Compositions and methods for the treatment or prevention of chemoresistant neoplasia

Abstract

The invention generally features compositions and methods useful for the treatment and diagnosis of a neoplasia in a subject. In particular, the invention provides therapeutic compositions that decrease the expression of an Nfr2 nucleic acid molecule or polypeptide for the treatment of a neoplasia, such as a chemoresistant neoplasia, in a subject.

1 . An inhibitory nucleic acid molecule that corresponds to or is complementary to at least a fragment of a Nrf2 nucleic acid molecule, and that decreases Nrf2 expression in a cell. 
     
     
         2 - 8 . (canceled) 
     
     
         9 . The inhibitory nucleic acid molecule of  claim 1 , wherein the inhibitory nucleic acid molecule comprises a nucleic acid sequence selected from the group consisting of: SEQ ID NO: 1/ND1, SEQ ID NO: 2/ND2, SEQ ID NO: 3/ND3, SEQ ID NO: 4/ND4, and SEQ ID NO: 5/ND5. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . A vector encoding an inhibitory nucleic acid molecule of  claim 1 . 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A cell comprising the vector of claim  14  or an inhibitory nucleic acid molecule of  claim 1 . 
     
     
         17 . (canceled) 
     
     
         18 . A method of decreasing Nrf2 expression in a cell, the method comprising contacting the cell with an effective amount of an inhibitory nucleic acid molecule corresponding to or complementary to at least a portion of a Nrf2 nucleic acid molecule, wherein the inhibitory nucleic acid molecule inhibits expression of a Nrf2 polypeptide, thereby decreasing Nrf2 expression in the cell. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . A method of increasing apoptosis in a neoplastic cell, the method comprising contacting the cell with an effective amount of an inhibitory nucleic acid molecule of  claim 1 , thereby increasing apoptosis in the cell. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A method of treating a subject having a neoplasm, the method comprising administering to the subject an effective amount of an inhibitory nucleic acid molecule corresponding to or complementary to a Nrf2 nucleic acid molecule, wherein the inhibitory nucleic acid molecule reduces Nrf2 expression thereby treating the neoplasm. 
     
     
         26 - 32 . (canceled) 
     
     
         33 . A method of treating a subject having a neoplasm, the method comprising administering to the subject an effective amount of an inhibitory nucleic acid molecule and a chemotherapeutic agent simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm. 
     
     
         34 . (canceled) 
     
     
         35 . The method of claim  31 , wherein the chemotherapeutic agent is selected from the group consisting of: cisplatin, etoposide, and carboplatin, and other anticancer drugs used for cancer chemotherapy 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 33 , wherein the inhibitory nucleic acid molecule comprises a nucleic acid sequence selected from the group consisting of: SEQ ID NO: 1/ND1, SEQ ID NO: 2/ND2, SEQ ID NO: 3/ND3, SEQ ID NO: 4/ND4, and SEQ ID NO: 5/ND5. 
     
     
         38 - 40 . (canceled) 
     
     
         41 . The method of claim  40 , wherein said cancer is lung cancer. 
     
     
         42 - 43 . (canceled) 
     
     
         44 . A method of treating or preventing chemoresistance in a subject having a neoplasm, the method comprising administering to the subject an effective amount of an inhibitory nucleic acid molecule that corresponds to or is complementary to at least a fragment of a Nrf2 nucleic acid molecule, and that decreases Nrf2 expression thereby treating or preventing chemoresistance. 
     
     
         45 - 53 . (canceled) 
     
     
         54 . A method of identifying an agent that inhibits chemoresistance, the method comprising
 (a) contacting a cell that expresses Nrf2 nucleic acid molecule with an agent, and   (b) comparing the level of Nrf2 nucleic acid molecule or polypeptide expression in the cell contacted by the agent with the level of expression in a control cell, wherein an agent that decreases Nrf2 expression thereby inhibits chemoresistance.   
     
     
         55 . (canceled) 
     
     
         56 . A pharmaceutical composition for decreasing chemoresistance in a subject comprising a therapeutically effective amount of an inhibitory nucleic acid molecule that corresponds to or is complementary to at least a fragment of a Nrf2 nucleic acid molecule in a pharmaceutically acceptable excipient. 
     
     
         57 . (canceled) 
     
     
         58 . A pharmaceutical composition for treating a neoplasm in a subject comprising a therapeutically effective amount of an inhibitory nucleic acid molecule that corresponds to or is complementary to at least a fragment of a Nrf2 nucleic acid molecule and a chemotherapeutic agent in a pharmaceutically acceptable excipient. 
     
     
         59 . (canceled) 
     
     
         60 . A method for diagnosing a subject as having or having a propensity to develop chemoresistance, the method comprising measuring markers in a biological sample from a patient at risk for developing chemoresistance and detecting an alteration in the expression of test marker molecules relative to the sequence or expression of a reference molecule, wherein the markers are selected from the group consisting of: Nrf2, Keap1, GSH, GST, and NQO1. 
     
     
         61 . A method for diagnosing a subject as having or having a propensity to develop a neoplasia, the method comprising
 (a) measuring the level of a Nrf2, Keap1, GSH, GST, or NQO1 nucleic acid molecule or polypeptide marker in a biological sample from the subject, and   (b) detecting an alteration in the level of the marker in the sample relative to the level in a control sample, wherein detection of an alteration in the marker level indicates the subject has or has a propensity to develop a neoplasia.   
     
     
         62 - 64 . (canceled) 
     
     
         65 . A method of diagnosing a subject as having, or having a propensity to develop, a neoplasia, the method comprising identifying a mutation in Keap1 gene present in a biological sample from the subject, wherein the mutation indicates that the subject has or has a propensity to develop a neoplasia. 
     
     
         66 . A method of diagnosing a subject as having, or having a propensity to develop chemoresistance, identifying a mutation in Keap1 gene present in a biological sample from the subject, wherein the mutation indicates that the subject has or has a propensity to develop chemoresistance. 
     
     
         67 .- 70 . (canceled) 
     
     
         71 . A kit for the diagnosis of a neoplasia or chemoresistance in a subject, the kit comprising a nucleic acid molecule selected from the group consisting of: Nrf2, Keap1, GSH, GST, NQO1 and written instructions for use of the kit for detection of a neoplasia or chemoresistance in a biological sample. 
     
     
         72 - 76 . (canceled) 
     
     
         77 . A method of identifying a therapeutic regimen for a subject having a neoplasia, the method comprising:
 (a) measuring the level of a Nrf2, Keap1, GSH, GST, or NQO1 nucleic acid molecule or polypeptide marker in a biological sample from the subject; and   (b) detecting an alteration in the level of the marker in the sample relative to the level in a control sample, wherein detection of the alteration in the marker level identifies a therapeutic regiment for treatment of the neoplasm in the subject.   
     
     
         78 - 80 . (canceled) 
     
     
         81 . A packaged pharmaceutical comprising a therapeutically effective amount of an inhibitory nucleic acid molecule corresponding or complementary to at least a fragment of a Nrf2 nucleic acid molecule, and that decreases Nrf2 expression in a cell, and instructions for use in treating a subject having a neoplasm. 
     
     
         82 - 84 . (canceled)