Methods and compositions for cell-proliferation-related disorders

Abstract

Methods of treating and evaluating subjects having neoactive mutants are described herein.

Description

CLAIM OF PRIORITY[0001]This application claims priority to U.S. Ser. No. 61 / 160,253, filed Mar. 13, 2009; U.S. Ser. No. 61 / 160,664, filed Mar. 16, 2009; U.S. Ser. No. 61 / 173,518, filed Apr. 28, 2009; U.S. Ser. No. 61 / 180,609, filed May 22, 2009; U.S. Ser. No. 61 / 220,543, filed Jun. 25, 2009; U.S. Ser. No. 61 / 227,649, filed Jul. 22, 2009; U.S. Ser. No. 61 / 229,689, filed Jul. 29, 2009; U.S. Ser. No. 61 / 253,820, filed Oct. 21, 2009; and U.S. Ser. No. 61 / 266,929, filed Dec. 4, 2009, the contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to methods and compositions for evaluating and treating cell proliferation-related disorders, e.g., proliferative disorders such as cancer.BACKGROUND[0003]Isocitrate dehydrogenase, also known as IDH, is an enzyme which participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate or α...

AI Technical Summary

Benefits of technology

[0004]Methods and compositions disclosed herein relate to the role played in disease by neoactive products produced by neoactive mutant enzymes, e.g., mutant metabolic pathway enzymes. The inventors have discovered, inter alia, a neoactivity associated with IDH mutants and that the product of the neoactivity can be significantly elevated in cancer cells. Disclosed herein are methods and compositions for treating, and methods of evaluating, subjects having or at risk for a disorder, e.g., a cell proliferation-related disorder characterized by a neoactivity in a metabolic pathway enzyme, e.g., IDH neoactivity. Such disorders include e.g., proliferative disorders such as cancer. The inventors have discovered and disclosed herein novel therapeutic agents for the treatment of disorders, e.g., cancers, characterized by, e.g., by a neoactivity, neoactive protein, neoactive mRNA, or neoactive mutations. In embodiments a therapeutic agent reduces levels of neoactivity or neoactive product or ameliorates an effect of a neoactive product. Methods described herein also allow the identification of a subject, or identification of a treatment for the subject, on the basis of neaoctivity genotype or phenotype. This evaluation can allow for optimal matching of subject with treatment, e.g., where the selection of subject, treatment, or both, is based on an analysis of neoactivity genotype or phenotype. E.g., methods describe herein can allow selection of a treatment regimen comprising administration of a novel compound, e.g., a novel compound disclosed herein, or a known compound, e.g., a known compound not previously recommended for a selected disorder. In embodiments the known compound reduces levels of neoactivity or neoactive product or ameliorates an effect of a neoactive product. Methods described herein can guide and provide a basis for selection and administration of a novel compound or a known compound, or combination of compounds, not previously recommended for subjects having a disorder characterized by a somatic neoactive mutation in a metabolic pathway enzyme. In embodiments the neoactive genotype or phenotype can act as a biomarker the presence of which indicates that a compound, either novel, or previously known, should be administered, to treat a disorder characterized by a somatic neoactive mutation in a metabolic pathway enzyme. Neoactive mutants of IDH1 having a neoactivity that results in the production of 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate and associated disorders are discussed in detail herein. They are exemplary, but not limiting, examples of embodiments of the invention.

Problems solved by technology

An incorrect balance is associated with disease.

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