Title Nove spoznaje o inhibitorima signalnog puta Wnt i njihova uloga u liječenju tumora Title (english) Novel findings on Wnt signaling inhibitors and their role in tumor treatment Author Sara Aničić Mentor Nives Pećina-Šlaus (mentor)Committee member Tamara Nikuševa Martić (predsjednik povjerenstva)Committee member Ljiljana Šerman (član povjerenstva)Committee member Nives Pećina-Šlaus (član povjerenstva)Granter University of Zagreb Defense date and country 2021-07-16, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract U neprekidnim nastojanjima za poboljšanjem antitumorske terapije, otkrivena je važnost promjena Wnt signalnog puta u tumorima čovjeka i prepoznata ideja da bi se njegovom inhibicijom mogao poboljšati ishod i preživljenje bolesnika. U ljudskom organizmu Wnt signalni put uključen je u regulaciju embrionalnog razvoja, kao i obnovu tkiva i organa u odrasloj dobi. Budući da su komponente Wnt puta često mutirane ili epigenetski promijenjene u tumorima te nerijetko doprinose malignosti i invazivnosti tumora, nove molekule koje inhibiraju taj put pojačano se istražuju. Rezultati prijašnjih istraživanja pokazali su da blokada Wnt puta putem knockdowna njegovih komponenata djeluje inhibitorno na rast tumora in vivo i in vitro. Stoga se slični efekti nastoje postići primjenom Wnt inhibitora. Uz to, pretpostavlja se da bi inhibicija Wnt puta mogla zaustaviti i epitelno-mezenhimsku tranziciju, proces kojim tumorska stanica stječe invazivni fenotip. U posljednjih tridesetak godina otkrivene su molekule koje mogu inhibirati Wnt signalizaciju djelujući na specifične molekularne ciljeve u signalnom putu Wnt. U ovom pregledu bit će opisani dosad otkriveni inhibitori kanonskog Wnt puta, dosadašnje studije o njihovoj učinkovitosti u monoterapiji ili u kombinaciji s drugim kemoterapeuticima, kao i primijećene nuspojave. Prije svega bit će objašnjen Wnt signalni put i uloga njegovih glavnih komponenata, često mutiranih u tumorima, koje su ujedno i mjesta djelovanja inhibitora. Neke od molekula koje su prepoznate kao inhibitori Wnt puta dospjele su do ranijih faza kliničkih ispitivanja, međutim neke od ovih molekula su tek otkrivene i nisu ušle u faze kliničkih ispitivanja te još nemaju svoju primjenu u liječenju humanih tumora. Nadalje, budući da Wnt signalni put osigurava diferencijaciju osteoblasta, kao i regeneraciju mnogih tkiva, posebno onih s brzom izmjenom stanica, poput hematopoetskog i gastrointestinalnog sustava, inhibicija β-katenina nosi određene rizike poput smanjene čvrstoće kostiju, kao i anemiju, neutropeniju, trombocitopeniju, mučninu, proljev i povraćanje. Unatoč tome, rana klinička ispitivanja pokazala su da ozbiljnost ovih nuspojava nije značajna u usporedbi s potencijalnom terapijskom koristi. Iz ovog preglednog rada jasno je vidljivo da inhibicija signalnog puta Wnt ima potencijala za budući razvoj terapeutskih djelovanja.
Abstract (english) In a continuous search for the improvement of antitumor therapies, the importance of alterations in the Wnt signaling pathway in human tumors was discovered and the idea that its inhibition could improve clinical outcomes and survival of patients was recognized. In the human body, the Wnt signaling pathway is involved in the regulation of embryonic development, as well as tissue and organ regeneration in adulthood. Because the components of the Wnt pathway are often mutated or epigenetically altered in tumors and often contribute to tumor malignancy and invasiveness, new molecules that inhibit this pathway are being intensively investigated. The results of previous studies have shown that blockade of the Wnt pathway by knockdown of its components has an inhibitory effect on tumor growth in vivo and in vitro, so similar effects are expected after the application of Wnt inhibitors. In addition, it is assumed that inhibition of Wnt signaling could stop epithelial-mesenchymal transition cellular process needed for the acquisition of an invasive phenotype. In the last thirty years, molecules that can inhibit Wnt signaling by acting on specific molecular targets in the Wnt pathway have been observed. This review will discuss the inhibitors of the canonical Wnt pathway that have been discovered so far, summarize previous studies on their effectiveness in monotherapy or in combination with other chemotherapeutics and debate on side effects. Primarily the thesis will explain the Wnt signaling pathway and the role of its main components, which are also the site of inhibitor action and the site of frequent mutations in tumors. Some of the molecules identified as Wnt pathway inhibitors have reached earlier stages of clinical trials, however some of these molecules have only just been discovered and have no application in the treatment of human tumors. Furthermore, since the Wnt signaling pathway ensures osteoblast differentiation as well as regeneration of many tissues, especially those with rapid cell turnover, such as the hematopoietic and gastrointestinal systems, inhibition of β-catenin carries certain risks for side effects such as decreased bone strength as well as anemia, neutropenia, thrombocytopenia, nausea, diarrhea and vomiting. Nevertheless, early clinical trials have shown that the severity of these side effects is not significant compared to the potential therapeutic benefits. From this review, it is clear that inhibition of the Wnt signaling pathway has the potential for development of future therapy.
Keywords
signalni put Wnt
β-katenin
Wnt inhibitori
mutacije
tumori
Keywords (english)
Wnt signaling pathway
β-catenin
Wnt inhibitors
mutations
tumors
Language croatian URN:NBN urn:nbn:hr:105:495911 Study programme Title: Medicine Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2022-01-20 13:00:08
