US2024042069A1PendingUtilityA1
Predicting peptide receptor radiotherapy using a gene expression assay

Assignee: LIQUID BIOPSY RES LLCPriority: Nov 30, 2017Filed: Jul 12, 2023Published: Feb 8, 2024
Est. expiryNov 30, 2037(~11.3 yrs left)· nominal 20-yr term from priority
Inventors:Irvin Mark Modlin Mark Kidd Ignat Drozdov
G01N 33/57557G01N 33/57585G01N 2800/52C12Q 2600/112C12Q 2537/165A61K 51/08C12Q 2600/158G01N 33/6893C12Q 1/6886A61K 51/088C12Q 1/6837G16B 25/10C12Q 1/6874C12Q 1/6806C12Q 1/686C12Q 1/6853A61P 35/00C12Q 2600/106
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References
Claims
Abstract

The present invention is directed to methods for providing a peptide receptor radiotherapy treatment recommendation for a subject having a neuroendocrine tumor by determining the expression level of each of at least 9 biomarkers comprising ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, and ALG9. In some embodiments, the methods can further include determining the expression level of each of NAP1L1, NOL3, and TECPR2.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of providing a peptide receptor radiotherapy (PRRT) treatment recommendation for a subject having a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of at least 9 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 9 biomarkers, wherein the 9 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3, thereby obtaining a summated expression level;   determining a first score, wherein the first score is 1 when the summated expression level is equal to or greater than a first predetermined cutoff value, or the first score is 0 when the summated expression level is below the first predetermined cutoff value;   determining a second score based on the histological grade of the NET, wherein the second score is 1 when the NET is designated high grade, or the second score is 0 when the NET is designated low grade;   calculating a third score based on the following equation:
   Third Score=39.22787−40.80341*(First Score)−18.441*(Second Score);
 
   
       and
 providing a recommendation that the NET will respond to PRRT when the third score is equal to or less than a second predetermined cutoff value, or 
 providing a recommendation that the NET will not respond to PRRT when the third score is above the second predetermined cutoff value. 
 
     
     
         2 . The method of  claim 1 , wherein the first predetermined cutoff value is 5.9. 
     
     
         3 . The method of  claim 1  or  2 , wherein the second predetermined cutoff value is 0. 
     
     
         4 . The method of  claim 1 , having a sensitivity of greater than 90%. 
     
     
         5 . The method of  claim 1 , having a specificity of greater than 90%. 
     
     
         6 . The method of  claim 1 , wherein at least one of the at least 9 biomarkers is RNA, cDNA, or protein. 
     
     
         7 . The method of  claim 6 , wherein when the biomarker is RNA, the RNA is reverse transcribed to produce cDNA, and the produced cDNA expression level is detected. 
     
     
         8 . The method of  claim 1 , wherein the expression level of the biomarker is detected by forming a complex between the biomarker and a labeled probe or primer. 
     
     
         9 . The method of  claim 6 , wherein when the biomarker is protein, the protein is detected by forming a complex between the protein and a labeled antibody. 
     
     
         10 . The method of  claim 6 , wherein when the biomarker is RNA or cDNA, the RNA or cDNA is detected by forming a complex between the RNA or cDNA and a labeled nucleic acid probe or primer. 
     
     
         11 . The method of  claim 10 , wherein the complex between the RNA or cDNA and the labeled nucleic acid probe or primer is a hybridization complex. 
     
     
         12 . The method of  claim 1 , wherein the test sample is blood, serum, plasma, or neoplastic tissue. 
     
     
         13 . The method of  claim 12 , wherein the test sample is blood. 
     
     
         14 . The method of  claim 1 , wherein the NET is designated high grade when the NET is poorly differentiated. 
     
     
         15 . The method of  claim 1 , wherein the NET is designated low grade when the NET is well differentiated, bronchial typical carcinoid, or bronchial atypical carcinoid. 
     
     
         16 . The method of  claim 1 , further comprising administering PRRT to the subject when the third score is equal to or less than the second predetermined cutoff value. 
     
     
         17 . A method of providing a peptide receptor radiotherapy (PRRT) treatment recommendation for a subject having a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2 PLD3, NAP1L1, NOL3, and TECPR2, thereby obtaining a summated expression level;   determining a first score, wherein the first score is 1 when the summated expression level is equal to or greater than a first predetermined cutoff value, or the first score is 0 when the summated expression level is below the first predetermined cutoff value;   determining a second score based on the histological grade of the NET, wherein the second score is 1 when the NET is designated high grade, or the second score is 0 when the NET is designated low grade;   calculating a third score based on the following equation:
   Third Score=39.22787−40.80341*(First Score)−18.441*(Second Score);
 
   
       and
 providing a recommendation that the NET will respond to PRRT when the third score is equal to or less than a second predetermined cutoff value, or 
 providing a recommendation that the NET will not respond to PRRT when the third score is above the second predetermined cutoff value. 
 
     
     
         18 . The method of  claim 17 , wherein the first predetermined cutoff value is 10.9. 
     
     
         19 . The method of  claim 17  or  claim 18 , wherein the second predetermined cutoff value is 0. 
     
     
         20 . A method of providing a peptide receptor radiotherapy (PRRT) treatment recommendation for a subject having a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 thereby obtaining a summated expression level; and   providing a recommendation that the NET will respond to PRRT when the summated expression level is equal to or greater than a predetermined cutoff value, or   providing a recommendation that the NET will not respond to PRRT when the summated expression level is less than the predetermined cutoff value.   
     
     
         21 . The method of  claim 20 , wherein the predetermined cutoff value is 10.9. 
     
     
         22 . A method of providing a peptide receptor radiotherapy (PRRT) treatment recommendation for a subject having a low grade or high grade neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2, thereby obtaining a summated expression level; and   providing a recommendation that the low grade or high grade NET will respond to PRRT when the summated expression level is equal to or greater than a predetermined cutoff value, or   providing a recommendation that the low grade or high grade NET will not respond to PRRT when the summated expression level is less than the predetermined cutoff value.   
     
     
         23 . The method of  claim 22 , wherein the predetermined cutoff value is 10.9. 
     
     
         24 . A method of providing a peptide receptor radiotherapy (PRRT) treatment recommendation for a subject having a low grade or high grade neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 9 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 9 biomarkers, wherein the 9 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3, thereby obtaining a summated expression level; and   providing a recommendation that the low grade or high grade NET will respond to PRRT when the summated expression level is equal to or greater than a predetermined cutoff value, or   providing a recommendation that the low grade or high grade NET will not respond to PRRT when the summated expression level is less than the predetermined cutoff value.   
     
     
         25 . The method of  claim 24 , wherein the NET is designated high grade when the NET is poorly differentiated. 
     
     
         26 . The method of  claim 24 , wherein the NET is designated low grade when the NET is well differentiated, bronchial typical carcinoid, or bronchial atypical carcinoid. 
     
     
         27 . The method of  claim 24 , wherein the predetermined cutoff value is 5.9. 
     
     
         28 . The method of  claim 24 , having a sensitivity of greater than 90%. 
     
     
         29 . The method of  claim 24 , having a specificity of greater than 90%. 
     
     
         30 . The method of  claim 24 , wherein at least one of the at least 9 biomarkers is RNA, cDNA, or protein. 
     
     
         31 . The method of  claim 30 , wherein when the biomarker is RNA, the RNA is reverse transcribed to produce cDNA, and the produced cDNA expression level is detected. 
     
     
         32 . The method of  claim 24 , wherein the expression level of the biomarker is detected by forming a complex between the biomarker and a labeled probe or primer. 
     
     
         33 . The method of  claim 30 , wherein when the biomarker is protein, the protein is detected by forming a complex between the protein and a labeled antibody. 
     
     
         34 . The method of  claim 30 , wherein when the biomarker is RNA or cDNA, the RNA or cDNA is detected by forming a complex between the RNA or cDNA and a labeled nucleic acid probe or primer. 
     
     
         35 . The method of  claim 34 , wherein the complex between the RNA or cDNA and the labeled nucleic acid probe or primer is a hybridization complex. 
     
     
         36 . The method of  claim 24 , wherein the test sample is blood, serum, plasma, or neoplastic tissue. 
     
     
         37 . The method of  claim 36 , wherein the test sample is blood. 
     
     
         38 . The method of  claim 24 , further comprising administering PRRT to the subject when the summated expression level is equal to or greater than the predetermined cutoff value. 
     
     
         39 . A method of treating a subject with peptide receptor radiotherapy (PRRT), wherein the subject has a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of at least 9 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 9 biomarkers, wherein the 9 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3, thereby obtaining a summated expression level;   determining a first score, wherein the first score is 1 when the summated expression level is equal to or greater than a first predetermined cutoff value, or the first score is 0 when the summated expression level is below the first predetermined cutoff value;   determining a second score based on the histological grade of the NET, wherein the second score is 1 when the NET is designated high grade, or the second score is 0 when the NET is designated low grade;   calculating a third score based on the following equation:
   Third Score=39.22787−40.80341*(First Score)−18.441*(Second Score);
 
   
       and
 administering PRRT to the subject when the third score is equal to or greater than the predetermined cutoff value. 
 
     
     
         40 . A method of treating a subject with peptide receptor radiotherapy (PRRT), wherein the subject has a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2 PLD3, NAP1L1, NOL3, and TECPR2, thereby obtaining a summated expression level;   determining a first score, wherein the first score is 1 when the summated expression level is equal to or greater than a first predetermined cutoff value, or the first score is 0 when the summated expression level is below the first predetermined cutoff value;   determining a second score based on the histological grade of the NET, wherein the second score is 1 when the NET is designated high grade, or the second score is 0 when the NET is designated low grade;   calculating a third score based on the following equation:
   Third Score=39.22787−40.80341*(First Score)−18.441*(Second Score);
 
   
       and
 administering PRRT to the subject when the third score is equal to or greater than the predetermined cutoff value. 
 
     
     
         41 . A method of treating a subject with peptide receptor radiotherapy (PRRT), wherein the subject has a neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 thereby obtaining a summated expression level; and   administering PRRT to the subject when the summated expression level is equal to or greater than the predetermined cutoff value.   
     
     
         42 . A method of treating a subject with peptide receptor radiotherapy (PRRT), wherein the subject has a low grade or high grade neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 12 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 12 biomarkers, wherein the 12 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, TECPR2, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, NAP1L1, NOL3, and TECPR2, thereby obtaining a summated expression level; and   administering PRRT to the subject when the summated expression level is equal to or greater than the predetermined cutoff value.   
     
     
         43 . A method of treating a subject with peptide receptor radiotherapy (PRRT), wherein the subject has a low grade or high grade neuroendocrine tumor (NET), the method comprising:
 determining the expression level of each of at least 9 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 9 biomarkers, wherein the 9 biomarkers comprise ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, PLD3, and ALG9;   normalizing the expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3 to the expression level of ALG9, thereby obtaining a normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3;   summing the normalized expression level of each of ARAF1, BRAF, KRAS, RAF-1, ATP6V1H, OAZ2, PANK2, and PLD3, thereby obtaining a summated expression level; and   administering PRRT to the subject when the summated expression level is equal to or greater than the predetermined cutoff value.   
     
     
         44 . The method of any of  claims 39 - 43 , wherein administering PRRT to the subject comprises administering a  177 Lu-based-PRRT. 
     
     
         45 . The method of  claim 44 , wherein the  177 Lu-based-PRRT is  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide. 
     
     
         46 . The method of  claim 45 , wherein  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide is administered at a dose of about 7.4 GBq (200 mCi) about once every 8 weeks for a total of about 4 doses. 
     
     
         49 . The method of  claim 45 , wherein  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide is administered at a dose of about 6.5 GBq about once every 8 weeks for a total of about 4 doses. 
     
     
         48 . The method of  claim 45 , wherein  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide is administered at a dose of about 4.6 GBq about once every 8 weeks for a total of about 4 doses. 
     
     
         47 . The method of  claim 45 , wherein  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide is administered at a dose of about 3.2 GBq (100 mCi) about once every 8 weeks for a total of about 4 doses. 
     
     
         50 . The method of  claim 45 , wherein  177 Lu-DOTA-Tyr 3 -Thr 8 -octreotide is administered at a dose of about 3.7 GBq about once every 8 weeks for a total of about 4 doses. 
     
     
         51 . The method of  claim 44 , wherein the  177 Lu-based-PRRT is administered intravenously. 
     
     
         51 . The method of  claim 44 , wherein the  177 Lu-based-PRRT is administered intra-arterially.
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