Therapeutic combinations using IGF1R pathway inhibitors, and methods to predict anti-IGF1R therapeutic efficacy
Disclosed herein are methods of treating a subject with an estrogen receptor-positive (ER+) breast cancer comprising obtaining a sample of the breast cancer from the subject; determining a level of E-cadherin in the sample is reduced compared to a control; and administering a therapeutically effective amount of an IGF1R pathway inhibitor and an endocrine therapeutic. Also disclosed herein are methods to treat a cancer in a subject comprising administering a therapeutically effective amount of an IGF1R pathway inhibitor and an E-cadherin inhibitor. Also disclosed are methods to predict the likelihood a subject with a breast cancer will respond therapeutically to a treatment comprising administering an IGF1R pathway inhibitor, the method comprising obtaining a sample of the cancer from the subject; and determining a level of E-cadherin in the sample.
1. A method of treating a subject with a cancer comprising:
a) obtaining a sample of the cancer from the subject;
b) determining a level of E-cadherin in the sample is reduced compared to a control; and
c) administering a therapeutically effective amount of an IGF1R pathway inhibitor and an endocrine therapeutic.
2. The method of claim 1 , wherein the cancer comprises an estrogen receptor-positive (ER+) breast cancer.
3. The method of claim 2 , wherein the control comprises one or more non-cancerous mammary epithelial cells of the subject.
4. The method of claim 2 , wherein the ER+ breast cancer comprises an invasive lobular breast cancer (ILC).
5. The method of claim 1 , wherein the IGF1R pathway inhibitor comprises MEDI-573, OSI-906, BMS-754807, BEZ235, xentuzumab, or a combination thereof.
6. The method of claim 1 , wherein the endocrine therapeutic comprises tamoxifen, ICI 182,780, or a combination thereof.
7. The method of claim 1 , wherein the level of E-cadherin is reduced by at least 50% compared to the control.
8. The method of claim 1 , wherein the determining step comprises determining a level of E-cadherin polypeptide expression.
9. A method of treating a cancer in a subject comprising administering a therapeutically effective amount of an IGF1R pathway inhibitor and an E-cadherin inhibitor.
10. The method of claim 9 , wherein the cancer in the subject comprises a level of E-cadherin which is not reduced compared to a control.
11. The method of claim 9 , wherein the IGF1R pathway inhibitor comprises MEDI-573, OSI-906, BMS-754807, BEZ235, xentuzumab, or a combination thereof.
12. The method of claim 9 , wherein the E-cadherin inhibitor comprises a small interfering RNA (siRNA), a short hairpin RNA (shRNA), or a combination thereof.
13. The method of claim 9 , wherein the cancer comprises a breast cancer.
14. The method of claim 9 , further comprising obtaining a cancerous tissue sample from the subject and detecting the level of E-cadherin in the sample.
15. The method of claim 14 , wherein the cancer comprises an invasive ductal breast carcinoma (IDC).
16. The method of claim 14 , wherein the level of E-cadherin is the level of E-cadherin polypeptide expression.
17. The method of claim 10 , wherein the control comprises one or more non-cancerous cells of the subject which are of a same cell type as a cell of the sample.
18. A method of increasing the sensitivity of a cancer in a subject to an IGF1 pathway inhibitor comprising
a) obtaining a sample of the cancer from the subject;
b) determining a level of E-cadherin in the sample is not reduced compared to a control; and
c) administering to the subject a therapeutically effective amount of an E-cadherin inhibitor.
19. The method of claim 18 , wherein the E-cadherin inhibitor comprises a small interfering RNA (siRNA), a short hairpin RNA (shRNA), or a combination thereof.
20. The method of claim 18 , wherein the E-cadherin inhibitor comprises a small interfering RNA (siRNA).
21. The method of claim 9 , wherein the E-cadherin inhibitor comprises a small interfering RNA (siRNA).
22. The method of claim 9 , wherein the IGF1R pathway inhibitor comprises xentuzumab.
23. The method of claim 1 , wherein the IGF1R pathway inhibitor comprises xentuzumab.
24. The method of claim 1 , wherein the endocrine therapeutic comprises tamoxifen.