{"id":3629,"date":"2024-09-01T09:51:33","date_gmt":"2024-09-01T00:51:33","guid":{"rendered":"https:\/\/plaza.umin.ac.jp\/~OIO\/?p=3629"},"modified":"2024-09-14T16:09:54","modified_gmt":"2024-09-14T07:09:54","slug":"what-are-the-molecular-targeted-drugs-for-cancers-with-brca1-and-brca2-gene-mutations","status":"publish","type":"post","link":"https:\/\/plaza.umin.ac.jp\/~OIO\/?p=3629","title":{"rendered":"What are the molecular targeted drugs for cancers with BRCA1 and BRCA2 gene mutations?"},"content":{"rendered":"\n

What are the molecular targeted drugs for cancers with BRCA1 and BRCA2 gene mutations?<\/p>\n\n\n\n

BRCA1\u304a\u3088\u3073BRCA2\u907a\u4f1d\u5b50\u5909\u7570\u3092\u6301\u3064\u304c\u3093\u306b\u5bfe\u3059\u308b\u5206\u5b50\u6a19\u7684\u85ac\u3067\u6ce8\u76ee\u3055\u308c\u3066\u3044\u308b\u306e\u306fPARP\u963b\u5bb3\u5264\uff08PARPi\uff09\u3067\u3059\u3002\u73fe\u5728\u3001FDA\u306b\u627f\u8a8d\u3055\u308c\u3066\u3044\u308bPARPi\u306f4\u7a2e\u985e\u3042\u308a\u3001\u3053\u308c\u3089\u306fBRCA1\/2\u6b20\u640d\u304c\u3093\u306e\u6cbb\u7642\u306b\u5229\u7528\u3055\u308c\u3066\u3044\u307e\u3059\uff08Ragupathi et al., 2023\uff09\u3002<\/p>\n\n\n\n

\u6700\u521d\u306b\u627f\u8a8d\u3055\u308c\u305fPARPi\u3067\u3042\u308b\u30aa\u30e9\u30d1\u30ea\u30d6\u306f\u3001BRCA\u5909\u7570\u3092\u6301\u3064\u5375\u5de3\u304c\u3093\u60a3\u8005\u306e\u6cbb\u7642\u306b\u304a\u3044\u3066\u975e\u5e38\u306b\u6709\u671b\u306a\u7d50\u679c\u3092\u793a\u3057\u3066\u3044\u307e\u3059\uff08Venkitaraman, 2009; Tangutoori et al., 2015\uff09\u3002PARPi\u306f\u3001\u304c\u3093\u7d30\u80de\u306e\u30b2\u30ce\u30e0\u4e0d\u5b89\u5b9a\u6027\u3092\u5229\u7528\u3057\u3066DNA\u640d\u50b7\u5fdc\u7b54\u3092\u6a19\u7684\u3068\u3057\u3001\u5f93\u6765\u306e\u5316\u5b66\u7642\u6cd5\u3068\u6bd4\u8f03\u3057\u3066\u3088\u308a\u816b\u760d\u7d30\u80de\u9078\u629e\u7684\u306a\u30a2\u30d7\u30ed\u30fc\u30c1\u3092\u63d0\u4f9b\u3057\u307e\u3059\uff08O\u2019Connor, 2015\uff09\u3002<\/p>\n\n\n\n

PARPi\u306e\u7d30\u80de\u6bd2\u6027\u306f\u3001BRCA1\/2\u5909\u7570\u816b\u760d\u306e\u8907\u88fd\u304c\u56f0\u96e3\u306a\u30b2\u30ce\u30e0\u9818\u57df\u306b\u904e\u5270\u306a\u8907\u88fd\u30b9\u30c8\u30ec\u30b9\u3092\u8a98\u5c0e\u3059\u308b\u3053\u3068\u306b\u3088\u308b\u3068\u8003\u3048\u3089\u308c\u3066\u3044\u307e\u3059\uff08Ragupathi et al., 2023\uff09\u3002\u73fe\u5728\u9032\u884c\u4e2d\u306e\u7814\u7a76\u3067\u306f\u3001PARPi\u3068\u514d\u75ab\u30c1\u30a7\u30c3\u30af\u30dd\u30a4\u30f3\u30c8\u963b\u5bb3\u85ac\u3092\u7d44\u307f\u5408\u308f\u305b\u3066\u81e8\u5e8a\u7d50\u679c\u3092\u5411\u4e0a\u3055\u305b\u308b\u65b9\u6cd5\u304c\u63a2\u6c42\u3055\u308c\u3066\u3044\u307e\u3059\uff08Ragupathi et al., 2023\uff09\u3002\u3055\u3089\u306b\u3001PARPi\u306f\u4ed6\u306e\u3055\u307e\u3056\u307e\u306a\u304c\u3093\u30bf\u30a4\u30d7\u306b\u5bfe\u3057\u3066\u3082\u3001\u5358\u72ec\u7642\u6cd5\u304a\u3088\u3073\u4ed6\u306e\u6cbb\u7642\u6cd5\u3068\u306e\u4f75\u7528\u7642\u6cd5\u3068\u3057\u3066\u306e\u5229\u7528\u304c\u691c\u8a0e\u3055\u308c\u3066\u3044\u307e\u3059\uff08Tangutoori et al., 2015\uff09\u3002<\/p>\n\n\n\n

\u3053\u306e\u3088\u3046\u306b\u3001PARP\u963b\u5bb3\u5264\u306fBRCA1\/2\u907a\u4f1d\u5b50\u5909\u7570\u3092\u6301\u3064\u304c\u3093\u60a3\u8005\u306b\u3068\u3063\u3066\u65b0\u305f\u306a\u5e0c\u671b\u3068\u306a\u308b\u6cbb\u7642\u6cd5\u3067\u3042\u308a\u3001\u4eca\u5f8c\u306e\u7814\u7a76\u3068\u81e8\u5e8a\u5fdc\u7528\u304c\u671f\u5f85\u3055\u308c\u3066\u3044\u307e\u3059\u3002<\/p>\n\n\n\n

Molecular targeted drugs for cancers with BRCA1 and BRCA2 gene mutations primarily focus on PARP inhibitors (PARPi). Four FDA-approved PARPi are currently available for treating BRCA1\/2-deficient cancers (Ragupathi et al., 2023). Olaparib, the first approved PARPi, has shown promise in treating ovarian cancer patients with BRCA mutations (Venkitaraman, 2009; Tangutoori et al., 2015). PARPi exploit the genomic instability of cancer cells by targeting the DNA damage response, offering a more selective approach compared to traditional chemotherapy (O’Connor, 2015). The cytotoxic effect of PARPi is believed to result from inducing excessive replication stress in difficult-to-replicate genomic regions of BRCA1\/2 mutated tumors (Ragupathi et al., 2023). Ongoing research explores combining PARPi with immuno-oncology drugs to enhance clinical outcomes (Ragupathi et al., 2023). Additionally, PARPi are being investigated for use in various other cancer types, both as monotherapies and in combination with other treatments (Tangutoori et al., 2015).<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

O\u2019Connor, M. J. (2015). Targeting the DNA Damage Response in Cancer<\/em>. 60<\/em>(4), 547\u2013560. https:\/\/doi.org\/10.1016\/j.molcel.2015.10.040<\/a><\/p>\n\n\n\n

Ragupathi, A., Singh, M., Perez, A. M., & Zhang, D. (2023). Targeting the BRCA1\/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights<\/em>. 11<\/em>, 1133472. https:\/\/doi.org\/10.3389\/fcell.2023.1133472<\/a><\/p>\n\n\n\n

Tangutoori, S., Baldwin, P., & Sridhar, S. (2015). PARP inhibitors: A new era of targeted therapy<\/em>. 81<\/em>(1), 5\u20139. https:\/\/doi.org\/10.1016\/j.maturitas.2015.01.015<\/a><\/p>\n\n\n\n

Venkitaraman, A. R. (2009). Targeting the molecular defect in BRCA-deficient tumors for cancer therapy<\/em>. 16<\/em>(2), 89\u201390. https:\/\/doi.org\/10.1016\/j.ccr.2009.07.011<\/a><\/p>\n\n\n\n

\u56f3\u306e\u89e3\u8aac\uff1aPARP\uff08\u30dd\u30ea\uff08ADP-\u30ea\u30dc\u30fc\u30b9\uff09\u30dd\u30ea\u30e1\u30e9\u30fc\u30bc\uff09\u306f\u3001\u4e3b\u306b\u4e00\u91cd\u9396DNA\u5207\u65ad\uff08single-strand breaks, SSB\uff09\u306e\u4fee\u5fa9\u306b\u95a2\u4e0e\u3057\u3066\u3044\u307e\u3059\u3002\u5177\u4f53\u7684\u306b\u306f\u3001\u4ee5\u4e0b\u306e\u3088\u3046\u306aDNA\u30c0\u30e1\u30fc\u30b8\u3092\u4fee\u5fa9\u3057\u307e\u3059\uff1a<\/p>\n\n\n\n

    \n
  1. \u4e00\u91cd\u9396\u5207\u65ad\uff08SSB<\/strong>\uff09<\/strong>: DNA\u306e\u7247\u65b9\u306e\u9396\u304c\u5207\u65ad\u3055\u308c\u308b\u640d\u50b7\u3067\u3059\u3002PARP\u306f\u3053\u306e\u640d\u50b7\u3092\u691c\u51fa\u3057\u3001\u4fee\u5fa9\u30d7\u30ed\u30bb\u30b9\u3092\u958b\u59cb\u3057\u307e\u3059\u3002<\/li>\n\n\n\n
  2. \u5869\u57fa\u9664\u53bb\u4fee\u5fa9\uff08BER<\/strong>\uff09<\/strong>: DNA\u306e\u5869\u57fa\u304c\u640d\u50b7\u3092\u53d7\u3051\u305f\u5834\u5408\u3001PARP\u306f\u3053\u306e\u4fee\u5fa9\u7d4c\u8def\u306b\u95a2\u4e0e\u3057\u3001\u640d\u50b7\u3057\u305f\u5869\u57fa\u3092\u9664\u53bb\u3057\u3001\u65b0\u3057\u3044\u5869\u57fa\u3092\u633f\u5165\u3059\u308b\u30d7\u30ed\u30bb\u30b9\u3092\u52a9\u3051\u307e\u3059\u3002<\/li>\n<\/ol>\n\n\n\n

    PARP\u306f\u3001\u3053\u308c\u3089\u306e\u640d\u50b7\u3092\u4fee\u5fa9\u3059\u308b\u3053\u3068\u3067\u3001\u7d30\u80de\u306e\u30b2\u30ce\u30e0\u5b89\u5b9a\u6027\u3092\u7dad\u6301\u3057\u3001\u7d30\u80de\u306e\u751f\u5b58\u3092\u52a9\u3051\u307e\u3059\u3002\u3057\u304b\u3057\u3001BRCA1\u3084BRCA2\u907a\u4f1d\u5b50\u306b\u5909\u7570\u304c\u3042\u308b\u5834\u5408\u3001\u3053\u308c\u3089\u306e\u4fee\u5fa9\u7d4c\u8def\u304c\u6b63\u5e38\u306b\u6a5f\u80fd\u3057\u306a\u3044\u305f\u3081\u3001PARP\u963b\u5bb3\u5264\uff08PARPi\uff09\u306f\u3053\u308c\u3089\u306e\u304c\u3093\u7d30\u80de\u306b\u5bfe\u3057\u3066\u7279\u306b\u52b9\u679c\u7684\u3067\u3059\u3002PARPi\u306fPARP\u306e\u6a5f\u80fd\u3092\u963b\u5bb3\u3059\u308b\u3053\u3068\u3067\u3001\u304c\u3093\u7d30\u80de\u306b\u84c4\u7a4d\u3059\u308bDNA\u640d\u50b7\u3092\u5897\u52a0\u3055\u305b\u3001\u6700\u7d42\u7684\u306b\u304c\u3093\u7d30\u80de\u306e\u6b7b\u3092\u8a98\u5c0e\u3057\u307e\u3059\u3002<\/p>\n\n\n\n

    \"\"<\/figure>\n\n\n\n

    PARP\u5206\u5b50\u3068\u3001Olaparib\u306e\u7d50\u5408\u3092\u7d50\u6676\u69cb\u9020<\/a>\u3067\u773a\u3081\u3066\u307f\u307e\u3057\u305f\u3002\u3053\u306e\u69cb\u9020\u3060\u3068\u3001PARP\u305f\u3093\u3071\u304f\u8cea\u306b\u7d50\u5408\u3057\u305fOlaparib\u306f\u5206\u5b50\u306e\u4e2d\u306b\u6df1\u304f\u57cb\u3082\u308c\u3066\u3044\u308b\u3088\u3046\u306b\u898b\u3048\u307e\u3059\u3002\uff08\u7d50\u5408\u3057\u305f\u5f8c\u306b\u305f\u3093\u3071\u304f\u8cea\u306e\u69cb\u9020\u5909\u5316\u304c\u8d77\u304d\u308b\uff1f\uff09\u7dd1\u8272\u306e\u5206\u5b50\u304colaparib\u3067\u3001\u305d\u308c\u4ee5\u5916\u304c human PARP\u306ecatalytic domain\u3002\u4e0b\u56f3\u306f\u4e0b\u8a18\u6587\u732e\u306e\u30c7\u30fc\u30bf\u3092\u57fa\u306b\u308f\u305f\u304f\u3057\u304c\u4f5c\u56f3\u3057\u307e\u3057\u305f\u3002<\/p>\n\n\n\n

    \"\"<\/figure>\n\n\n\n

    Ogden, T. E. H., Yang, J.-C., Schimpl, M., Easton, L. E., Underwood, E., Rawlins, P. B., McCauley, M. M., Langelier, M.-F., Pascal, J. M., Embrey, K. J., & Neuhaus, D. (2021). Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition<\/em>. 49<\/em>(4), 2266\u20132288.
    https:\/\/doi.org\/10.1093\/nar\/gkab020<\/p>\n\n\n\n

    <\/p>\n\n\n\n

    <\/p>\n","protected":false},"excerpt":{"rendered":"

    What are the molecular targeted drugs for cancers with BRCA1 and BRCA2 gene mutations? BRCA1\u304a\u3088\u3073BRCA2\u907a\u4f1d\u5b50\u5909\u7570\u3092\u6301\u3064\u304c\u3093…<\/p>\n","protected":false},"author":5,"featured_media":3631,"comment_status":"open","ping_status":"open","sticky":true,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[4],"tags":[],"class_list":["post-3629","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science"],"jetpack_featured_media_url":"https:\/\/plaza.umin.ac.jp\/~OIO\/wp-content\/uploads\/2024\/09\/66c19942ab4ba346fdb64ccc04cde373-1.jpg","jetpack_shortlink":"https:\/\/wp.me\/p9b6zl-Wx","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/posts\/3629","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3629"}],"version-history":[{"count":4,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/posts\/3629\/revisions"}],"predecessor-version":[{"id":3640,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/posts\/3629\/revisions\/3640"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=\/wp\/v2\/media\/3631"}],"wp:attachment":[{"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3629"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3629"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/plaza.umin.ac.jp\/~OIO\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3629"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}