wherein the subject has MDS.
18. The method of claim 7 , wherein the step of detecting the IFR8 mRNA level or the RARA mRNA level is performed using qPCR.
19. The method of claim 2 , wherein the cutoff value is based on a pre-determined prevalence cutoff.
20. The method of claim 19 , wherein the pre-determined prevalence cutoff is based on IRF8 enhancer strength.
21. The method of claim 20 , wherein samples from the population were rank ordered based on IRF8 mRNA levels and the pre-determined prevalence cutoff applied to the rank ordered IRF8 mRNA levels to obtain an IRF8 mRNA cutoff value.
22. The method of claim 1 , wherein at least some of the samples from the population have been tested for responsiveness to tamibarotene.