Biomarkers for cancer
The use of PHGDH as a biomarker for detecting the occurrence of epithelial-to-mesenchymal transition (EMT) in a subject, and the use of PHGDH modulators to treat cancer is disclosed herein. Also disclosed are various methods for detecting the occurrence of epithelial-to-mesenchymal transition (EMT) in a subject by measuring PHGDH expression and/or activity.
1. A method of treating acute myelocytic leukemia (AML) in a human subject in need thereof, comprising:
(a) identifying a human subject with AML, comprising:
(i) detecting a level of expression of 3-phosphoglycerate dehydrogenase (PHGDH) in the subject by contacting a sample from the subject with a reagent that specifically binds PHGDH protein or PHGDH mRNA;
(ii) diagnosing the subject with AML when the level of PHGDH is increased relative to a control sample; and
(b) administering an effective amount of an Axl inhibitor to the subject with AML;
wherein the sample from the subject is a blood sample, a serum sample, a plasma sample, a bone marrow biopsy, or a spleen biopsy; and
wherein the sample from the subject and the control sample are the same sample type.
2. The method of claim 1 , wherein the method comprises detecting a level of expression or activity of PHGDH and one or more biomarkers selected from Axl, Akt, Erk, PLCγ, and SLFN11, in the subject or in a sample from the subject.
3. The method of claim 2 , wherein the method comprises detecting a level of expression or activity of:
(a) PHGDH, PLCγ1, and SLFN11; or
(b) Axl, Akt, Erk, PLCγ1, PHGDH, and SLFN11;
in the subject or in a sample from the subject.
4. The method of claim 1 , further comprising periodically assessing PHGDH activity or expression in the subject.
5. The method of claim 1 , wherein the method comprises administering an effective amount of 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (BGB324/R428).
6. A method of treating acute myelocytic leukemia (AML) in a human subject in need thereof, comprising administering an effective amount of an Axl inhibitor to the subject, wherein the subject was previously determined to have AML by:
(a) contacting a sample from the subject with a reagent that specifically binds 3-phosphoglycerate dehydrogenase (PHGDH) protein or mRNA; and
(b) detecting an increased level of expression of PHGDH in the sample relative to a control sample;
wherein the sample from the subject is a blood sample, a serum sample, a plasma sample, a bone marrow biopsy, or a spleen biopsy; and
wherein the sample from the subject and the control sample are the same sample type.
7. The method of claim 6 , wherein a sample from the subject has been determined to have an altered level of expression or activity of PHGDH and one or more biomarkers selected from Axl, Akt, Erk, PLCγ, and SLFN11 relative to a control sample.
8. The method of claim 6 , wherein a sample from the subject has been determined to have an altered level of expression or activity of:
(i) PHGDH, PLCγ1, and SLFN11; or
(ii) Axl, Akt, Erk, PLCγ1, PHGDH, and SLFN11;
relative to a control sample.
9. The method of claim 6 , further comprising periodically assessing PHGDH activity or expression in the subject.
10. The method of claim 6 , wherein the method comprises administering an effective amount of 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (BGB324/R428).