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Qsox1 as an Anti-neoplastic drug target

a technology of antineoplastic drugs and qsox1, which is applied in the direction of antibody medical ingredients, peptide/protein ingredients, instruments, etc., can solve problems such as unresectable tumors, and achieve the effect of limiting tumor metastasis

Inactive Publication Date: 2016-05-05
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for treating tumors by administering an inhibitor of quiescin sulfhydryl oxidase 1 (QSOX1) expression and / or activity. The inhibitor can be an anti-QSOX1 antibody, QSOX1-binding aptamer, QSOX1 antisense oligonucleotide, QSOX1 siRNA, or QSOX1 shRNA. The method is effective in treating tumors that over-express QSOX1. It has also been found to limit tumor metastasis, particularly in pancreatic tumors.

Problems solved by technology

It is often detected in stage III resulting in an unresectable tumor at the time of diagnosis.

Method used

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  • Qsox1 as an Anti-neoplastic drug target
  • Qsox1 as an Anti-neoplastic drug target
  • Qsox1 as an Anti-neoplastic drug target

Examples

Experimental program
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example 1

REFERENCES FOR EXAMPLE 1

[0145]1. Bardeesy N, DePinho R A. Pancreatic cancer biology and genetics. Nature Publishing Group 2002; 12:897-909.[0146]2. Koshiba T, Hosotani R, Wada M, Miyamoto Y, Fujimoto K, Lee J U, et al.[0147]Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer; 1998. p. 642-50.[0148]3. Strimpakos A, Saif M W, Syrigos K N. Pancreatic cancer: from molecular pathogenesis to targeted therapy. Cancer Metastasis Rev 2008; 3:495-522.[0149]4. Antwi K, Hostetter G, Demeure M J, Katchman B A, Decker G A, Ruiz Y, et al. Analysis of the plasma peptidome from pancreas cancer patients connects a peptide in plasma to overexpression of the parent protein in tumors. J Proteome Res 2009; 10:4722-31.[0150]5. Coppock D L, Cina-Poppe D, Gilleran S. The quiescin Q6 gene (QSCN6) is a fusion of two ancient gene families: thioredoxin and ERV1. Genomics 1998; 3:460-8.[0151]6. Coppock D. Regulation of the Quiescence-Induced Genes: Quiesc...

example 2

[0179]We designed two short hairpin RNAs (shRNA1 and shRHA2) to knock-down QSOX1 protein expression in tumor cells.

shRNA1 - Targeting QSOX1 sequence beginsat the 970th base pair -(SEQ ID NO: 17)ATCTACATGGCTGACCTGGAAshRNA2 - Targeting QSOX1 sequence beginsat the 1207th base pair -(SEQ ID NO: 18)AGGAAAGAGGGTGCCGTTCTT

[0180]QSOX1 shRNA1 hybridizes with nucleotides 970-989 of the QSOX1 transcript. QSOX1 shRNA2 hybridizes to nucleotides 1207-1226 of the transcript. Both shRNAs, independently and together suppressed the production of QSOX1 protein (data not shown) and cell proliferation. Upon cloning the QSOX1 shRNA into a eukaryotic expression vector (pCS2 mammalian overexpression vector with a CMV promoter) and using it to transfect a pancreatic tumor cell line (BxPC-3), a 30-40% decrease in cell viability was observed, over a 4 to 6 day period, compared to untreated and scrambled shRNA controls. (FIG. 6) Using the same transfection protocol in a separate experiment, we made an additiona...

example 3

[0183]MIAPaCa2 and Panc-1 pancreatic tumor cells were transduced with shRNA that specifically knocked down QSOX1 protein in the tumor cells. The shRNAs used to knockdown QSOX1 in tumor cells were

QSOX1 sh742(SEQ ID NO: 26)(5′-CCGGGCCAATGTGGTGAGAAAGTTTCTCGAGAAACTTTCTCACCACATTGGCTTTTTG-3′)andshRNA QSOX1 sh528(SEQ ID NO: 21)5′-CCGGACAATGAAGAAGCCTTT-3′ (sense),

Nude mice Human pancreatic tumor cells (MIAPaCa2) were transduced with a lentivirus encoding shQSOX1 (sh528 and sh742) and shScramble (control). One million MIAPaCa2 cells were mixed with Matrigel™ and used to inoculate nude mice (5 mice / group) on day 0. After day 12, tumor growth was measured every 3 days (x-axis) and reported as “Tumor volume” on the Y-axis. “Untreated” indicates that tumor cells were not transduced. (see FIGS. 8 and 9). This in vivo experiment thus validates QSOX1 as a potential target for anti-neoplastic drugs. Any other type of inhibitor of QSOX1 expression or function would have a similar effect on tumor cell...

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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.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 169,612 filed on Jan. 31, 2014, which is a continuation-in-part (CIP) of U.S. patent application Ser. No. 13 / 847,930 filed on Mar. 20, 2013, now U.S. Pat. No. 8,946,186, which claims the benefit of priority under 35 USC §119(e) of U.S. Provisional Patent Application No. 61 / 722,396 filed on Nov. 5, 2012, and is a continuation-in-part (CIP) of PCT Patent Application No. PCT / US2011 / 052122 filed on Sep. 19, 2011, which claims the benefit of priority under 35 USC §119(e) of U.S. Provisional Patent Application No. 61 / 384,502 filed on Sep. 20, 2010. The contents of the above applications are all incorporated by reference as if fully set forth herein in their entirety.BACKGROUND[0002]Pancreatic ductal adenocarcinoma (PDA) is a disease that carries a poor prognosis. It is often detected in stage III resulting in an unresectable tumor at the time of diagnosis. However, even if pancreatic cancer...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113
CPCC12N15/1137C12N2310/531C12N2310/14C12N2320/30C12Y108/03002A61K38/44C07K16/40C12Q1/26G01N33/5008C12N15/1135C12N2310/11C12Q1/6886C12Q2600/118C12Q2600/158G01N33/5011A61K39/3955A61K39/39558A61K2121/00
Inventor LAKE, DOUGLASKATCHMAN, BENJAMINFASS, DEBORAH
Owner YEDA RES & DEV CO LTD
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