Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists
The invention provides methods that define cellular populations that are sensitive to RARA agonists and identify patient subgroups that will benefit from treatment with RARA agonists. The invention also provides packaged pharmaceutical compositions that comprise a RARA agonist and instructions for determining if such agonist is suitable for use in treatment.
1. A method of diagnosing and treating a human subject suffering from myelodysplastic syndrome (MDS), the method comprising:
a. diagnosing whether the subject has a tamibarotene-sensitive form of the MDS based on a level of retinoic acid receptor alpha (RARA) mRNA previously determined to be present in a sample of diseased cells from the subject, wherein the RARA mRNA is transcribed from a RARA gene that encodes a functional retinoic acid receptor-α and specifically excludes gene fusions that comprise all or a portion of the RARA gene; and
b. administering to the subject an amount of tamibarotene effective to treat the MDS,
wherein the level of RARA mRNA is equal to or above a predetermined threshold.
2. The method of claim 1 , wherein the pre-determined threshold is a cutoff value.
3. The method of claim 2 , wherein the cutoff value is set at a value that is equal to or up to 5% above the RARA mRNA level in the lowest responder in a population of acute myelocytic leukemia (AML) test samples.
4. The method of claim 3 , wherein the test samples are samples obtained from AML patient-derived xenografts.
5. The method of claim 4 , wherein the cutoff value is the RARA mRNA level in xenograft AM5512.
6. The method of claim 1 , wherein the level of RARA mRNA in the subject is determined using qPCR.
7. The method of claim 2 , wherein the cutoff value is determined using qPCR.