Methods and compositions for the detection and treatment of cancer involving miRNAs and miRNA inhibitors and targets
The present invention relates to microRNAs (miRNAs) which are associated with cancer, particularly including hematologic malignancies, and particularly T-cell acute lymphoblastic leukemia (T-ALL), and to the assessment and modulation thereof in the treatment and management of cancer. The present invention is directed to methods and compositions for diagnosing and treating cancer, particularly T-ALL, by modulating miRNAs, and the use of miRNAs and antagonists thereof, particularly antagomirs, for predicting and assessing response to treatment, in assays for isolating and selecting antagonists, and as compositions for the treatment and management of cancer. Methods and compositions are provided for treatment or alleviation of cancer, particularly T-ALL, with antagonists/antagomirs of miRNAs, particularly one or more of miR-19b, miR-20a, miR26, miR92, miR148 and miR223.
1. A pharmaceutical composition for use in treatment of a lymphoid malignancy consisting of a combination of an antagomir or RNA oligonucleotide which is complementary to miRNA miR-26 and an antagomir or RNA oligonucleotide which is complementary to miRNA miR-223, and a pharmaceutically acceptable carrier or diluent wherein the antagomir or RNA oligonucleotide specifically inhibits or blocks the expression or activity of the complementary miR-26 or miR-223 and wherein at least 90% of the corresponding antagomir or RNA oligonucleotide nucleotides are complementary to the miR-26 sequence SEQ ID NO:5 or the miR-223 sequence SEQ ID NO:10.
2. The pharmaceutical composition of claim 1 wherein said antagomir or oligonucleotide comprises at least one modified nucleotide.
3. A pharmaceutical composition for use in treatment of a lymphoid malignancy consisting of a combination of an antagomir or RNA oligonucleotide which is complementary to miRNA miR-26 and an antagomir or RNA oligonucleotide which is complementary to miRNA miR-223, and an antagomir or RNA oligonucleotide complementary to the miRNA miR-19, miR-92 or the combination thereof, and a pharmaceutically acceptable carrier or diluent wherein the antagomir or RNA oligonucleotide specifically inhibits or blocks the expression or activity of the complementary miR-26 or miR-223, and miR-19, mIR-92 or the combination thereof, and wherein at least 90% of the corresponding antagomir or RNA oligonucleotide nucleotides is complementary to the miR-26 sequence SEQ ID NO:5, the miR-223 sequence SEQ ID NO:10, and the miR-19 sequence SEQ ID NO: 1 or SEQ ID NO: 2 or the miR-92 sequence SEQ ID NO: 6 or SEQ ID NO: 7.
4. A pharmaceutical composition for use in treatment of a lymphoid malignancy comprising a therapeutically effective amount of a combination of an antagomir or RNA oligonucleotide complementary to miRNA miR-26, an antagomir or RNA oligonucleotide which is complementary to miRNA miR-223, and an antagomir or RNA oligonucleotide complementary to miRNA miR-148, wherein the antagomir or RNA oligonucleotide specifically inhibits or blocks the expression or activity of the complementary miR-26, miR-223 or miR-148 and wherein at least 90% of the corresponding antagomir or RNA oligonucleotide nucleotides are complementary to the miR-26 sequence SEQ ID NO:5, the miR-223 sequence SEQ ID NO:10 or the miR-148 sequence SEQ ID NO:8, and a pharmaceutically acceptable carrier or diluent.
5. The pharmaceutical composition of claim 4 which further comprises an antagomir or RNA oligonucleotide complementary to the miRNA miR-19, miR-92 or the combination thereof, wherein the antagomir or RNA oligonucleotide specifically inhibits or blocks the expression or activity of the complementary miR-19 or miR-92 and wherein at least 90% of the corresponding antagomir or RNA oligonucleotide nucleotide is complementary to the miR-19 sequence SEQ ID NO: 1 or SEQ ID NO: 2 or the miR-92 sequence SEQ ID NO: 6 or SEQ ID NO: 7.
6. A method of enhancing or increasing the expression of a tumor suppressor gene selected from Pten, Bim/Bcl2l11, Phf6, Ikzf1, Nf1 and Fbxw7 comprising contacting cells which are capable of expressing one or more of said tumor suppressor gene with the pharmaceutical composition of any of claim 1 , 2 , 3 or 4 .
7. A method of treating or alleviating a lymphoid malignancy, wherein the lymphoid malignancy is selected from T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma, wherein the miR17˜92 cluster is amplified or overexpressed comprising administering the pharmaceutical composition of any of claim 1 , 2 , 3 or 4 .