US2023074781A1PendingUtilityA1
Methods and composition for the prediction of the activity of enzastaurin
Est. expirySep 1, 2036(~10.1 yrs left)· nominal 20-yr term from priority
C12Q 2600/106C12Q 2600/156C12Q 1/6886A61P 35/00C12Q 2600/136
67
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Claims
Abstract
The present invention describes biomarkers that have been discovered to correlate with varied individual responses (e.g., efficacy, adverse effect, and other end points) to enzastaurin, in treating diseases such as, DLBCL, GBM, and other cancer types. The newly discovered biomarkers and others in linkage disequilibrium with them can be used in companion diagnostic tests which can help to predict drug responses and apply drugs only to those who will be benefited, or exclude those who might not be beneficial, by the treatment.
Claims
exact text as granted — not AI-modified1 . A method of selecting and treating a subject that has diffuse large B-cell lymphoma (DLBCL) or glioblastoma (GBM) and is being considered for treatment with enzastaurin, comprising:
a) obtaining a biological sample from the subject; b) optionally isolating genomic DNA from the biological sample; c) assaying a biological sample from a subject for one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of rs309605, a SNP in linkage disequilibrium with rs309605, and a complementary SNP thereof, wherein a SNP is in linkage disequilibrium with rs309605 when the SNP has a D′ value of linkage equilibrium about ≥0.900, an r 2 value of ≥0.913, or both; d) identifying a subject to be a selected subject if determined to be homozygous or heterozygous for one or more alleles selected from the group consisting of: the T allele of rs309605, a complement of the T allele of rs309605, a corresponding allele for a SNP in linkage disequilibrium with rs309605, and a complement of the corresponding allele; and, e) administering an effective amount of enzastaurin to the selected subject.
2 . The method of claim 1 , wherein:
c) the biological sample is assayed using polymerase chain reaction (PCR) for the presence of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of rs309605, rs309604, rs5894240, rs1494748, rs7836309, rs309607, rs2132025, rs11990158, rs6469570, rs309603, rs923967, rs1494751, rs2575943, rs167446, rs309606, rs72675965, rs309602, rs309608, rs309610, rs2575911, rs309609, rs170132, rs386413735, rs2642789, rs2642788, rs2575944, rs309614, rs309601, and a complementary SNP thereof; and, d) the subject is selected if determined to be homozygous or heterozygous for one or more alleles shown in the following table or a corresponding complement;
SNP
Allele
rs309605
T
rs309604
T
rs5894240
Del (−)
rs1494748
T
rs7836309
T
rs309607
A
rs2132025
C
rs11990158
G
rs6469570
T
rs309603
G
rs923967
T
rs1494751
G
rs2575943
T
rs167446
C
rs309606
A
rs72675965
C
rs309602
G
rs309608
A
rs309610
G
rs2575911
C
rs309609
C
rs170132
G
rs386413735
Del (−)
rs2642789
C
rs2642788
A
rs2575944
C
rs309614
T
rs309601
A
3 . The method of claim 1 , wherein the biological sample is assayed using a reagent, comprising:
i. one or more primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, ii. one or more probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
4 . The method of claim 3 , wherein the reagent, comprises:
i. a plurality of primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, ii. a plurality of probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
5 . The method of claim 3 , wherein each SNP assayed comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
6 . The method of claim 4 , wherein each SNP assayed comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
7 . The method of claim 2 , wherein the biological sample is assayed using a reagent, comprising:
iii. one or more primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, iv. one or more probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
8 . The method of claim 7 , wherein the reagent, comprises:
iii. a plurality of primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, iv. a plurality of probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
9 . The method of claim 7 , wherein each SNP assayed comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
10 . The method of claim 8 , wherein each SNP assayed comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
11 . A reagent for detecting one or more SNPs, wherein the SNPs are selected from the group consisting of rs309605, a SNP in linkage disequilibrium with rs309605, and a complementary SNP thereof, wherein a SNP is in linkage disequilibrium with rs309605 when the SNP has a D′ value of linkage equilibrium about ≥0.900, an r 2 value of ≥0.913, or both; the reagent, comprising:
a) one or more primers that allow for amplification of a specific part of or all of the SNP or SNPs being detected; and,
b) one or more probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being detected.
12 . The reagent of claim 11 , wherein the reagent is for detecting one or more SNPs by PCR and the SNPs are selected from the group consisting of rs309605, rs309604, rs5894240, rs1494748, rs7836309, rs309607, rs2132025, rs11990158, rs6469570, rs309603, rs923967, rs1494751, rs2575943, rs167446, rs309606, rs72675965, rs309602, rs309608, rs309610, rs2575911, rs309609, rs170132, rs386413735, rs2642789, rs2642788, rs2575944, rs309614, rs309601, and a complementary SNP thereof.
13 . The reagent of claim 11 , wherein the reagent, comprises:
a) a plurality of primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, b) a plurality of probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
14 . The reagent of claim 11 , wherein each SNP detected comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
15 . The reagent of claim 13 , wherein each SNP detected comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
16 . The reagent of claim 12 , wherein the reagent, comprises:
a) a plurality of primers that allow for amplification of a specific part of or all of the SNP or SNPs being assayed; and, b) a plurality of probes that selectively or specifically hybridize to a specific part of or all of the SNP or SNPs being assayed.
17 . The reagent of claim 12 , wherein each SNP detected comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
18 . The reagent of claim 16 , wherein each SNP detected comprises 4, 8, 10, 15, 20, 25, 30, 50, 60, 100, 300, or 500 nucleotides on either side of the SNP position.
19 . The reagent of claim 12 , wherein the reagent is configured to detect one or more of the following alleles or a complement thereof:
SNP
Allele
rs309605
T
rs309604
T
rs5894240
Del (−)
rs1494748
T
rs7836309
T
rs309607
A
rs2132025
C
rs11990158
G
rs6469570
T
rs309603
G
rs923967
T
rs1494751
G
rs2575943
T
rs167446
C
rs309606
A
rs72675965
C
rs309602
G
rs309608
A
rs309610
G
rs2575911
C
rs309609
C
rs170132
G
rs386413735
Del (−)
rs2642789
C
rs2642788
A
rs2575944
C
rs309614
T
rs309601
A
20 . The reagent of claim 13 , wherein the reagent is configured to detect one or more of the following alleles or a complement thereof:
SNP
Allele
rs309605
T
rs309604
T
rs5894240
Del (−)
rs1494748
T
rs7836309
T
rs309607
A
rs2132025
C
rs11990158
G
rs6469570
T
rs309603
G
rs923967
T
rs1494751
G
rs2575943
T
rs167446
C
rs309606
A
rs72675965
C
rs309602
G
rs309608
A
rs309610
G
rs2575911
C
rs309609
C
rs170132
G
rs386413735
Del (−)
rs2642789
C
rs2642788
A
rs2575944
C
rs309614
T
rs309601
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