Patent
Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors
| العنوان: | Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors |
|---|---|
| Patent Number: | 9,555,033 |
| تاريخ النشر: | January 31, 2017 |
| Appl. No: | 13/020031 |
| Application Filed: | February 03, 2011 |
| مستخلص: | Provided herein are methods for treating and/or preventing a cancer or a tumor syndrome in a patient, comprising administering an effective amount of a TOR kinase inhibitor to a patient having cancer or a tumor syndrome, characterized by a LKB1 and/or AMPK gene or protein loss or mutation. |
| Inventors: | Chopra, Rajesh (Summit, NJ, US); Ning, Yuhong (San Diego, CA, US); Sankar, Sabita (Portland, OR, US); Xu, Shuichan (San Diego, CA, US); Xu, Weiming (San Diego, CA, US) |
| Assignees: | Signal Pharmaceuticals, LLC (San Diego, CA, US) |
| Claim: | 1. A method for treating non-small cell lung carcinoma, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma characterized by a LKB1 gene loss, LKB1 protein loss, LKB1 gene mutation, or LKB1 protein mutation, relative to wild type, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more alkoxy or hydroxyalkyl groups. |
| Claim: | 2. A method for treating non-small cell lung carcinoma, comprising screening a patient's carcinoma for the presence of a LKB1 gene loss, LKB1 protein loss, LKB1 gene mutation, or LKB1 protein mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma characterized by a LKB1 gene loss, LKB1 protein loss, LKB1 gene mutation, or LKB1 protein mutation, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more alkoxy or hydroxyalkyl groups. |
| Claim: | 3. A method for treating non-small cell lung carcinoma, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of one or more agents that modulate AMP levels, glucose uptake, metabolism or a stress response to a patient having non-small cell lung carcinoma, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more alkoxy or hydroxyalkyl groups. |
| Claim: | 4. A method for treating non-small cell lung carcinoma, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma characterized by an AMPK gene loss, AMPK protein loss, AMPK gene mutation, or AMPK protein mutation, relative to wild type, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more alkoxy or hydroxyalkyl groups. |
| Claim: | 5. A method for treating non-small cell lung carcinoma, comprising screening a patient's carcinoma for the presence of an AMPK gene loss, AMPK protein loss, AMPK gene mutation, or AMPK protein mutation, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma characterized by an AMPK gene loss, AMPK protein loss, AMPK gene mutation, or AMPK protein mutation, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more or hydroxyalkyl groups. |
| Claim: | 6. A method for treating non-small cell lung carcinoma, comprising administering an effective amount of a TOR kinase inhibitor to a patient having non-small cell lung carcinoma characterized by a reduced level of pAMPK protein, AMPK activity, or both, relative to wild type, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more or hydroxyalkyl groups. |
| Claim: | 7. A method for treating non-small cell lung carcinoma, comprising screening a patient's carcinoma for the presence of a reduced level of pAMPK protein, AMPK activity, or both, relative to wild type, and administering an effective amount of a TOR kinase inhibitor to the patient having non-small cell lung carcinoma characterized by a reduced level of pAMPK protein, AMPK activity, or both, wherein the TOR kinase inhibitor is a compound of Formula (Ie): [chemical expression included] or a pharmaceutically acceptable salt, stereoisomer, or tautomer, thereof, wherein: L is a direct bond; R 1 is substituted or unsubstituted pyridine; and R 2 is substituted or unsubstituted cyclohexyl, wherein substituted groups can be substituted with one or more alkoxy or hydroxyalkyl groups. |
| Claim: | 8. The method of claim 1 , wherein R 1 is substituted pyridine. |
| Claim: | 9. The method of claim 2 , wherein R 1 is substituted pyridine. |
| Claim: | 10. The method of claim 3 , wherein R 1 is substituted pyridine. |
| Claim: | 11. The method of claim 4 , wherein R 1 is substituted pyridine. |
| Claim: | 12. The method of claim 5 , wherein R 1 is substituted pyridine. |
| Claim: | 13. The method of claim 6 , wherein R 1 is substituted pyridine. |
| Claim: | 14. The method of claim 7 , wherein R 1 is substituted pyridine. |
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| Assistant Examiner: | Lee, William |
| Primary Examiner: | Klinkel, Kortney L |
| Attorney, Agent or Firm: | Jones Day |
| رقم الانضمام: | edspgr.09555033 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |