Pyrazoloanthrone and derivatives thereof for the treatment of cancer expressing 'mullerian inhibiting substance' type ii receptor (misrii) and of excess androgen states

Abstract

The present invention relates to pyrazoloanthrones or functional derivatives or functional analogues thereof to activate MIS receptor-mediated downstream effects in a cell. In particular, the present invention relates to method to prevent and treat cancer that expresses MIS receptor type II (MISRII) by administering to a subject at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect of the present invention relates to methods to lower plasma androgen levels in a subject, and/or for the treatment of a subject with a disease characterized by excess androgen, whereby the subject is administered at least one pyrazoloanthrone or a functional derivative or a functional analogue thereof. Another aspect provides pharmaceutical compositions comprising at least one pyrazoloanthrone or functional a derivative or a functional analogue thereof, and optionally with one or more additional agents such as chemotherapeutic agents. Another aspect of the present invention relates to methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with a pyrazoloanthrone or a functional derivative or a functional analogue thereof that lowers the effective dose of the chemotherapeutic agent, such as for example, paclitaxel.

1 - 34 . (canceled) 
     
     
         35 . The method of identifying an agent that modulates MISRII-mediated signal transduction in a cell, comprising:
 a) providing a cell containing a nucleic acid construct comprising a nucleic acid sequence encoding a BMP-responsive element (BME) or fragment thereof, which is operatively linked to a nucleic acid sequence encoding a reporter gene; and   b) contacting the cell or an extract of the cell with an agent; and   c) measuring the signal from the reporter gene, whereby a change in the signal from the reporter gene in the presence of the agent compared to the signal from the reporter gene in the absence of the agent indicates the agent modulates MISRII-mediated signal transduction.   
     
     
         36 . The method of  claim 35 , wherein a change which is an increase in the signal in step (c) indicates the agent activates or increases MISRII mediated signal transduction, or activates and increases MISRII mediated signal transduction. 
     
     
         37 . The method of  claim 35 , wherein a change which is a decrease in the signal in step (c) indicates the agent inhibits or decreases MISRII mediated signal transduction, or inhibits and decreases MISRII mediated signal transduction. 
     
     
         38 . The method of  claim 35 , further comprising introducing a nucleic acid construct comprising a nucleic acid sequence encoding MISRII or a homologue or fragment thereof, wherein the nucleic acid sequence encoding MISRII is operatively linked to a promoter. 
     
     
         39 . The method of  claim 38 , wherein the promoter is a constitutive or inducible or tissue-specific promoter. 
     
     
         40 . The method of  claim 35 , wherein the BMP-responsive element is SEQ ID NO: 1 or a functional fragment thereof. 
     
     
         41 . The method of  claim 35 , wherein the reporter gene encodes a protein with fluorescent and/or chromogenic activity or variants or functional fragments thereof. 
     
     
         42 . The method of  claim 41 , wherein the chromogenic protein is the bioluminescent protein or functional variants thereof. 
     
     
         43 . The method of  claim 42 , wherein the bioluminescent protein is luciferase or functional fragments or modified functional versions thereof. 
     
     
         44 . The method of  claim 35 , wherein the agent is a small molecule, nucleic acid, nucleic acid analogue, aptamer, ribosome, peptide, protein, antibody, or variants and functional fragments thereof. 
     
     
         45 . The method of  claim 44 , wherein the antibody is a recombinant antibody, humanized antibody, chimeric antibody, modified antibody, monoclonal antibody, polyclonal antibody, miniantibody, dimeric miniantibody, minibody, diabody or tribody or functional variants, functional analogues or functional modified versions thereof. 
     
     
         46 . The method of  claim 44 , wherein the nucleic acid is DNA, RNA, nucleic acid analogue, peptide nucleic acid (PNA), pseudo-complementary PNA (pcPNA), locked nucleic acid (LNA) or functional analogues thereof. 
     
     
         47 . The method of  claim 46 , wherein the RNA is a small inhibitory RNA, siRNA, microRNA, shRNA, miRNA and functional analogues and homologues and functional variants thereof. 
     
     
         48 .- 79 . (canceled)