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US 10,472,677 B2Granted
Translational dysfunction based therapeutics
AssigneeTranslational Therapeutics, Inc.
InventorsGordon A. Jamieson, Jr., Katherine L. B. Borden, Biljana Culjkovic, Alex Kentsis
Life of this patent
Estimating the term…
Abstract
Provided are methods and compositions for inhibiting eukaryotic translation initiation factor eIF4E. Such methods and compositions may be used alone or in conjunction with other therapies, such as gene therapies, for inhibiting cell proliferation and/or treating cancer.
Claims23
A method for diagnosing and treating a disease wherein eIF4E regulon activity is dysfunctional in a subject, wherein the disease is selected from the group consisting of cellular hypertrophy, cancer, and ischemia reperfusion, the method comprising the steps of:
- (a) obtaining a biological sample from the subject;
- (b) performing a mass spectroscopy assay on the biological sample to determine the levels of, phosphorylation states of, or activities of eIF4E, HuR and at least one eIF4E regulon component gene product selected from the group consisting of Cyclin Dl;
- NBS/Nibrin;
- Pim-1;
- Cyclin Bl;
- Cyclin A2;
- ODC;
- VEGF;
- Skp2;
- Cyclin El;
- c-myc;
- FGF2;
- MMP-9;
- mdm2;
- caspase-9;
- bcl2;
- Bcl/xL;
- Fboxl;
- CGGbpl;
- P54nrb/NONO.1;
- Selenoprotein S;
- eIF4E-BP1;
- Aktl;
- PI3K;
- GSK3B;
- and mTOR/FRAPl;
- (c) determining whether the subject has or is likely to develop the disease when the levels of, phosphorylation states of, or activities of eIF4E, Hur and the at least one eIF4E regulon component gene products in the sample are similar to the levels of, phosphorylation states of, or activities of the eIF4E, HuR and at least one eIF4E regulon component gene products that are associated with the disease;
- and
- (d) administering a prodrug form of a compound of Formula I to the subject having or who has developed the disease, wherein the compound of Formula I is represented by:
- wherein:
- R1 is selected from the group consisting of null, a linear or branched alkyl, alkenyl, hydrogen, and alkynyl group;
- R2 is selected from the group consisting of a primary amine, a secondary amine, a tertiary amine, an aromatic amine, an amino group and an amido group;
- R3 is selected from the group consisting of nitrogen, oxygen and sulfur;
- and
- R4 is hydroxyl, and
- wherein the prodrug form of a compound of Formula I excludes Ribavirin.
33 more elements
A method for prognosing or staging and treating a disease wherein eIF4E regulon activity is dysfunctional, wherein the disease is selected from the group consisting of cellular hypertrophy, cancer, and ischemia reperfusion, the method comprising the steps of:
- (a) obtaining a biological sample from a subject;
- (b) performing a mass spectroscopy assay on the biological sample to determine the levels of, phosphorylation states of, or activities of eIF4E, HuR and at least one eIF4E regulon component gene product selected from the group consisting of Cyclin Dl;
- NBS/Nibrin;
- Pim-1;
- Cyclin B1;
- Cyclin A2;
- ODC;
- VEGF;
- Skp2;
- Cyclin El;
- c-myc;
- FGF2;
- MMP-9;
- mdm2;
- caspase-9;
- bcl2;
- Bcl/xL;
- Fboxl;
- CGGbpl;
- P54nrb/NONO.l;
- Selenoprotein S;
- eIF4E-BP1;
- Aktl;
- PI3K;
- GSK3B;
- and mTOR/FRAPl;
- (c) prognosing or staging the subject as having the disease when the levels of, phosphorylation states of, or activities of eIF4E, Hur and the at least one eIF4E regulon component gene products are similar to the levels of, phosphorylation states of, or activities of the eIF4E, HuR and at least one eIF4E regulon component gene products that are associated with the degree of, severity of, or stage of the disease;
- and
- (d) administering a prodrug form of a compound of Formula I to the subject having or who has developed the disease, wherein the compound of Formula I is represented by:
- wherein:
- R1 is selected from the group consisting of null, a linear or branched alkyl, alkenyl, hydrogen, and alkynyl group;
- R2 is selected from the group consisting of a primary amine, a secondary amine, a tertiary amine, an aromatic amine, an amino group and an amido group;
- R3 is selected from the group consisting of nitrogen, oxygen and sulfur;
- and
- R4 is hydroxyl, and
- wherein the prodrug form of a compound of Formula I excludes Ribavirin.
33 more elements
A diagnostic method for selecting a therapeutic regimen for a subject having a disease, wherein the disease is selected from the group consisting of cellular hypertrophy, cancer, and ischemia reperfusion, the method comprising:
- (a) obtaining a biological sample from the subject;
- (b) performing a mass spectroscopy assay on the biological sample to determine the levels of, phosphorylation states of, or activities of eIF4E, HuR and at least one eIF4E regulon component gene product selected from the group consisting of Cyclin D1;
- NBS/Nibrin;
- Pim-1;
- Cyclin Bl;
- Cyclin A2;
- ODC;
- VEGF;
- Skp2;
- Cyclin El;
- c-myc;
- FGF2;
- MMP-9;
- mdm2;
- caspase-9;
- bcl2;
- Bcl/xL;
- Fboxl;
- CGGbpl;
- P54nrb/NONO.l;
- Selenoprotein S;
- eIF4E-BP1;
- Aktl;
- PI3K;
- GSK3B;
- and mTOR/FRAPl;
- (c) performing a mass spectroscopy assay on the biological sample previously obtained from the subject, to determine the levels of, phosphorylation states of, or activities of eIF4E, HuR and at least one non-eIF4E regulon component gene products selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor (EGFR), and Her2/neu;
- (d) determining the relative changes in the levels of, phosphorylation states of, or activities of the eIF4E or non-eIF4E component gene products, to thereby select a therapy for said subject;
- and
- (e) administering a prodrug form of a compound of Formula I to the subject having the disease, wherein the compound of Formula I is represented by:
- wherein:
- R1 is selected from the group consisting of null, a linear or branched alkyl, alkenyl, hydrogen, and alkynyl group;
- R2 is selected from the group consisting of a primary amine, a secondary amine, a tertiary amine, an aromatic amine, an amino group and an amido group;
- R3 is selected from the group consisting of nitrogen, oxygen and sulfur;
- and
- R4 is hydroxyl, and
- wherein a prodrug form of a compound of Formula I excludes Ribavirin, when the relative changes of the levels of, phosphorylation states of, or activities of eIF4E component gene products are increased;
- or
- (f) administering an inhibitor of HER2, ER, PR, or EGFR, or combination thereof to the subject having the disease, when the relative changes of the levels of, phosphorylation states of, or activities of non-eIF4E component gene products are increased, or
- (g) administering both (e) and (f), when the relative changes of levels of, phosphorylation states of, or activities of the eIF4E and non-eIF4E component gene products are increased.
37 more elements
Dependencies are inferred from the claim text.