Compositions and methods for the diagnosis and therapy of BCL2-associated cancers
Provided are methods and compositions for the treatment of cancers associated with overexpression of a BCL2 gene and/or gene product in a subject, and methods and compositions for the improvement of anti-cancer therapy, such as chemotherapy and radiation therapy. Also provided are methods for determining the efficacy of a cancer therapy in a subject, methods for diagnosing cancer, methods for assessing patient prognosis, and methods for inducing apoptosis of a cell.
1. A pharmaceutical composition for treating a Bcl2-associated cancer, comprising at least one anti-cancer agent and at least one miR-15a or miR-16-1 gene product,
wherein the at least one miR-15a or miR-16-1 gene product consists of a nucleotide sequence that is complementary to nucleotides 3741-3749 of SEQ ID NO: 55, and is present in an amount to increase the efficacy of the anti-cancer agent.
2. The pharmaceutical composition of claim 1 , wherein the anti-cancer agent is a chemotherapeutic agent.
3. The pharmaceutical composition of claim 1 , wherein the cancer is chronic lymphocytic leukemia (CLL).
4. The pharmaceutical composition of claim 1 , wherein the cancer is prostate cancer.
5. The pharmaceutical composition of claim 1 , wherein the cancer is lung cancer.
6. The pharmaceutical composition of claim 1 , wherein the cancer is colorectal cancer.
7. The pharmaceutical composition of claim 1 , wherein the composition is formulated for administration to a human subject.
8. The pharmaceutical composition of claim 1 , wherein the composition is formulated for administration to a human subject by intratumoral injection.
9. The pharmaceutical composition of claim 1 , wherein the composition is formulated for administration to a human subject by intravenous infusion.
10. The pharmaceutical composition of claim 1 , wherein the at least one miR-15a or miR-16-1 gene product comprises one or more ribonucleotides that are modified at the 2′ position.
11. The pharmaceutical composition of claim 10 , wherein the 2′ modification is selected from the group consisting of fluoro, amino, alkyl, alkoxy, and O-allyl.
12. The pharmaceutical composition of claim 10 , wherein the 2′ modification comprises the formula 2′ AR-nucleotide, wherein:
A is oxygen or a halogen; and
R is hydrogen or a straight or branched chain C 1-6 alkyl;
provided that when A is a halogen, R is omitted.
13. The pharmaceutical composition of claim 12 , wherein A is selected from the group consisting of fluorine, chlorine, and bromine.
14. The pharmaceutical composition of claim 10 , wherein the at least one miR-15a or miR-16-1 gene product comprises a 2′-O methyl ribonucleotide.
15. The pharmaceutical composition of claim 10 , wherein each ribonucleotide in the miR-15a or miR-16-1 gene product is a 2′-modified ribonucleotide.
16. The pharmaceutical composition of claim 1 , wherein the anti-cancer agent is radiation therapy.
17. The pharmaceutical composition of claim 2 , wherein the amount of the chemotherapeutic agent ranges from about 0.0001 mg/k to about 1000 mg/kg.
18. The pharmaceutical composition of claim 2 , wherein the amount of the chemotherapeutic agent ranges from about 0.5 mg/kg to about 70 mg/kg.
19. The pharmaceutical composition of claim 2 , wherein the amount of the chemotherapeutic agent ranges from about 1 mg/kg to about 50 mg/kg.
20. The pharmaceutical composition of claim 1 , wherein the at least one miR-15a or miR-16-1 gene product is encapsulated in a liposome.