Biomarkers of response to hif-2-alpha inhibition in cancer and methods for the use thereof

Abstract

Described herein are methods and systems for identifying and/or treating subjects having cancer who are more likely to respond to treatment with an inhibitor of the transcription factor HIF-2α.

1 . A method of treating a subject for cancer, comprising administering an effective dose of a HIF-2α inhibitor to the subject, wherein a cancer cell of the subject exhibits (1) differential expression of one or more genes or gene products, or (2) aberrant activity of one or more gene products encoded by the one or more genes, wherein the one or more genes predict for HIF-2α inhibitor sensitivity. 
     
     
         2 . The method of  claim 1 , wherein the differential expression of the one or more genes is assessed by detecting a level of mRNA transcribed from the one or more genes. 
     
     
         3 . The method of  claim 1 , wherein the differential expression of the one or more genes is assessed by detecting a level of cDNA produced from reverse transcription of mRNA transcribed from the one or more genes. 
     
     
         4 . The method of  claim 1 , wherein the differential expression of the one or more genes is assessed by detecting a level of polypeptide encoded by the one or more genes. 
     
     
         5 . The method of  claim 1 , wherein the one or more genes are selected from Table 3. 
     
     
         6 . The method of  claim 1 , wherein the one or more genes are involved in a pathway selected from the group consisting of hypoxia signaling, DNA damage response, GPCR signaling, insulin signaling, non-canonical Wnt signaling, dopaminiergic signaling, ion and solute transport signaling, and neurotrophic growth factor signaling. 
     
     
         7 . The method of  claim 1 , wherein the differential expression comprises overexpression of the one or more genes, wherein the one or more genes are selected from Table 4. 
     
     
         8 . The method of  claim 1 , wherein the differential expression comprises underexpression of the one or more genes, wherein the one or more genes are selected from Table 5. 
     
     
         9 . The method of  claim 1 , wherein the differential expression comprises overexpression of the one or more genes, wherein the one or more genes are involved in a pathway selected from the group consisting of hypoxia signaling, GPCR signaling, dopaminiergic signaling, and neurotrophic growth factor signaling. 
     
     
         10 . The method of  claim 1 , wherein the differential expression comprises underexpression of the one or more genes, wherein the one or more genes are involved in a pathway selected from the group consisting of DNA damage response, insulin signaling, non-canonical Wnt signaling, and ion and solute transport. 
     
     
         11 . The method of  claim 1 , wherein the differential expression is assessed relative to a reference level. 
     
     
         12 . The method of  claim 11 , wherein the reference level is derived from a patient population having a known HIF-2α inhibitor treatment status. 
     
     
         13 . A method of treating a subject having cancer, comprising:
 (a) screening the subject for the presence or absence of at least one biomarker for HIF-2α inhibitor response;   (b) administering a HIF-2α inhibitor to the subject if the at least one biomarker for HIF-2α inhibitor response is determined to be present; and   (c) applying an alternative therapy to the subject if the at least one biomarker for HIF-2α inhibitor response is determined to be absent,   thereby treating the subject.   
     
     
         14 . The method of  claim 13 , wherein presence of the at least one biomarker comprises an expression level of the at least one biomarker that is equal to or above a reference level. 
     
     
         15 . The method of  claim 13 , wherein presence of the at least one biomarker comprises overexpression of one or more genes selected from Table 4. 
     
     
         16 . The method of  claim 13 , wherein absence of the at least one biomarker comprises underexpression of one or more genes selected from Table 5. 
     
     
         17 . The method of  claim 13 , wherein the alternative therapy is chemotherapy, radiotherapy, or surgery 
     
     
         18 . A method of treating a plurality of cancer cells with a HIF-2α inhibitor, comprising:
 (a) assessing, by nucleic acid hybridization assay and/or protein assay, an expression level of at least one biomarker selected from Table 4 in a biological sample comprising a cancer cell of the plurality of cells, or a portion thereof; and 
 (b) administering an effective dose of the HIF-2α inhibitor to the plurality of cells if the at least one biomarker is present in the sample at an increased level as compared to a reference level. 
 
     
     
         19 . The method of  claim 18 , wherein the expression level of the at least one biomarker is assessed by detecting a level of mRNA transcribed from the at least one biomarker. 
     
     
         20 . The method of  claim 18 , wherein the expression level of the at least one biomarker is assessed by detecting a level of cDNA produced from reverse transcription of mRNA transcribed from the at least one biomarker. 
     
     
         21 . The method of  claim 18 , wherein the expression level of the at least one biomarker is assessed by detecting a level of polypeptide encoded by the at least one biomarker. 
     
     
         22 . The method of  claim 18 , wherein the at least one biomarker is present in the sample at an increased level of at least 2-fold as compared to the reference level. 
     
     
         23 . The method of  claim 18 , wherein the biological sample is a tissue sample. 
     
     
         24 . The method of  claim 23 , wherein the tissue sample is fixed, paraffin-embedded, fresh, or frozen. 
     
     
         25 . The method of  claim 23 , wherein the tissue sample is derived from fine needle, core, or other types of biopsy. 
     
     
         26 .- 111 . (canceled)