Methods and compositions related to glucocorticoid receptor antagonists and breast cancer
Embodiments of the invention are directed to methods of determining the prognosis of a breast cancer patient by evaluating the activity of the glucocorticoid receptor in tumor cells. Other embodiment include methods of treating breast cancer cells, particularly, chemo-resistant cells, with a glucocorticoid receptor antagonist and an anticancer agent or compound.
1. A method for treating estrogen receptor alpha-negative breast cancer in a patient, the method comprising: determining that the breast cancer does not express detectable levels of estrogen receptor alpha; and a) administering radiation or at least a first chemotherapeutic agent to said patient; then b) administering an effective amount of a glucocorticoid receptor antagonist (GRA) to the patient; then c) administering radiation again or at least a second chemotherapeutic agent to the patient after the glucocorticoid receptor antagonist is administered to the patient, whereby said estrogen receptor alpha-negative breast cancer is treated in the patient.
2. The method of claim 1 , wherein the breast cancer comprises cancer cells that are glucocorticoid receptor-positive (GR+).
3. The method of claim 1 , wherein the glucocorticoid receptor antagonist (GRA) has an undetectable or a lower level of activity as a progesterone receptor antagonist as compared to its level of activity as a glucocorticoid receptor antagonist.
4. The method of claim 1 wherein the first or the second chemotherapeutic agent is a platinum based agent selected from carboplatin and cisplatin.
5. The method of claim 1 wherein the first or the second chemotherapeutic agent is a taxane.
6. The method of claim 1 wherein the first or the second chemotherapy agent is selected from the group consisting of a serine/threonine kinase inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anti-epidermal growth factor receptor antibody, and trastuzumab.
7. The method of claim 1 wherein the GRA comprises an azadecalin moiety.
8. The method of claim 1 wherein the GRA comprises a pyrimidinedione moiety.
9. The method of claim 1 wherein the GRA comprises a dihydropyridine moiety.
10. The method of claim 1 wherein the GRA comprises an octahydrophenanthrene moiety.
11. The method of claim 1 wherein the GRA is mifepristone.
12. The method of claim 1 , wherein said first chemotherapeutic agent, said second chemotherapeutic agent, or both, comprises an apoptosis-inducing agent.
13. The method of claim 12 , wherein said apoptosis inducing-agent is radiation, a chemotherapeutic, or an immunotherapy.
14. The method of claim 12 wherein the GRA is in a class of compounds selected from the group of classes of compounds consisting of steroids, octahydrophenanthrenes, pyrimidinediones, dihydropyridines, dihydroisoquinolines and azadecalins.
15. The method of claim 14 wherein the GRA is an aryl pyrazolo azadecalin.
16. The method of claim 12 wherein the GRA is a selective GRA having an undetectable or a lower level of activity as a progesterone receptor antagonist as compared to its level of activity as a glucocorticoid receptor antagonist.
17. The method of claim 12 wherein the GRA is a non-selective GRA.
18. The method of claim 17 wherein the GRA is mifepristone.
19. The method of claim 1 wherein the GRA comprises a dihydroisoquinoline moiety.
20. The method of claim 1 wherein the first or the second chemotherapeutic agent is a camptothecin.