Camkk-beta as a target for treating cancer
AssigneeDuke University
InventorsDonald P. McDonnell, Daniel Frigo, Anthony R. Means
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds, compositions, including pharmaceutical compositions, having anti-cancer activity. Also provided are methods for diagnosing, detecting, and treating cancer in a subject, as well as a method for evaluating cancer stage in a subject, wherein the methods include determining the amount of a Ca2+/calmodulin dependent kinase kinase (CaMKK) in a sample. Further provided are methods of screening and identifying a compound that inhibits CaMKK.
Claims30
A method of diagnosing prostate cancer in a subject comprising:
- a) obtaining a sample from the subject;
- b) determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject;
- and
- c) comparing the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit from the sample from the subject to an amount of the CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in a control sample;
- wherein the subject is diagnosed as having prostate cancer when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the sample from the subject is greater than the amount in the control sample.
6-16. (canceled)
A method of screening a test compound for its anti-cancer activity comprising:
- i) contacting CaMKKβ and a substrate therefor in the presence of the test compound, under conditions that allow for CaMKKβ-dependent phosphorylation of the substrate, and
- ii) determining the level of phosphorylation of the substrate resulting from step (i) and comparing the level with a level of phosphorylation of the substrate obtained in the absence of the test compound, wherein a reduction in the level of phosphorylation of the substrate in the presence of the test compound indicates that the test compound has said anti-cancer activity.
22-26. (canceled)
A method of treating prostate cancer in a subject, comprising administering to the subject an effective amount of a compound that inhibits activity of at least one of CaMKKβ, CaMKKβ splice variant 2, or CaMKKβ splice variant 7.
33-41. (canceled)
A method of inhibiting proliferation of a prostate cancer cell in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AMPK, AMPKα1 subunit, or AMPKα2 subunit, or any combination thereof.
A method of determining the efficacy of therapy in a patient being treated for prostate cancer, the method comprising:
- a) obtaining a series of samples from the subject;
- a) determining an amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 subunit in the series of samples from the subject, where the samples are taken from the subject at different time points during the therapy;
- and
- b) comparing the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 from the series of samples from the subject;
- wherein when the amount of at least one of CaMKKβ, CaMKKβ splice variant 2, CaMKKβ splice variant 7, phosphorylated AMPK, phosphorylated AMPKα1 subunit, and phosphorylated AMPKα2 in the series of samples is about the same or increases the therapy is determined to be not effective.
45-47. (canceled)
A nucleic acid molecule comprising a sequence that binds under stringent conditions to a region that is about 2.3 kb upstream (5′) relative to a CaMKKβtranscriptional start site.
A nucleic acid molecule comprising a double stranded siRNA that down-regulates expression of a CaMKKβ gene via RNA interference (RNAi), wherein:
- a) each strand of the siRNA molecule is independently about 18 to about 28 nucleotides in length;
- and b) one strand of the siRNA molecule comprises a sequence that binds under stringent conditions to a CaMKKβ RNA of the CaMKKβ gene and directs cleavage of the CaMKKβ RNA via RNA interference.
Dependencies are inferred from the claim text.