{"id":59510,"date":"2025-09-11T10:46:20","date_gmt":"2025-09-11T08:46:20","guid":{"rendered":"https:\/\/www.oncomed.cz\/?post_type=studies&p=59510"},"modified":"2025-09-11T10:46:22","modified_gmt":"2025-09-11T08:46:22","slug":"projekt-nadina-od-preklinickych-dat-az-k-vyrobe-klinicke-sarze","status":"publish","type":"studies","link":"https:\/\/www.oncomed.cz\/cs\/blog\/projekt-nadina-od-preklinickych-dat-az-k-vyrobe-klinicke-sarze\/","title":{"rendered":"Projekt NaDiNa: Od preklinick\u00fdch dat a\u017e k v\u00fdrob\u011b klinick\u00e9 \u0161ar\u017ee"},"content":{"rendered":"
\n

V r\u00e1mci medac CDMO jsme \u00fasp\u011b\u0161n\u011b dokon\u010dili projekt NaDiNa, jeho\u017e hlavn\u00edm c\u00edlem bylo vyvinout formulaci, v\u00fdrobn\u00ed proces a p\u0159ipravit prototyp nov\u00e9ho protin\u00e1dorov\u00e9ho l\u00e9\u010diva do f\u00e1ze umo\u017e\u0148uj\u00edc\u00ed jeho klinick\u00e9 hodnocen\u00ed. Projekt prob\u00edhal v \u00fazk\u00e9 spolupr\u00e1ci s L\u00e9ka\u0159skou fakultou Univerzity Palack\u00e9ho v Olomouci (UPOL) za finan\u010dn\u00ed podpory Technologick\u00e9 agentury \u010cR (TA\u010cR).<\/p>\n

L\u00e9\u010div\u00fd p\u0159\u00edpravek NaDiNa<\/strong>
\nL\u00e9\u010div\u00fd p\u0159\u00edpravek NaDiNa je protin\u00e1dorov\u00fd prost\u0159edek zalo\u017een\u00fd na nanoformulaci m\u011b\u010fnat\u00e9 soli diethyldithiokarbam\u00e1tu (CuET) s vyu\u017eit\u00edm albuminu jako nosi\u010de. P\u0159\u00edpravek byl vyvinut v\u011bdci UPOLu pro intraven\u00f3zn\u00ed pod\u00e1n\u00ed a c\u00edlenou l\u00e9\u010dbu solidn\u00edch n\u00e1dor\u016f a hematologick\u00fdch malignit. Mechanismus \u00fa\u010dinku spo\u010d\u00edv\u00e1 ve specifick\u00e9 vazb\u011b CuET na protein NPL4, co\u017e vyvol\u00e1v\u00e1 proteotoxick\u00fd stres a vede k bun\u011b\u010dn\u00e9 smrti n\u00e1dorov\u00fdch bun\u011bk. V\u00fdsledky tohoto dlouholet\u00e9ho v\u00fdzkumu byly publikov\u00e1ny v presti\u017en\u00edm v\u011bdeck\u00e9m \u010dasopise Nature (14. prosince 2017, ro\u010dn\u00edk 552, \u010d\u00edslo 7684, s. 194\u2013199).<\/p>\n

Pr\u016fb\u011bh a v\u00fdsledky projektu<\/strong>
\nProjekt m\u011bl dva hlavn\u00ed sm\u011bry. Na\u0161e spole\u010dnost se zam\u011b\u0159ila na industri\u00e1ln\u00ed v\u00fdvoj l\u00e9kov\u00e9 formy v regulovan\u00e9m re\u017eimu SVP, zat\u00edmco UPOL prov\u00e1d\u011bl preklinick\u00e9 testov\u00e1n\u00ed l\u00e9\u010diva.<\/p>\n

V\u00fdvoj veden\u00fd \u00dastavem molekul\u00e1rn\u00ed a transla\u010dn\u00ed medic\u00edny (\u00daMTM) L\u00e9ka\u0159sk\u00e9 fakulty UPOL zahrnoval optimalizaci nano\u010d\u00e1sticov\u00e9 formulace a testy stabilit v infuzn\u00edm roztoku. V r\u00e1mci preklinick\u00fdch studi\u00ed byly hodnoceny farmakokinetika, toxicita a \u00fa\u010dinnost na n\u00e1dorov\u00fdch in vivo modelech. Krom\u011b toho byla vypracov\u00e1na SLP certifikovan\u00e1 metoda pro stanoven\u00ed CuET v biologick\u00e9m materi\u00e1lu. <\/p>\n

Experiment\u00e1ln\u00ed data in vitro potvrzuj\u00ed selektivn\u00ed cytotoxick\u00fd \u00fa\u010dinek v\u016f\u010di n\u00e1dorov\u00fdm bu\u0148k\u00e1m v\u010detn\u011b bun\u011bk rezistentn\u00edch na konven\u010dn\u00ed chemoterapii. L\u00e9\u010divo tedy reprezentuje slibn\u00e9ho kandid\u00e1ta pro dal\u0161\u00ed preklinick\u00e9 a klinick\u00e9 hodnocen\u00ed v onkologii.<\/p>\n

V\u00fdznamn\u00fdm \u00fasp\u011bchem je tak\u00e9 ud\u011blen\u00ed n\u011bkolika n\u00e1rodn\u00edch patent\u016f pokr\u00fdvaj\u00edc\u00ed n\u00e1roky na p\u0159\u00edpravu albumin-CuET nano\u010d\u00e1stic, a to i v USA.<\/p>\n

K nejd\u016fle\u017eit\u011bj\u0161\u00edm v\u00fdstup\u016fm na stran\u011b oncomedu pat\u0159\u00ed nejen v\u00fdvoj formulace a optimalizace v\u00fdrobn\u00edho postupu dan\u00e9ho l\u00e9\u010diva, ale zejm\u00e9na v\u00fdroba klinick\u00e9 \u0161ar\u017ee CuET v\u010detn\u011b kompletn\u00ed dokumentace umo\u017e\u0148uj\u00edc\u00ed jej\u00ed pou\u017eit\u00ed pro f\u00e1zi I klinick\u00e9ho hodnocen\u00ed. Ned\u00edlnou sou\u010d\u00e1st\u00ed projektu byl i v\u00fdvoj a zaveden\u00ed metod nezbytn\u00fdch pro analytick\u00e9 testov\u00e1n\u00ed vyroben\u00e9 \u0161ar\u017ee, p\u0159\u00edprava v\u00fdrobn\u00ed a technick\u00e9 dokumentace, kter\u00e1 zaji\u0161\u0165uje reprodukovatelnou v\u00fdrobu a vyu\u017eit\u00ed v dal\u0161\u00edm klinick\u00e9m v\u00fdvoji i smluvn\u00ed v\u00fdrob\u011b.<\/p>\n

Ofici\u00e1ln\u00ed schv\u00e1len\u00ed<\/strong>
\nProjekt byl dne 8. \u010dervence 2025 \u00fasp\u011b\u0161n\u011b obh\u00e1jen v r\u00e1mci z\u00e1v\u011bre\u010dn\u00e9ho oponentn\u00edho \u0159\u00edzen\u00ed a n\u00e1sledn\u011b 7. srpna 2025 schv\u00e1len k ukon\u010den\u00ed p\u0159edsednictvem TA \u010cR.
\n\u201eOfici\u00e1ln\u00ed hodnocen\u00ed Technologick\u00e9 agentury \u010cR potvrdilo, \u017ee projekt dos\u00e1hl v\u00fdsledk\u016f odpov\u00eddaj\u00edc\u00edch stanoven\u00fdm c\u00edl\u016fm a vytvo\u0159il pevn\u00fd z\u00e1klad pro dal\u0161\u00ed klinick\u00fd rozvoj l\u00e9\u010diva i jeho p\u0159\u00edpadn\u00e9 vyu\u017eit\u00ed v praxi,\u201c uvedl Radek Fialka, obchodn\u00ed \u0159editel v r\u00e1mci medac CDMO.<\/p>\n

Z\u00e1v\u011br <\/strong>
\nRealizace projektu uk\u00e1zala, \u017ee dok\u00e1\u017eeme efektivn\u011b propojit akademick\u00fd v\u00fdzkum s pr\u016fmyslovou v\u00fdrobou a p\u0159in\u00e9st v\u00fdsledky s v\u00fdznamn\u00fdm p\u0159\u00ednosem pro dal\u0161\u00ed rozvoj modern\u00ed medic\u00edny.<\/p>\n

Complete list of publications and sources cited in Annex 15 \u2013 Loffelmann (European Journal of Medicinal Chemistry, 2023). All are listed, including DOI\/links:<\/p>\n

References \u2013 Loffelmann et al., EJMECH 2023<\/p>\n

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\n11.\tMeyer H, Bug M, Bremer S. Functions of VCP\/p97 AAA-ATPase\u2026 Nat Cell Biol (2012). https:\/\/doi.org\/10.1038\/ncb2407
\n12.\tDeshaies RJ. Proteotoxic crisis and cancer therapy. BMC Biol (2014). https:\/\/doi.org\/10.1186\/s12915-014-0094-0
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\n14.\tPan M, Zheng Q, Yu Y, et al. Seesaw conformations of Npl4 in p97 complex. Nat Commun (2021). https:\/\/doi.org\/10.1038\/s41467-020-20359-x
\n15.\tMajera D, Skrott Z, et al. Targeting NPL4 by disulfiram evokes replication stress. Cells (2020). https:\/\/doi.org\/10.3390\/cells9020469
\n16.\tKanellis DC, Zisi A, Skrott Z, et al. Cancer vulnerability due to translational arrest and p53 aggregation. Cell Death Differ (2023). https:\/\/doi.org\/10.1038\/s41418-023-01167-4
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Annex 17 \u2013 Patent (US 11,766,404 B2) has its own bibliography, the official application is available here: https:\/\/patents.google.com\/patent\/US11766404B2<\/p>\n

From patent US 11,766,404 B2 (Annex 17) \u2013 complete list:
\nPatent citations
\n\u2022\tUS20170143729A1
\n\u2022\tUS20190337106A1
\n\u2022\tWO2017207317A1
\n\u2022\tWO2018202283A1
\n\u2022\tEP3402581A1
\n\u2022\tCN110293998A<\/p>\n

Non-patent literature<\/strong>
\n1.\tSkrott Z. et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552 (2017): 194\u2013199. https:\/\/doi.org\/10.1038\/nature25016
\n2.\tCvek B. Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells. Mini-Rev Med Chem 12 (2012): 1184\u20131192. https:\/\/doi.org\/10.2174\/138955712802762068
\n3.\tLiu P. et al. Cytotoxic effect of disulfiram\/copper on human glioblastoma cell lines and ALDH-positive cancer stem-like cells. Br J Cancer 107 (2012): 1488\u20131497. https:\/\/doi.org\/10.1038\/bjc.2012.442
\n4.\tKanellis D.C. et al. Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET. Cell Death Differ (2023). https:\/\/doi.org\/10.1038\/s41418-023-01167-4
\n5.\tMajera D. et al. Targeting the NPL4 adaptor of p97\/VCP segregase by disulfiram as an emerging cancer vulnerability evokes replication stress and DNA damage while silencing the ATR pathway. Cells 9 (2020): 469. https:\/\/doi.org\/10.3390\/cells9020469
\n6.\tKaul L. et al. The revival of dithiocarbamates: from pesticides to innovative medical treatments. iScience 24 (2021). https:\/\/doi.org\/10.1016\/j.isci.2021.102092<\/p>\n<\/div>\n<\/div>\n\n","protected":false},"author":13,"featured_media":0,"template":"","meta":{"_acf_changed":false,"advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","footnotes":""},"categories_studies":[13,15],"class_list":["post-59510","studies","type-studies","status-publish","hentry"],"acf":[],"aioseo_notices":[],"featured_img":false,"coauthors":[],"author_meta":{"author_link":"https:\/\/www.oncomed.cz\/cs\/author\/karna\/","display_name":"Aneta K\u00e1rn\u00e1"},"relative_dates":{"created":"Posted 9 m\u011bs\u00edc\u016f ago","modified":"Updated 9 m\u011bs\u00edc\u016f ago"},"absolute_dates":{"created":"Posted on 11. 9. 2025","modified":"Updated on 11. 9. 2025"},"absolute_dates_time":{"created":"Posted on 11. 9. 2025 10:46","modified":"Updated on 11. 9. 2025 10:46"},"featured_img_caption":"","tax_additional":{"categories_studies":{"linked":["\u010cl\u00e1nky<\/a>","Novinky<\/a>"],"unlinked":["\u010cl\u00e1nky<\/span>","Novinky<\/span>"],"slug":"categories_studies","name":"Kategorie blogu"},"translation_priority":{"linked":["Optional<\/a>"],"unlinked":["Optional<\/span>"],"slug":"translation_priority","name":"Translation Priorities"}},"series_order":"","_links":{"self":[{"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/studies\/59510","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/studies"}],"about":[{"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/types\/studies"}],"version-history":[{"count":1,"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/studies\/59510\/revisions"}],"predecessor-version":[{"id":59517,"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/studies\/59510\/revisions\/59517"}],"wp:attachment":[{"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/media?parent=59510"}],"wp:term":[{"taxonomy":"categories_studies","embeddable":true,"href":"https:\/\/www.oncomed.cz\/cs\/wp-json\/wp\/v2\/categories_studies?post=59510"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}