US2014141015A1PendingUtilityA1
QSOX1 as an Anti-Neoplastic Drug Target
Est. expirySep 20, 2030(~4.2 yrs left)· nominal 20-yr term from priority
C12Y 108/03002C12N 2320/30C12Q 2600/158C12Q 2600/118C12Q 1/26A61K 39/39558G01N 33/5011C07K 16/40C12N 2310/531A61K 2121/00C12N 15/1137C12N 15/1135A61K 38/44C12N 2310/14G01N 33/5008C12N 2310/11A61K 39/3955C12Q 1/6886
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Claims
Abstract
The present invention provides methods for tumor treatment by administering an inhibitor of quiescin sulfhydryl oxidase 1 (QSOX1), compositions comprising such inhibitors, and methods for identifying such inhibitors.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for tumor treatment, comprising administering to a subject having a tumor an amount effective of an inhibitor of quiescin sulfhydryl oxidase 1 (QSOX1) expression and/or activity, or a pharmaceutically acceptable salt thereof, to treat the tumor.
2 . The method of claim 1 , wherein the inhibitor of QSOX1 is selected from the group consisting of anti-QSOX1 antibodies, QSOX1-binding aptamers, QSOX1 antisense oligonucleotides, QSOX1 siRNA, and QSOX1.
3 . The method of claim 1 , wherein the tumor is a tumor that over-expresses QSOX1 compared to control.
4 . The method of claim 1 , wherein the subject is one from which tumor-derived QSOX1 peptides can be obtained.
5 . The method of claim 4 , wherein the tumor-derived QSOX1 peptides are selected from the group consisting of NEQEQPLGQWHLS (SEQ ID NO:3), NEQEQPLGQWH (SEQ ID NO:4), EQPLGQWHLS (SEQ ID NO:5), AAPGQEPPEHMAELQR (SEQ ID NO:6), AAPGQEPPEHMAELQ (SEQ ID NO:7), AAPGQEPPEHMAELQRNEQEQPLGQWHLS (SEQ ID NO:8), NEQEQPL (SEQ ID NO:9), and GQWHLS (SEQ ID NO:10).
6 . The method of claim 4 wherein the tumor-derived QSOX1 peptides are obtained from a tissue sample selected from the group consisting of plasma, serum, urine, saliva, and tumor tissue.
7 . The method of claim 1 , wherein the tumor is a pancreatic tumor.
8 . The method of claim 7 , wherein the pancreatic tumor comprises a pancreatic adenocarcinoma.
9 . The method of claim 1 , wherein the tumor is a breast tumor.
10 . The method of claim 9 , wherein the tumor is an estrogen receptor positive (ER+) breast tumor.
11 . The method of claim 9 , wherein the breast tumor is a Luminal B breast tumor.
12 . The method of claim 1 , wherein the inhibitor comprises an isolated nucleic acid molecule selected from the group comprising antisense, siRNA, miRNA, and/or shRNA having a nucleic acid sequence perfectly complementary to at least 10 contiguous nucleotides of SEQ ID NO:1 or SEQ ID NO: 2, or an RNA equivalent thereof.
13 . The method of claim 12 , where the inhibitor comprises a nucleic acid selected from the group consisting of:
5′-A(T/U)C(T/U)ACA(T/U)GGC(T/U)GACC(T/U)GGAA-3′
(SEQ ID NO: 11)
5′-AGGAAAGAGGG(T/U)GCCG(T/U)(T/U)C(T/U)(T/U)-3′
(SEQ ID NO: 12),
5′-GCCAA(T/U)G(T/U)GG(T/U)GAGAAAG(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 13),
5′-GCCAAGAAGG(T/U)GAAC(T/U)GGA(T/U)(T/U)-3′
(SEQ ID NO: 14).
5′-CCGGACAA(T/U)GAAGAAGCC(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 15)
5′-(T/U)C(T/U)AGCCACAACAGGG(T/U)CAA(T/U)-3′
(SEQ ID NO: 16)
5′-ATCTACATGGCTGACCTGGAA-3′
(SEQ ID NO: 17),
5′-AGGAAAGAGGGTGCCGTTCTT-3′
(SEQ ID NO: 18),
5′-GCCAATGTGGTGAGAAAGTTT-3′
(SEQ ID NO: 19),
5′-GCCAAGAAGGTGAACTGGATT-3′
(SEQ ID NO: 20),
5′-CCGGACAATGAAGAAGCCTTT-3′
(SEQ ID NO: 21);
5′-TCTAGCCACAACAGGGTCAAT-3′
(SEQ ID NO: 22); and
5′-CCGGGCCAATGTGGTGAGAAAGTTTCTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′
(SEQ ID NO: 26).
14 . The method of claim 12 , wherein the inhibitor comprises a nucleic acid of the general formula: CCGG-X1-CTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′ (SEQ ID NO:23)
wherein X1 is a nucleic acid sequence selected from the group consisting of
5′-A(T/U)C(T/U)ACA(T/U)GGC(T/U)GACC(T/U)GGAA-3′
(SEQ ID NO: 11)
5′-AGGAAAGAGGG(T/U)GCCG(T/U)(T/U)C(T/U)(T/U)-3′
(SEQ ID NO: 12),
5′-GCCAA(T/U)G(T/U)GG(T/U)GAGAAAG(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 13),
5′-GCCAAGAAGG(T/U)GAAC(T/U)GGA(T/U)(T/U)-3′
(SEQ ID NO: 14).
5′-CCGGACAA(T/U)GAAGAAGCC(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 15)
5′-(T/U)C(T/U)AGCCACAACAGGG(T/U)CAA(T/U)-3′
(SEQ ID NO: 16)
5′-ATCTACATGGCTGACCTGGAA-3′
(SEQ ID NO: 17),
5′-AGGAAAGAGGGTGCCGTTCTT-3′
(SEQ ID NO: 18),
5′-GCCAATGTGGTGAGAAAGTTT-3′
(SEQ ID NO: 19),
5′-GCCAAGAAGGTGAACTGGATT-3′
(SEQ ID NO: 20),
5′-CCGGACAATGAAGAAGCCTTT-3′
(SEQ ID NO: 21); and
5′-TCTAGCCACAACAGGGTCAAT-3′
(SEQ ID NO: 22).
15 . The method of claim 12 , wherein the nucleic acid inhibitor is administered to the subject in a viral vector.
16 . The method of claim 1 , wherein the method limits tumor metastasis.
17 . An isolated nucleic acid comprising an antisense, siRNA, miRNA, and/or shRNA molecule having a nucleic acid sequence perfectly complementary to least 10 contiguous nucleotides of SEQ ID NO:1 or SEQ ID NO:2, or an RNA equivalent thereof.
18 . The isolated nucleic acid of claim 17 comprising a nucleotide sequence selected from the group consisting of
5′-A(T/U)C(T/U)ACA(T/U)GGC(T/U)GACC(T/U)GGAA-3′
(SEQ ID NO: 11)
5′-AGGAAAGAGGG(T/U)GCCG(T/U)(T/U)C(T/U)(T/U)-3′
(SEQ ID NO: 12),
5′-GCCAA(T/U)G(T/U)GG(T/U)GAGAAAG(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 13),
5′-GCCAAGAAGG(T/U)GAAC(T/U)GGA(T/U)(T/U)-3′
(SEQ ID NO: 14).
5′-CCGGACAA(T/U)GAAGAAGCC(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 15)
5′-(T/U)C(T/U)AGCCACAACAGGG(T/U)CAA(T/U)-3′
(SEQ ID NO: 16)
5′-ATCTACATGGCTGACCTGGAA-3′
(SEQ ID NO: 17),
5′-AGGAAAGAGGGTGCCGTTCTT-3′
(SEQ ID NO: 18),
5′-GCCAATGTGGTGAGAAAGTTT-3′
(SEQ ID NO: 19),
5′-GCCAAGAAGGTGAACTGGATT-3′
(SEQ ID NO: 20),
5′-CCGGACAATGAAGAAGCCTTT-3′
(SEQ ID NO: 21);
5′-TCTAGCCACAACAGGGTCAAT-3′
(SEQ ID NO: 22); and
5′-CCGGGCCAATGTGGTGAGAAAGTTTCTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′
(SEQ ID NO: 26).
19 . A short hairpin RNA (shRNA) comprising the isolated nucleic acid of claim 18 .
20 . The shRNA of claim 19 , wherein the shRNA is of the general formula: CCGG-X1-CTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′ (SEQ ID NO:23)
wherein X1 is a nucleic acid sequence selected from the group consisting of
5′-A(T/U)C(T/U)ACA(T/U)GGC(T/U)GACC(T/U)GGAA-3′
(SEQ ID NO: 11)
5′-AGGAAAGAGGG(T/U)GCCG(T/U)(T/U)C(T/U)(T/U)-3′
(SEQ ID NO: 12),
5′-GCCAA(T/U)G(T/U)GG(T/U)GAGAAAG(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 13),
5′-GCCAAGAAGG(T/U)GAAC(T/U)GGA(T/U)(T/U)-3′
(SEQ ID NO: 14).
5′-CCGGACAA(T/U)GAAGAAGCC(T/U)(T/U)(T/U)-3′
(SEQ ID NO: 15)
5′-(T/U)C(T/U)AGCCACAACAGGG(T/U)CAA(T/U)-3′
(SEQ ID NO: 16)
5′-ATCTACATGGCTGACCTGGAA-3′
(SEQ ID NO: 17),
5′-AGGAAAGAGGGTGCCGTTCTT-3′
(SEQ ID NO: 18),
5′-GCCAATGTGGTGAGAAAGTTT-3′
(SEQ ID NO: 19),
5′-GCCAAGAAGGTGAACTGGATT-3′
(SEQ ID NO: 20),
5′-CCGGACAATGAAGAAGCCTTT-3′
(SEQ ID NO: 21);
5′-TCTAGCCACAACAGGGTCAAT-3′
(SEQ ID NO: 22)); and
5′-CCGGGCCAATGTGGTGAGAAAGTTTCTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′
(SEQ ID NO: 26).
21 . A recombinant expression vector comprising the isolated nucleic acid of claim 17 operatively linked to a promoter.
22 . The recombinant expression vector of claim 21 , wherein the vector comprises a viral vector.
23 . A recombinant host cell comprising the recombinant expression vector of claim 21 .
24 . A pharmaceutical composition, comprising
(a) the isolated nucleic acid of claim 17 ; and (b) a pharmaceutically acceptable carrier.
25 . A pharmaceutical composition, comprising
(a) the recombinant expression vector of claim 21 ; and (b) a pharmaceutically acceptable carrier.
26 . A pharmaceutical composition, comprising
(a) the recombinant host cell of claim 23 ; and (b) a pharmaceutically acceptable carrier.
27 . A method for identifying candidate compounds for treating a tumor, comprising
(a) contacting tumor cells capable of expressing QSOX1 with one or more candidate compounds under conditions suitable for expression of QSOX1; and (b) determining a level of QSOX1 expression and/or activity in the tumor cells and comparing to control; wherein a compound that decreases QSOX1 expression and/or activity in the tumor cells relative to control is a candidate compound for treating a tumor.
28 . The method of claim 27 wherein the tumor cells are pancreatic tumor cells or breast tumor cells.
29 . A method for prognosing a tumor, comprising
(a) determining a QSOX1 expression level in a sample from a subject having a tumor; (b) comparing the QSOX1 expression level to control; and (c) prognosing the progression of the tumor in the subject.
30 . The method of claim 29 , wherein the tumor is a pancreatic tumor.
31 . The method of claim 29 wherein the tumor is a breast tumor.
32 . The method of claim 31 wherein the breast tumor is an ER+ breast tumor or a Luminal B breast tumor.
33 . The method of claim 29 , wherein the determining comprises determining a QSOX1 protein expression level.Cited by (0)
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