Methods and Monitoring of Treatment with a WNT Pathway Inhibitor

Abstract

Methods for treating diseases such as cancer comprising administering a Wnt pathway inhibitor, either alone or in combination with other anti-cancer agents, and monitoring for skeletal-related side effects and/or toxicity.

1 - 84 . (canceled) 
     
     
         85 . A method for reducing a skeletal-related side effect and/or toxicity in a human subject having cancer and receiving treatment with a Wnt pathway inhibitor for the cancer, comprising:
 (a) administering a therapeutically effective amount of a Wnt pathway inhibitor to the subject;   (b) determining the level of collagen type 1 cross-linked C-telopeptide (β-CTX) in a sample from the subject after the administration of the Wnt pathway inhibitor; and   (c) administering to the subject a therapeutically effective amount of a bisphosphonate if the level of β-CTX in the sample is higher than a predetermined level of the β-CTX; and   wherein the Wnt pathway inhibitor is a FZD antagonist or a Wnt antagonist.   
     
     
         86 . The method of  claim 85 , wherein the FZD antagonist is a FZD binding agent. 
     
     
         87 . The method of  claim 86 , wherein the FZD binding agent is an antibody. 
     
     
         88 . The method of  claim 85 , wherein the Wnt antagonist is a Wnt binding agent. 
     
     
         89 . The method of  claim 88 , wherein the Wnt binding agent is an antibody or a polypeptide comprising a FZD soluble receptor. 
     
     
         90 . The method of  claim 88 , wherein the Wnt binding agent comprises a Fri domain of a human FZD protein, or a fragment or variant of the Fri domain that binds one or more human Wnt proteins. 
     
     
         91 . The method of  claim 85 , wherein the sample is blood, serum, or plasma. 
     
     
         92 . The method of  claim 85 , wherein the predetermined level of β-CTX is determined at an earlier timepoint, at an initial screening, and/or prior to treatment. 
     
     
         93 . The method of  claim 85 , wherein the level of β-CTX in the sample is at least two-fold higher than the predetermined level of the β-CTX. 
     
     
         94 . The method of  claim 85 , wherein the skeletal-related side effect and/or toxicity is an increased risk of bone fracture, osteopenia, or osteoporosis. 
     
     
         95 . The method of  claim 85 , wherein the bisphosphonate is zoledronic acid. 
     
     
         96 . The method of  claim 85 , wherein the subject is treated with the Wnt pathway inhibitor in combination with one or more additional therapeutic agents. 
     
     
         97 . A method of preventing or attenuating the development of a skeletal-related side effect and/or toxicity in a human subject having cancer, comprising:
 (a) determining the level of β-CTX in a sample from the subject prior to treatment for cancer;   (b) administering to the subject a therapeutically effective amount of a bisphosphonate if the level of β-CTX in the sample is higher than a predetermined level of β-CTX; and   (c) administering to the subject a Wnt pathway inhibitor; wherein steps (b) and (c) are performed in any order after step (a); and   wherein the Wnt pathway inhibitor is a FZD antagonist or a Wnt antagonist.   
     
     
         98 . The method of  claim 97 , wherein the sample is blood, serum, or plasma. 
     
     
         99 . The method of  claim 97 , wherein the predetermined level of β-CTX is determined at an earlier timepoint, at an initial screening, and/or prior to treatment. 
     
     
         100 . The method of  claim 97 , wherein the level of β-CTX in the sample is at least two-fold higher than the predetermined level of the β-CTX. 
     
     
         101 . The method of  claim 97 , wherein the skeletal-related side effect and/or toxicity is an increased risk of bone fracture, osteopenia, or osteoporosis. 
     
     
         102 . The method of  claim 97 , wherein the bisphosphonate is zoledronic acid. 
     
     
         103 . The method of  claim 97 , wherein the subject is treated with the Wnt pathway inhibitor in combination with one or more additional therapeutic agents. 
     
     
         104 . A method of preventing or attenuating the development of a skeletal-related side effect and/or toxicity in a human subject having cancer and receiving treatment with a Wnt pathway inhibitor, comprising administering to the subject a therapeutically effective amount of a bisphosphonate; wherein the Wnt pathway inhibitor is a FZD antagonist or a Wnt antagonist. 
     
     
         105 . A method of treating cancer in a subject in need thereof, comprising:
 (a) administering to the subject a therapeutically effective amount of a Wnt pathway inhibitor;   (b) determining the level of a bone resorption biomarker in a sample from the subject; and   wherein the Wnt pathway inhibitor is a FZD antagonist or a Wnt antagonist.   
     
     
         106 . The method of  claim 105 , wherein the bone resorption biomarker is selected from the group consisting of: urinary hydroxyproline, urinary total pyridinoline (PYD), urinary free deoxypyridinoline (DPD), urinary collagen type 1 cross-linked N-telopeptide (NTX), urinary or serum collagen type 1 cross-linked C-telopeptide (CTX), bone sialoprotein (BSP), and tartrate-resistant acid phosphatase 5b and β-CTX. 
     
     
         107 . The method of  claim 106 , wherein the bone resorption biomarker is β-CTX.