METHODS FOR TREATING TRIPLE-NEGATIVE BREAST CANCER
The invention is directed to methods of treating TNBC in a patient by administering to the patient an agent that inhibits the expression or activity of cyclin-dependent kinase 19 (CDK19). In some embodiments, the agent may be a small molecule inhibitor, a polynucleotide (e.g., shRNA. siRNA), or a protein (e.g., an antibody). In some embodiments, the agent does not inhibit the activity or expression of CDK8.
1 . A method of treating a patient diagnosed with triple-negative breast cancer (TNBC), comprising administering a therapeutically effective dose of an agent that inhibits expression or activity of cyclin-dependent kinase 19 (CDK19), wherein the agent comprises a small molecule inhibitor of CDK19 activity, and wherein administration of the agent results in at least one of a reduction in cachexia, increase in survival time, elongation in time to tumor progression, reduction in tumor mass, reduction in tumor burden, prolongation in time to tumor metastasis, a prolongation in time to tumor recurrence, tumor response, complete response, partial response, stable disease, progressive disease, or progression free survival.
2 . A method of treating a patient diagnosed with triple-negative breast cancer (TNBC), wherein the cancer is characterized by a tumor comprising EpCAM med/high and CD10- /low epithelial cells, the method comprising administering a therapeutically effective dose of an agent that inhibits cyclin-dependent kinase 19 (CDK19) expression or activity, wherein the agent is a small molecule inhibitor of CDK19 activity, wherein the treatment reduces the number of EpCAM med/high and CD10- /low cells in the tumor, reduces to number of EpCAM med/high and CD10- /low cells per unit volume of the tumor, or results in a reduction of the ratio of EpCAM med/high and CD10- /low epithelial cells to normal cells in the tumor.
3 . A method of reducing metastasis of TNBC in a patient, the method comprising administering a therapeutically effective dose of an agent that inhibits expression or activity of CDK19, wherein the agent is a small molecule inhibitor of CDK19 activity.
4 . The method of claim 1 , wherein the patient is treated with a combination therapy comprising (a) an agent that inhibits expression or activity of CDK19 and (b) radiation therapy and/or chemotherapy.
5 . The method of claim 1 , comprising detecting EpCAM med/high /CD10- /low cells in a tissue sample from the patient prior to or after initiating therapy.
6 . (canceled)
7 . The method of any of claim 1 wherein the agent inhibits expression or activity of CDK19 to a greater extent than it inhibits expression or activity of CDK8.
8 . The method of claim 1 claim 1 wherein the agent is a small molecule inhibitor that binds to the ATP binding site of CDK19 to inhibit its activity.
9 . The method of claim 1 , wherein the agent binds to parts of CDK19 outside of the ATP binding site.
10 . The method of claim 1 , wherein the agent binds to CDK19 with a higher affinity than to CDK8.
11 . The method of claim 1 wherein the agent is a small molecule inhibitor other than one or more compounds selected from the group consisting of Cortistatin A, Sorafenib, Linifanib, Ponatinib, Senexin B, CCT251545, and CCT251921.
12 - 15 . (canceled)
16 . The method of claim 1 , wherein the agent binds CDK 19 in the cytoplasm of a breast epithelial cell.
17 . A method of predicting the likely therapeutic responsiveness of a subject with TNBC to the method of treatment of claim 1 comprising:
(a) quantitating EpCAM med/high /CD10- /low cells in a tumor sample obtained from the subject;
(b) comparing the quantity of EpCAM med/high /CD10′ /low cells in (a) to a reference value characteristic of tumors responsive to a CDK19 targeting therapy, and
(c) treating the patient with the agent that inhibits expression or activity of cyclin-dependent kinase 19 (CDK19) if the quantity of EpCAM med/high /CD10- /low cells is equal to or exceeds the reference value.
18 . The method of claim 2 , wherein the agent inhibits expression or activity of CDK 19 to a greater extent than it inhibits expression or activity of CDK8.
19 . The method of claim 2 , wherein the agent is a small molecule inhibitor other than one or more compounds selected from the group consisting of Cortistatin A, Sorafenib, Linifanib, Ponatinib, Senexin B, CCT251545, and CCT251921.
20 . The method of claim 3 , comprising detecting EpCAM med/high /CD10′ /low cells in a tissue sample from the patient prior to the administering.
21 . The method of claim 3 , wherein the agent inhibits expression or activity of CDK 19 to a greater extent than it inhibits expression or activity of CDK8.
22 . The method of claim 3 , wherein the agent binds to CDK19 with a higher affinity than to CDK8.
23 . The method of claim 3 , wherein the agent is a small molecule inhibitor that binds to the ATP binding site of CDK19 to inhibit its activity.
24 . The method of claim 3 , wherein the agent binds to parts of CDK19 outside of the ATP binding site.
25 . The method of claim 3 , wherein the agent is a small molecule inhibitor other than one or more compounds selected from the group consisting of Cortistatin A, Sorafenib, Linifanib, Ponatinib, Senexin B, CCT251545, and CCT251921.