Biomarkers and therapeutics for endocrine therapy resistance
Cancer cells can develop resistance to endocrine therapies, such as Tamoxifen, through acquisition of the Y537S mutation. Cells transfected with the Y537S mutation showed significant increases in mitochondrial mass and membrane potential, consistent with an increase in mitochondrial biogenesis. Certain biomarkers are identified that have prognostic value of endocrine therapy resistance. The mechanism resulting in this resistance, however, leaves these treatment-resistant cells vulnerable to therapeutics that inhibit mitochondrial biogenesis. Numerous mitochondrial biogenesis inhibitors are disclosed, as well as methods for reducing or eliminating endocrine treatment resistance, improving the effectiveness of an endocrine therapy, and for treating cancer.
1. A method for identifying and treating endocrine therapy resistance due to the Y537S mutation of estrogen receptor ESR1 in a breast cancer, the method comprising:
obtaining a biological epithelial sample of the cancer from a patient;
determining, or having determined, the level of a plurality of biomarkers prognostic of endocrine therapy resistance in the biological epithelial sample selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, and TALDO1;
comparing the determined level to a threshold level from MCF7 cells transduced with ESR1 (wild type) for the plurality of biomarkers; and
administering to the patient a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor if the determined level exceeds the threshold level.
2. The method of claim 1 , wherein the plurality of biomarkers prognostic of endocrine therapy comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, and ENO2.
3. The method of claim 1 , wherein the plurality of biomarkers prognostic of endocrine therapy resistance comprises at least one of (i) a biomarker prognostic of tumor recurrence and (ii) a biomarker prognostic of distant metastasis.
4. The method of claim 1 , wherein the plurality of biomarkers prognostic of endocrine therapy resistance comprises at least one biomarker prognostic of tumor recurrence, and at least one biomarker prognostic of distant metastasis.
5. The method of claim 3 , wherein the plurality of biomarkers prognostic of tumor recurrence comprises at least one of HSPD1, MRPL15, MRPL4, AKAP1, PTRH2, COX4|1, GRPEL1, HSPA9, MRPS16, ENO1, TALDO1, and ENO2.
6. The method of claim 3 , wherein the plurality of biomarkers prognostic of distant metastasis comprises at least one of HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO2, and ENO1.
7. The method of claim 1 , wherein the the combination comprises:
an oxidative metabolism inhibitor selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
a glycolytic metabolism inhibitor selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
8. The method of claim 7 , wherein the glycolytic metabolism inhibitor is at least one of the following:
a glycolysis inhibitor comprising one of 2-deoxy-glucose, ascorbic acid, and stiripentol;
an OXPHOS inhibitor comprising one of atoravaquone, irinotecan, sorafenib, niclosamide, and berberine chloride; and
an autophagy inhibitor comprising chloroquine.
9. The method of claim 7 , wherein the combination comprises doxycycline, azithromycin, and ascorbic acid.
10. A method for identifying and treating endocrine therapy resistance due to the Y537S mutation of estrogen receptor ESR1 in a breast cancer, the method comprising:
obtaining a biological epithelial sample of the cancer from a patient;
determining, or having determined, the level of a plurality of biomarkers prognostic of endocrine therapy resistance in the biological epithelial sample selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, TALDO1, and TIGAR;
comparing the determined level to a threshold level from MCF7 cells transduced with ESR1 (wild type) for the plurality of biomarkers; and
administering to the patient a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor if the determined level exceeds the threshold level,
wherein the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
11. The method of claim 10 , wherein the a plurality of biomarkers prognostic of endocrine therapy comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
12. A method for increasing the effectiveness of an endocrine therapy on a breast cancer having the Y537 mutation of estrogen receptor ESR1, the method comprising:
obtaining a biological epithelial sample of the cancer from a patient;
determining, or having determined, the level of a plurality of biomarkers prognostic of endocrine therapy resistance in the biological epithelial sample selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, TALDO1, and TIGAR;
comparing the determined level to a threshold level from MCF7 cells transduced with ESR1 (wild type) for the plurality of biomarkers; and
administering to the patient, in conjunction with an endocrine therapy, a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor if the determined level exceeds the threshold level.
13. The method of claim 12 , wherein the endocrine therapy comprises Tamoxifen.
14. The method of claim 12 , wherein the biomarker prognostic of endocrine therapy resistance comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
15. The method of claim 12 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
16. A method for treating breast cancer having the Y537S mutation of estrogen receptor ESR1, the method comprising:
obtaining a biological epithelial sample of the cancer from a patient;
determining, or having determined, the level of a plurality of biomarkers prognostic of endocrine therapy resistance in the biological epithelial sample selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, TALDO1, and TIGAR;
comparing the determined level to a threshold level from MCF7 cells transduced with ESR1 (wild type) for the plurality of biomarkers; and
administering to the patient, in conjunction with an endocrine therapy, a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor if the determined level exceeds the threshold level.
17. The method of claim 16 , wherein the endocrine therapy comprises Tamoxifen.
18. The method of claim 16 , wherein the cancer comprises breast cancer.
19. The method of claim 16 , wherein the biomarker prognostic of endocrine therapy resistance comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
20. A method for treating breast cancer endocrine therapy resistance due to the Y537S mutation of estrogen receptor ESR1, the method comprising:
determining, or having determined, the level in a biological epithelial sample from a patient, of a plurality of biomarkers prognostic of endocrine therapy resistance in a biological epithelial sample selected from HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, TALDO1, and TIGAR;
comparing the determined level to a threshold level from MCF7 cells transduced with ESR1 (wild type) for the plurality of biomarkers; and
administering to the patient a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor if the determined level exceeds the threshold level.
21. The method of claim 20 , wherein at least one biomarker prognostic of endocrine therapy resistance is up-regulated.
22. The method of claim 20 , wherein the endocrine therapy comprises Tamoxifen.
23. The method of claim 21 , wherein the biomarker prognostic of endocrine therapy resistance comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
24. The method of claim 20 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
25. A method of treating breast cancer in a patient having an upregulated expression of a plurality of biomarkers prognostic of endocrine therapy resistance selected from epithelial HSPD1, GRPEL1, MRPL15, MRPS16, COX4|1, ENO1, ENO2, MRPL4, AKAP1, PTRH2, HSPA9, and TALDO1, the method comprising administering a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor.
26. The method of claim 25 , wherein the biomarkers prognostic of endocrine therapy resistance comprises a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
27. The method of claim 25 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
28. A method of treating a patient's breast cancer in cancer cells having a resistance to endocrine therapy due to the Y537S mutation of estrogen receptor ESR1, the method comprising administering to the patient a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor;
wherein an epithelial biological sample of the cancer cells have an up-regulated expression of a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, MRPL4, AKAP1, PTRH2, COX4|1, GRPEL1, HSPA9, MRPS16, ENO1, TALDO1, and ENO2.
29. The method of claim 28 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
30. The method of claim 28 , wherein the epithelial biological sample of the cancer cells has an up-regulated expression of a plurality of biomarkers prognostic of endocrine therapy resistance selected from of HSPD1, MRPL15, COX4|1, GRPEL1, MRPS16, ENO1, and ENO2.
31. A method of increasing the effectiveness of an endocrine therapy on breast cancer cells having the Y537S mutation of estrogen receptor ESR1, the method comprising administering a pharmaceutically effective amount of a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor;
wherein an epithelial biological sample of the cancer cells has an up-regulated expression of a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, MRPL4, AKAP1, PTRH2, COX4|1, GRPEL1, HSPA9, MRPS16, ENO1, TALDO1, and ENO2.
32. The method of claim 31 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
33. A method of treating breast cancer having the Y537S mutation of estrogen receptor ESR1, the method comprising administering at least one endocrine therapy and a combination of an oxidative metabolism inhibitor and a glycolytic metabolism inhibitor, wherein an epithelial biological sample of the cancer has an up-regulated expression of a plurality of biomarkers prognostic of endocrine therapy resistance selected from HSPD1, MRPL15, MRPL4, AKAP1, PTRH2, COX4|1, GRPEL1, HSPA9, MRPS16, ENO1, TALDO1, and ENO2.
34. The method of claim 33 , wherein:
the oxidative metabolism inhibitor is selected from the group comprising: tetracycline, doxycycline, tigecycline, minocycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, rolitetracycline, chlortetracycline, omadacycline, sarecycline, erythromycin, azithromycin, and clarithromycin; and
the glycolytic metabolism inhibitor is selected from the group comprising: a glycolysis inhibitor, an OXPHOS inhibitor, and an autophagy inhibitor.
35. The method of claim 33 , wherein the endocrine therapy comprises Tamoxifen.