United States Patent Application 20020127714
Kind Code A1
Housman, David E. ; et al. September 12, 2002
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Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
Abstract
Disclosed are methods for the treatment of proliferative disorders using compounds and/or environmental conditions which result in a difference in sensitivity of targeted and non-targeted cells. Certain of the methods involve the identification and use of allele-specific inhibitors of conditionally essential genes.
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Inventors: Housman, David E.; (Newton, MA) ; Ledley, Fred D.; (Needham, MA) ; Stanton, Vincent P. JR.; (Belmont, MA)
Correspondence Name and Address: ANITA L. MEIKLEJOHN, PH.D.
FISH & RICHARDSON P.C.
225 Franklin Street
Boston
MA
02110-2804
US
Assignee Name and Adress: Variagenics, Inc., a Delaware corporation
Serial No.: 782837
Series Code: 09
Filed: February 14, 2001
U.S. Current Class: 435/344; 536/23.1
U.S. Class at Publication: 435/344; 536/23.1
Intern'l Class: C07H 021/02; C07H 021/04; C12N 005/06; C12N 005/16
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Claims
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What we claim is:
1. A method for identifying an inhibitor potentially useful for treatment of cancer, wherein said inhibitor is active on a conditionally essential gene, and wherein said gene is subject to loss of heterozygosity in a cancer, said method comprising the steps of: (a) determining at least two alleles of a said gene; (b) testing a potential allele specific inhibitor to determine whether said potential allele specific inhibitor is active on at least one but less than all of said alleles; wherein inhibition of expression of at least one but less than all of said alleles or reduction of the level of activity of a product of at least one but less than all of said alleles in the presence of said potential allele specific inhibitor is indicative that said potential allele specific inhibitor is a said inhibitor.
2. An inhibitor potentially useful for treatment of cancer, wherein said inhibitor is active on an allelic form of a conditionally essential gene, said gene has at least two alternative alleles in a population, and wherein said inhibitor targets at least one but less than all of said alternative alleles.
3. A pharmaceutical composition, comprising at least one allele specific inhibitor targeting at least one but less than all allelic forms of a conditionally essential gene in a population; and a pharmaceutically acceptable carrier or excipient.
4. A method for producing an inhibitor potentially useful for cancer treatment, wherein said inhibitor is active on at least one but less than all alternative alleles of a conditionally essential gene having at least two alternative alleles, comprising the steps of: (a) identifying a conditionally essential gene that has alternative allelic forms in a noncancerous cell, wherein one of said alternative allelic forms is deleted in a cancer cell; (b) screening to identify an inhibitor which inhibits said at least one but less than all of said at least two alternative alleles; and (c) synthesizing said inhibitor in an amount sufficient to produce a therapeutic effect when administered to a patient suffering from a cancer in whom cancerous cells have only an allele of said gene inhibited by said inhibitor and in whom normal cells are heterozygous for said gene and contain an allelic form not inhibited by said inhibitor.
5. A method for preventing the development of cancer in a patient having a precancerous condition, comprising the steps of: a. subjecting cells of said precancerous condition to an altered condition such that a first conditionally essential becomes essential; b. administering to said patient a therapeutic amount of a first allele specific inhibitor targeted to an allele of said first conditionally essential gene present in cells of said precancerous condition, wherein the normal somatic cells of said patient are heterozygous for said first gene, said inhibitor is active on at least one but less than all allelic forms of said gene present in a population and targets only one allelic form present in said normal somatic cells; and wherein cells of said precancerous condition have undergone LOH of said first gene.
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