Methods and pharmaceutical compositions for inhibiting tumor cell growth
AssigneeDana-Farber Cancer Institute, Inc.
InventorsBruce M. Spiegelman, Elisabetta Mueller, Pasha Sarraf, Soner Altiok, Peter Tontonoz, Samuel Singer
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Abstract
The present invention is based on the finding that activation of PPARγ plays a key role in inducing growth arrest and differentiation of certain actively proliferating cells. We show that administration of PPARγ agonists, such as thiazolidinedione ligands (TZDs), is effective both in vitro and in vivo at inhibiting the proiferation of such cells.
Claims48
A method for inhibiting proliferation of a PPARγ-responsive hyperproliferative cell, comprising ectopically contacting the cell with a PPARγ agonist in an amount effective to induce differentiation of the cell to a phenotype of lower proliferative index.
A method of treating or prophylactically preventing, in a subject animal, a disorder characterized by unwanted proliferation of PPARγ-responsive hyperproliferative cells, comprising administering to the animal a pharmaceutical preparation of a PPARγ agonist in an amount effective to inhibit growth of the PPARγ-responsive hyperproliferative cells.
A pharmaceutical composition comprising:
- (i) a PPARγ ligand in a therapeutically effective amount to induce terminal differentiation of a PPARγ-responsive hyperproliferative cell in an subject animal;
- (ii) one or more agents selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, and agents which increase immune responses to tumors;
- and (iii) and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a PPARγ agonist and an R×R agonist in a pharmaceutically acceptable carrier, the PPARγ and R×R agonists being present in a therapeutically effective amount to induce terminal differentiation of a PPARγ-responsive hyperproliferative cell in a subject animal.
A method for augmenting diagnosis of liposarcomas, comprising detecting in a sample of hyperproliferative cells one or both of a diagnostic level of PPARγ mRNA or PPARγ protein, wherein elevated expression of PPARγ mRNA or protein in cells of the sample increases the likelihood that at least a portion of the transformed cells of the sample are liposarcoma cells.
An assay for screening test compounds to identify agents which inhibit growth of PPARγ-responsive hyperproliferative cells, comprising:
- (a) forming a reaction mixture including:
- (i) a PPARγ protein, and
- (ii) a test compound;
- and
- (b) detecting interaction of the PPARγ protein with the test compound,
- (c) contacting test compounds of step (b) which specifically bind to the PPARγ protein with a PPARγ-responsive hyperproliferative cell;
- and
- (d) identifying agents from step (c) which inhibit growth of the transformed cell.
Dependencies are inferred from the claim text.