Methods of inhibiting cancer stem cells with HMGA1 inhibitors
The presently disclosed subject matter relates to methods of inhibiting cancer stem cells and growth of aggressive and/or poorly differentiated metastatic tumors comprising the cancer stem cells with HMGA1 inhibitors. The presently disclosed subject matter also provides methods of selecting and treating a subject with aggressive and/or poorly differentiated metastatic cancer using HMGA1 inhibitors.
1. A method of treating an aggressive and/or poorly differentiated metastatic cancer in a subject in need thereof comprising administering a therapeutically effective amount of at least one HMGA1 inhibitor to the subject, wherein the aggressive and/or poorly differentiated metastatic cancer comprises at least one cancer stem cell that overexpresses HMA1 protein.
2. The method of claim 1 , wherein the aggressive and/or poorly differentiated metastatic cancer is selected from the group consisting of triple-negative breast cancer, pancreatic ductal adenocarcinoma cell, colorectal cancer cell, and leukemia.
3. The method of claim 1 , further comprising selecting the subject for treatment of the aggressive and/or poorly differentiated metastatic cancer with the at least one HMGA1 inhibitor.
4. The method of claim 3 , wherein selecting the subject for treatment of the aggressive and/or poorly differentiated metastatic cancer comprises: (i) obtaining a biological sample comprising cells from the aggressive and/or poorly differentiated metastatic cancer; (ii) assaying the level of HMGA1 expression in the cells from the aggressive and/or poorly differentiated metastatic cancer; (iii) comparing the level of HMGA1 expression in the cells to the level of HMGA1 expression in a normal control cell; and (iv) selecting the subject for treatment of the aggressive and/or poorly differentiated metastatic cancer with the at least one HMGA1 inhibitor if the level of HMGA1 expression in the cells is greater than the level of HMGA1 expression in the normal control cell.
5. The method of claim 4 , wherein the biological sample is selected from the group consisting of a breast tissue sample, a pancreatic tissue sample, a colon tissue sample, and a bone marrow tissue sample.
6. The method of claim 4 , wherein at least some of the cells from the aggressive and/or poorly differentiated metastatic cancer comprise cancer stem cells.
7. The method of claim 1 , wherein the at least one HMGA1 inhibitor reduces the expression level and/or activity of HMGA1.
8. The method of claim 1 , wherein the at least one HMGA1 inhibitor is formulated for delivery in a nanoparticle.
9. The method of claim 1 , wherein the at least one HMGA1 inhibitor is an RNA interfering agent.
10. The method of claim 9 , wherein the at least one HMGA1 inhibitor is an shRNA.
11. The method of claim 10 , wherein the shRNA targets the nucleotide sequence of SEQ ID NO:1.
12. The method of claim 10 , wherein the shRNA is formulated for delivery in a nanoparticle.
13. The method of claim 1 , wherein the subject is a human subject.
14. The method of claim 1 , further comprising administering an effective amount of a chemotherapeutic agent to the subject.
15. The method of claim 14 , wherein the chemotherapeutic agent is gemcitabine.