Methods of inhibiting cancer stem cells with hmga1 inhibitors

Abstract

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.

That which is claimed: 
     
         1 . A method of inhibiting at least one cancer stem cell, the method comprising contacting the at least one cancer stem cell with an effective amount of at least one HMGA1 inhibitor. 
     
     
         2 . The method of  claim 1 , wherein inhibiting the at least one cancer stem cell is selected from the group consisting of:
 i) inhibiting proliferation of the at least one cancer stem cell;   ii) inhibiting self-renewal of the at least one cancer stem cell;   iii) inhibiting anchorage-independent growth of the at least one cancer stem cell;   iv) inhibiting migration of the at least one cancer stem cell;   v) inhibiting invasion of the at least one cancer stem cell;   vi) reprogramming the at least one cancer stem cell from a stem-like state that is refractory to apoptosis to a non stem-like state that is susceptible to apoptosis; and   vii) combinations thereof.   
     
     
         3 . The method of  claim 1 , wherein the at least one cancer stem cell is in an aggressive and/or poorly differentiated metastatic tumor, and inhibiting the at least one cancer stem cell inhibits at least one of:
 i) growth of the aggressive and/or poorly differentiated metastatic tumor;   ii) proliferation of the aggressive and/or poorly differentiated metastatic tumor;   iii) migration of the aggressive and/or poorly differentiated metastatic tumor;   iv) invasion of the aggressive and/or poorly differentiated metastatic tumor;   v) initiation of new aggressive and/or poorly differentiated metastatic tumors; and   vi) combinations thereof.   
     
     
         4 . The method of  claim 1 , wherein the at least one cancer stem cell expresses greater levels of HMGA1 as compared to non-stem cancer cells in the aggressive and/or poorly differentiated metastatic tumor. 
     
     
         5 . The method of  claim 1 , wherein the at least one cancer stem cell is selected from the group consisting of a triple-negative breast cancer cell, a pancreatic ductal adenocarcinoma cell, a colorectal cancer cell, and a leukemia cell. 
     
     
         6 . The method of  claim 1 , wherein the at least one HMGA1 inhibitor reduces the expression level and/or activity of HMGA1. 
     
     
         7 . The method of  claim 1 , wherein the at least one HMG1 inhibitor is an RNA interfering agent. 
     
     
         8 . The method of  claim 7 , wherein the at least one HMGA1 inhibitor is an shRNA. 
     
     
         9 . The method of  claim 8 , wherein the shRNA targets the nucleotide sequence of SEQ ID NO:1. 
     
     
         10 . The method of  claim 1 , further comprising contacting the at least one cancer stem cell with a chemotherapeutic agent. 
     
     
         11 . The method of  claim 10 , wherein the chemotherapeutic agent is gemcitabine. 
     
     
         12 . The method of  claim 1 , wherein the at least one cancer stem cell is contacted in a subject. 
     
     
         13 . The method of  claim 12 , wherein the subject is a human subject. 
     
     
         14 . 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. 
     
     
         15 . The method of  claim 14 , 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. 
     
     
         16 . The method of  claim 14 , wherein the aggressive and/or poorly differentiated metastatic cancer comprises at least one cancer stem cell that overexpresses HMGA1 protein. 
     
     
         17 . The method of  claim 14 , further comprising selecting the subject for treatment of the aggressive and/or poorly differentiated metastatic cancer with the at least one HMGA1 inhibitor. 
     
     
         18 . The method of  claim 17 , 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.   
     
     
         19 . The method of  claim 18 , 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. 
     
     
         20 . The method of  claim 18 , wherein at least some of the cells from the aggressive and/or poorly differentiated metastatic cancer comprise cancer stem cells. 
     
     
         21 . The method of  claim 14 , wherein the at least one HMGA1 inhibitor reduces the expression level and/or activity of HMGA1. 
     
     
         22 . The method of  claim 14 , wherein the at least one HMGA1 inhibitor is formulated for delivery in a nanoparticle. 
     
     
         23 . The method of  claim 14 , wherein the at least one HMG1 inhibitor is an RNA interfering agent. 
     
     
         24 . The method of  claim 23 , wherein the at least one HMGA1 inhibitor is an shRNA. 
     
     
         25 . The method of  claim 24 , wherein the shRNA targets the nucleotide sequence of SEQ ID NO:1. 
     
     
         26 . The method of  claim 24 , wherein the shRNA is formulated for delivery in a nanoparticle. 
     
     
         27 . The method of  claim 14 , wherein the subject is a human subject. 
     
     
         28 . The method of  claim 14 , further comprising administering an effective amount of a chemotherapeutic agent to the subject. 
     
     
         29 . The method of  claim 28 , wherein the chemotherapeutic agent is gemcitabine. 
     
     
         30 . A method of selecting a subject with an aggressive and/or poorly differentiated metastatic cancer for treatment with at least one HMGA1 inhibitor, the method comprising:
 (a) obtaining a biological sample from the subject, wherein the biological sample comprises cells from the aggressive and/or poorly differentiated metastatic cancer;   (b) determining the level of expression of HMGA1 in the biological sample;   (c) comparing the level of expression of HMGA1 in the biological sample with the level of expression of HMGA1 in a control sample; and   (d) selecting the subject with aggressive and/or poorly differentiated metastatic cancer for treatment with at least one HMGA1 inhibitor when the level of HMGA1 expression in the biological sample is greater than the level of HMGA1 expression in the control sample.   
     
     
         31 . The method of  claim 30 , 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. 
     
     
         32 . The method of  claim 30 , 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. 
     
     
         33 . The method of  claim 30 , wherein the subject is a human subject. 
     
     
         34 . The method of  claim 30 , further comprising treating the subject with aggressive and/or poorly differentiated metastatic cancer by administering an effective amount of at least one HMGA1 inhibitor to the subject. 
     
     
         35 . The method of  claim 34 , further comprising administering an effective amount of at least one chemotherapeutic agent to the subject.