STAT5a and its functional tumor suppressor analogs for treatment of malignancies expressing NPM/ALK and other oncogenic kinases
The invention provides methods of inhibiting epigenetic gene silencing in a cell expressing NPM/ALK or decreasing NPM/ALK content in a cell, by contacting a cell with an agent capable of increasing the concentration of Stat5a protein or its functional analog. Further, the invention provides a method of treating malignancies expressing oncogenic kinase by administering to a patient affected with a malignancy an agent capable of increasing the concentration of Stat5a protein or its epigenetically silenced functional tumor suppressor analog in a malignant cell. Finally, it provides a method to diagnose malignancy and monitor patient's response to therapy by analysis of the degree of DNA methylation of the gene encoding for Stat5a or its analog, their mRNA, or protein.
1. A method of treating a malignancy expressing a chimeric tyrosine kinase in a subject, the method comprising the step of administering to the subject a composition comprising an agent in an effective amount to increase expression of Stat5a protein in the malignancy, wherein said agent is a small molecule chemical compound, wherein the small molecule chemical compound is a DNA Methyltransferase (DNMT) inhibitor, and wherein the chimeric tyrosine kinase is an ALK + chimeric tyrosine kinase.
2. The method of claim 1 , whereby the composition further comprises an agent capable of inhibiting the expression or function of a methylated DNA capping family (MBD) protein, Stat3 or their combination.
3. The method of claim 2 , wherein the methylated DNA capping family (MBD) protein is Methylation binding domain protein.
4. The method of claim 2 , whereby the agent capable of inhibiting the function of a methylated DNA capping family (MBD) protein is an antibody or a fragment thereof, specific against a methylated DNA capping family (MBD) protein.
5. The method of claim 4 , whereby the agent capable of inhibiting the function of Methylation binding domain protein, or Stat3, is a small molecule chemical compound.
6. The method of claim 4 , whereby the agent capable of inhibiting the expression of a methylated DNA capping family (MBD) protein is a siRNA, a polyamide, a triple-helix-forming agent, an antisense RNA, a synthetic peptide nucleic acids (PNAs), an agRNA, a LNA/DNA copolymer, a small molecule chemical compound, or a combination thereof, specific against a nucleotide sequence encoding a methylated DNA capping family (MBD) protein, or Stat3.
7. The method of claim 1 , wherein the DNMT inhibitor is 5′-aza-2′-deoxycytidine, or 5-azacytidine.
8. The method of claim 1 , wherein the malignancy is a lymphoma, leukemia, sarcoma, or carcinoma.
9. The method of claim 8 , wherein the malignancy is a lymphoma.
10. The method of claim 1 , wherein the chimeric tyrosine kinase is NPM/ALK.
11. The method of claim 9 , wherein the lymphoma is an anaplastic large cell lymphoma.