NOL3 is a predictor of patient outcome
The present invention features a method for determining the prognosis for survival of a cancer patient. Methods for measuring the level of NOL3 expression in a cancer cell-containing sample from a patient, and comparing the level of NOL3 expression in the sample to a reference level of NOL3 expression are also included. A higher level of NOL3 relative to the reference level correlates with decreased survival of the patient, and an equivalent or lower level of NOL3 relative to the reference level correlates with increased survival of the patient.
1. A method of treating a glioma in a subject, the method comprising:
administering a therapeutically effective amount of a receptor tyrosine kinase inhibitor and a therapeutically effective amount of an IAP inhibitor to the subject having the glioma when a level of NOL3 expression in the subject's glioma is higher than a reference level of NOL3 expression in a reference sample, wherein the IAP inhibitor is a compound of formula (II)
or pharmaceutically acceptable salts thereof, wherein
R 1 is H or C 1 C 4 alkyl;
R 2 is H or C 1 C 4 -alkyl;
R 3 is H or C 1 C 4 alkyl;
A is 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the heteroaryl being unsubstituted or substituted with lower alkyl, amino, or halo;
D is O, C(O), or NCH 3 ;
A 1 is phenyl or 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the phenyl and the heteroaryl being unsubstituted or substituted with halogen;
M is H; and
n is 0.
2. The method of claim 1 further comprising measuring the level of NOL3 expression in the subject's glioma.
3. The method of claim 2 , wherein measuring the level of NOL3 expression comprises measuring NOL3 mRNA expression or measuring NOL3 polypeptide expression.
4. The method of claim 1 , wherein the glioma is an astrocytoma, an ependymoma, an oligodendroglioma, a mixed glioma, or glioblastoma multiforme.
5. The method of claim 1 , wherein the IAP inhibitor is (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylaminopropionamide, or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the receptor tyrosine kinase inhibitor is selected from imatinib, AMN107, AEW541, and PKI166.
7. A method of increasing apoptosis of a glioma in a subject, the method comprising: administering a therapeutically effective amount of a receptor tyrosine kinase inhibitor and a therapeutically effective amount of an IAP inhibitor to the subject having the glioma when a level of NOL3 expression in the subject's glioma is higher than a reference level of NOL3 expression in a reference sample, wherein the IAP inhibitor is a compound of formula (II)
or pharmaceutically acceptable salts thereof, wherein
R 1 is H or C 1 C 4 alkyl;
R 2 is H or C 1 C 4 -alkyl;
R 3 is H or C 1 C 4 alkyl; 0
A is 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the heteroaryl being unsubstituted or substituted with lower alkyl, amino, or halo;
D is O, C(O), or NCH 3 ;
A 1 is phenyl or 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the phenyl and the heteroaryl being unsubstituted or substituted with halogen;
M is H; and
n is 0.
8. The method of claim 7 further comprising measuring the level of NOL3 expression in the subject's glioma.
9. The method of claim 8 , wherein measuring the level of NOL3 expression comprises measuring NOL3 mRNA expression or measuring NOL3 polypeptide expression.
10. The method of claim 7 , wherein the glioma is an astrocytoma, an ependymoma, an oligodendroglioma, a mixed glioma, or glioblastoma multiforme.
11. The method of claim 7 , wherein the IAP inhibitor is (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylaminopropionamide, or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 , wherein the receptor tyrosine kinase inhibitor is selected from imatinib, AMN107, AEW541, and PKI166.
13. A method of increasing apoptosis of a glioma in a subject, the method comprising: administering a therapeutically effective amount of NOL3 siRNA and a therapeutically effective amount of an IAP inhibitor to the subject having the glioma when a level of NOL3 expression in the subject's glioma is higher than a reference level of NOL3 expression in a reference sample, wherein the IAP inhibitor is a compound of formula (II)
or pharmaceutically acceptable salts thereof, wherein
R 1 is H or C 1 C 4 alkyl;
R 2 is H or C 1 C 4 -alkyl;
R 3 is H or C 1 C 4 alkyl;
A is 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the heteroaryl being unsubstituted or substituted with lower alkyl, amino, or halo;
D is O, C(O), or NCH 3 ;
A 1 is phenyl or 5- or 6-membered heteroaryl containing 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the phenyl and the heteroaryl being unsubstituted or substituted with halogen;
M is H; and
N is 0.
14. The method of claim 13 further comprising measuring the level of NOL3 expression in the subject's glioma.
15. The method of claim 14 , wherein measuring the level of NOL3 expression comprises measuring NOL3 mRNA expression or measuring NOL3 polypeptide expression.
16. The method of claim 13 , wherein the glioma is an astrocytoma, an ependymoma, an oligodendroglioma, a mixed glioma, or glioblastoma multiforme.
17. The method of claim 13 , wherein the IAP inhibitor is (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylaminopropionamide, or a pharmaceutically acceptable salt thereof.