{"id":1513,"date":"2020-05-14T09:01:31","date_gmt":"2020-05-14T00:01:31","guid":{"rendered":"https:\/\/bionauts.jp\/?p=1513"},"modified":"2025-01-21T17:18:04","modified_gmt":"2025-01-21T08:18:04","slug":"antisense-oligonucleotide-therapy-for-liver-cancer","status":"publish","type":"post","link":"https:\/\/bionauts.jp\/?p=1513","title":{"rendered":"ASO Therapy for Solid Tumors"},"content":{"rendered":"<h3><span style=\"color: #008080;\">Abstract<\/span><\/h3>\n<ul style=\"list-style-type: square;\">\n<li>GREB1 is one of the key regulators of cell proliferation and has been shown experimentally to be an effective therapeutic target for malignant melanoma and hepatoblastoma.<\/li>\n<li>Arl4c is overexpressed in several solid tumors and has been detected as an important factor in cancer cell motility, invasion, and proliferation, confirming that treatment with ASO targeting <em>ARL4C<\/em> gene is effective against lung adenocarcinoma and pancreatic cancer as well as liver metastatic foci of colon cancer.<\/li>\n<\/ul>\n<h3><span style=\"color: #008080;\">Advantages<\/span><\/h3>\n<ul style=\"list-style-type: square;\">\n<li>ASOs targeting <em>GREB1<\/em> or <em>ARL4C<\/em> genes can reduce and inhibit tumor growth.<\/li>\n<li>Combined with tumor lesion integration techniques and effective nuclear delivery techniques, the effectiveness of these ASOs can be further enhanced.<\/li>\n<\/ul>\n<h3><span style=\"color: #008080;\">Technology Overview &amp;\u00a0Background<\/span><\/h3>\n<p>Researchers focus on comprehensively understanding the molecular mechanisms of Wnt signaling, regulated with other pathways such as TGF-\u03b2, EGF, and Hedgehog signaling.<\/p>\n<p><strong><u>1. GREB1 (Growth Regulating Estrogen Receptor Binding 1) <\/u><\/strong><\/p>\n<p>Hepatoblastoma is a rare form of liver cancer, affecting just a few individuals per million, it is the leading cause of liver cancer in infants and young children. Researchers identified GREB1 as an unknown target gene for Wnt\/\u03b2-catenin signaling. Analysis of publicly available data sets showed that GREB1 was overexpressed in tumor lesions in more than 90% of hepatoblastoma tissues. The region-specific expression pattern of GREB1 in hepatoblastoma tended to be positively correlated with the accumulation of \u03b2-catenin.<\/p>\n<p>Overexpression in other tumor patients was also identified in the dataset, and more recently, their team found that one isoform of GREB1 is specifically expressed in melanocytic melanoma.<\/p>\n<p><strong><u>2. Arl4c (ADP-ribosylation factor-like 4c) <\/u><\/strong><\/p>\n<p>Arl4c was identified as a small molecule GTP-binding protein, which is expressed by Wnt and EGF signaling, plays an important role in tubulogenesis of cultured cells and the ureters.<\/p>\n<p>Researchers of this project found that expression of the mRNA of <em>ARL4C<\/em> is highly expressed in some tumor lesions, for example, colon cancer and lung adenocarcinomas, where genetic alterations of Wnt\/\u03b2-catenin and EGF\/Ras pathways are frequently observed, and Arl4c expression promoted migration, invasion, and proliferation of cancer cells both <em>in vitro<\/em> and <em>in vivo<\/em>. Immunohistochemical analysis showed that Arl4c was not observed in non-tumor regions, however, Arl4c is overexpressed in tumor lesions in 70-80% of lung and tongue squamous cell carcinoma.<\/p>\n<h3><span style=\"color: #008080;\">Data \/ Methods<\/span><\/h3>\n<p>Researchers investigated the suppressing tumor formation effect and inhibiting growth effect <em>in vivo<\/em> study using <em>GREB1<\/em>&#8211; and <em>ARL4C<\/em>-targeted AmNA-modified ASOs.<br \/>\n* AmNA-modified ASOs: In these projects, Amido-bridged nucleic acid (AmNA) was used to improve nuclease resistance and decrease hepatotoxicity.<\/p>\n<ul>\n<li>The therapeutic effect of <em>GREB1<\/em> ASO was investigated by implantation of HepG2 cells into the liver of nude mice. In ASO treated mice, suppressed tumor formation compared with control.<br \/>\nSee Fig. (a).<\/li>\n<li>The therapeutic effect of <em>ARL4C<\/em> ASO was investigated by metastatic colorectal cancer in the liver (implantation of HCT116 cells into spleen). <em>ARL4C<\/em> ASO inhibited the growth of tumor.<br \/>\nSee Fig. (b).<\/li>\n<\/ul>\n<p><a href=\"http:\/\/bionauts.jp\/wp-content\/uploads\/2020\/05\/0513.png\"><img decoding=\"async\" loading=\"lazy\" class=\"aligncenter size-full wp-image-1515\" src=\"http:\/\/bionauts.jp\/wp-content\/uploads\/2020\/05\/0513.png\" alt=\"\" width=\"826\" height=\"232\" srcset=\"https:\/\/bionauts.jp\/wp-content\/uploads\/2020\/05\/0513.png 826w, https:\/\/bionauts.jp\/wp-content\/uploads\/2020\/05\/0513-300x84.png 300w, https:\/\/bionauts.jp\/wp-content\/uploads\/2020\/05\/0513-768x216.png 768w\" sizes=\"(max-width: 709px) 85vw, (max-width: 909px) 67vw, (max-width: 984px) 61vw, (max-width: 1362px) 45vw, 600px\" \/><\/a><\/p>\n<p>For more detailed data and more experiments on the effects on other solid tumors, see related papers below.<\/p>\n<h3><span style=\"color: #008080;\">Publications<\/span><\/h3>\n<p><strong>GREB1 Project:\u00a0<\/strong><\/p>\n<ul>\n<li>Matsumoto S, <i>et al., Nat <\/i><i>Commun<\/i><i>.<\/i> (2019) 10(1):3882.<\/li>\n<li>Matsumoto S, <i>et al., Cancer Res.<\/i> (2023) 83(14):2312-2327.\u00a0 <span style=\"color: #3366ff;\"># hepatocellular carcinoma<\/span><\/li>\n<li>Shinzawa K, <i>et al., Oncogene.<\/i> (2023) 42(42):3142-3156.\u00a0 <span style=\"color: #3366ff;\"># melanoma<\/span><\/li>\n<\/ul>\n<p><strong>Alr4c Project:\u00a0<\/strong><\/p>\n<ul>\n<li>Matsumoto S, <i>et al.<\/i>, <i>EMBO J.<\/i> (2014) 33(7):702-718.<\/li>\n<li>Fujii S, <i>et al.<\/i>, <i>Oncogene<\/i> (2015) 34, 4834-4844.<\/li>\n<li>Matsumoto S, <i>et al.<\/i>, <i>J <\/i><i>Biochem<\/i><i>.<\/i> (2017) 161(1):27-35.<\/li>\n<li>Harada T, <i>et al.<\/i>, <i>Mol Cancer <\/i><i>Ther<\/i><i>.<\/i> (2019) 18(3):602-612.\u00a0 <span style=\"color: #3366ff;\"># liver tumor<\/span><\/li>\n<li>Kimura K, <i>et al.<\/i>, <i>Cancer Sci.<\/i> (2020) 111(3):951-961.\u00a0 <span style=\"color: #3366ff;\"># lung adenocarcinoma<\/span><\/li>\n<li>Harada A, <i>et al.<\/i>, <i>eLife<\/i> (2021) 10:e66721.\u00a0 <span style=\"color: #3366ff;\"># pancreatic cancer<\/span><\/li>\n<\/ul>\n<h3><span style=\"color: #008080;\">Patents<\/span><\/h3>\n<p><strong>GREB1 Project:\u00a0<\/strong><\/p>\n<p>PCT\/JP2020\/020274<br \/>\n\u2192 <b>Japan<\/b> (pend.) pub. # JPWO2020\/235671(A1)<br \/>\n\u2192 <b>U.S.<\/b> (Granted) pub. # US2022\/0249538(A1)<\/p>\n<p><strong>Arl4c Project:\u00a0<\/strong><\/p>\n<p>PCT\/JP2019\/034746<br \/>\n\u2192 <b>EPO<\/b> (pend.) pub. # EP3848460(A4)<br \/>\n\u2192 <b>Japan<\/b> (Issued) pub. # JP7396577(B2)<br \/>\n\u2192 <b>U.S.<\/b> (Issued) pub. # US12,071,624(B1)<\/p>\n<h3><span style=\"color: #008080;\">Principal Investigator<\/span><\/h3>\n<p>Akira Kikuchi, MD, PhD<br \/>\nSpecially Appointed Professor, CiDER, The University of Osaka (Japan)<\/p>\n<h3><span style=\"color: #008080;\">Expectations<\/span><\/h3>\n<p>Tech Manage\u00a0is now looking for companies to collaborate with the PI and develop this technology further under the licensing of the related patent(s) described above.\u00a0You can also consider joint research using the invention, providing know-how under a confidentiality agreement (CDA), or setting up evaluation or licensing options for a certain period.<\/p>\n<p>&nbsp;<\/p>\n<p>Project IDs: JT-01084 (Arl4c) &amp; JT-02374 (GREB1)<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Antisense oligonucleotide (ASO) therapy for two independent targets, GREB1 and ARL4C genes.<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0},"categories":[1],"tags":[],"categories_of_inventions":[46],"disease_categories___indication":[61],"asset_type":[73],"development_phase":[],"medicine":[105,108],"other_than_medicine":[],"material":[],"engineering":[],"software_it":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/1513"}],"collection":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1513"}],"version-history":[{"count":10,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/1513\/revisions"}],"predecessor-version":[{"id":4176,"href":"https:\/\/bionauts.jp\/index.php?rest_route=\/wp\/v2\/posts\/1513\/revisions\/4176"}],"wp:attachment":[{"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1513"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1513"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1513"},{"taxonomy":"categories_of_inventions","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories_of_inventions&post=1513"},{"taxonomy":"disease_categories___indication","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fdisease_categories___indication&post=1513"},{"taxonomy":"asset_type","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fasset_type&post=1513"},{"taxonomy":"development_phase","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fdevelopment_phase&post=1513"},{"taxonomy":"medicine","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmedicine&post=1513"},{"taxonomy":"other_than_medicine","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fother_than_medicine&post=1513"},{"taxonomy":"material","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fmaterial&post=1513"},{"taxonomy":"engineering","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fengineering&post=1513"},{"taxonomy":"software_it","embeddable":true,"href":"https:\/\/bionauts.jp\/index.php?rest_route=%2Fwp%2Fv2%2Fsoftware_it&post=1513"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}