Fred Hutchinson Cancer Center

Other

Sloan-kettering Institute for Cancer Research

Memorial Sloan Kettering Cancer Center

Andrew C Koff

James M Roberts

Joan Massague

Motoaki Ohtsubo

Frederick Cross

Kornelia Polyak

Carlos Cordon-Cardo

Howard Scher

Gary K Schwartz

Samuel Singer

Aimee Crago

Marta Kovatcheva

Mark A Dickson

Mary Elizabeth Klein

David Liu

Peggy L Porter

The present invention relates to the use of one or more biomarkers to evaluate the likelihood that a CDK4 inhibitor would produce an anti-cancer effect in a subject. It is based, at least in part, on the discovery that cancer treatment with a CDK4 inhibitor is more effective where treated cancer cells undergo cellular senescence rather than a transient cell cycle arrest, where cellular senescence is associated with decreased MDM2 protein level. Accordingly, in non-limiting embodiments, the present invention provides for methods, compositions, and kits for a companion diagnostic for CDK4 inhibitors, and in particular, to the use of MDM2 expression as a biomarker for the likelihood that a cancer can be successfully treated by CDK4 inhibition.

Companion diagnostic for CDK4 inhibitors

This invention provides a method for determining the aggressiveness of a prostate carcinoma comprising: (a) obtaining a sample of the prostate carcinoma; and (b) detecting the presence of p27 protein in the prostate carcinoma, the absence of p27 indicating that the prostate carcinoma is aggressive. This invention also provides a method for diagnosing a beign prostate hyperplasia comprising: (a) obtaining an appropriate sample of the hyperplasia; and (b) detecting the presence of the p27 RNA, a decrease of the p27 RNA indicating that the hyperplasia is beign. This invention provides various uses of p27 in prostate cancer. Finally, this invention also provides different marker for prostate cancer.

Markers for prostate cancer

An isolated protein designated p27 is disclosed. The p27 protein has an apparent molecular weight of about 27 kD, and is capable of binding to and inhibiting the activation of a cyclin E-Cdk2 complex. A nucleic acid sequence encoding p27 protein is disclosed, as well as a method for producing p27 in cultured cells. in vitro assays for discovering agents which effect the activity of p27 are also provided. Methods of diagnosing and treating hypoproliferative and hyperproliferative disorders are provided.

Isolated P27 protein, nucleic acid molecules encoding same, methods of identifying agents acting on same, and uses of said agents

An isolated protein designated p27 is disclosed. The p27 protein has an apparent molecular weight of about 27 kD, and is capable of binding to and inhibiting the activation of a cyclin E-Cdk2 complex. A nucleic acid sequence encoding p27 protein is disclosed, as well as a method for producing p27 in cultured cells. In vitro assays for discovering agents which affect the activity of p27 are also provided. Methods of diagnosing and treating hypoproliferative disorders are provided.

Isolated p27 protein

The subject invention is directed to the discovery of a protein involved in regulation of cell-cycle progression, and includes reagents and methods related thereto.

Methods for determining isolated p27 protein levels and uses thereof

The subject invention provides an isolated protein having an apparent molecular weight of about 27 kD and capable of binding to and inhibiting the activation of a cyclin E-Cdk2 complex. The subject invention further provides an isolated antibody and a purified preparation of polyclonal and monoclonal antibodies which are specifically immunoreactive with a p27 protein. The subject invention further provides a kit for detecting a p27 protein.

Antibodies for detecting p27 protein

Methods are provided for determining in biological material the presence or amount human cyclin E polypeptide and/or cyclin E:cell division kinase complexes.

Immunoassays for human cyclin E

Nucleic acid molecules capable of hybridizing under stringent conditions to the nucleotide sequence residing between positions 1 and 1185 of the human cyclin E cDNA sequence shown in FIG. 2. Polypeptides encoded by such nucleic acid molecules, and immunologic binding partners directed to such polypeptides.

Human cyclin E

Human cyclin E polypeptides

The subject invention provides an isolated protein having an apparent molecular weight of about 27 kD and capable of binding to and inhibiting the activation of a cyclin E-Cdk2 complex. The subject invention further provides a recombinant nucleic acid molecule which encodes the p27 protein of the subject invention, and related vectors and host vector systems. The subject invention further provides a method for producing the p27 protein of the subject invention using the host vector system. The subject invention further provides methods of determining whether an agent is capable of specifically inhibiting or enhancing the ability of p27 protein to inhibit the activation of cyclin E-Cdk2 complex. Finally, this subject invention provides different uses of the isolated protein, the recombinant nucleic acid molecule encoding the isolated protein and the agent capable of inhibiting or enchancing the ability of p27 protein to inhibit the activation of cyclin E-Cdk2 complex.

Isolated nucleic acid molecules encoding the p27 KIP-1 protein

Whole cell or cell-free test systems for screening and identifying compounds that modulate or alter Cyclin E activity. Whole cell assays measure the G1 phase of cells in the presence or absence of the test compound. Additional whole cell or cell-free assays measure binding of cyclin E to a cell division kinase, measure cyclin E activity directly, or measure the cell division kinase activity directly in the presence or absence of the test compound.

Assays for compounds that modulate or alter cyclin E activity

Nucleic acid molecules capable of hybridizing under stringent conditions to the nucleotide sequence residing between positions 1 and 1185 of the human cyclin E cDNA sequence shown in FIG. 2 . Polypeptides encoded by such nucleic acid molecules, and immunologic binding partners directed to such polypeptides.

Growing community of inventors

Seattle, WA, United States of America

Andrew C Koff