VU Research Portal

VU Research Portal

Targeted chemoprevention of head and neck cancer

de Boer, D.V.

2021

document version

Publisher's PDF, also known as Version of record

Link to publication in VU Research Portal

citation for published version (APA)

de Boer, D. V. (2021). Targeted chemoprevention of head and neck cancer.

General rights

Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain

• You may freely distribute the URL identifying the publication in the public portal ?

Take down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

E-mail address:

vuresearchportal.ub@vu.nl

Chapter 8

Summary

Nederlandse Samenvatting

Summary Chapter 8  

8

In Chapter 3 ZHDSSOLHG51$LQWHUIHUHQFHVFUHHQVWRLGHQWLI\WKHUDSHXWLFWDUJHWJHQHV RISUHFDQFHUFHOOVDQGFRPSDUHGWKHÀQGLQJVWRFDQFHUFHOOV%\SHUIRUPLQJDQDUUD\ EDVHGVFUHHQZLWKSUHYLRXVO\LGHQWLÀHGWXPRUOHWKDOVL51$VZHZHUHDEOHWRGHWHFW JHQHVEHLQJHVVHQWLDOHLWKHUIRUWKHSUHFDQFHUFHOOVDQGRUIRUWKHFDQFHUFHOOV7KLV UHVXOWHGLQVHYHUDOSURPLVLQJFDQGLGDWHJHQHVRIZKLFK3ROROLNHNLQDVH3/.ZDV IXUWKHUYDOLGDWHGin vitro and in vivo3/.LQKLELWRUVZHUHDEOHWRHUDGLFDWHSUHFDQFHU FHOOVDVZHOODVLQYDVLYHFDQFHUFHOOVEXWKDGOHVVHͿHFWRQQRUPDOSULPDU\FHOOV. In WKHVXEVHTXHQWChapters 4 and 5ZHGHPRQVWUDWHGVLPLODUUHVXOWVIRUWKUHHRWKHUKLWV LGHQWLÀHGZLWKVXFK51$LQWHUIHUHQFHVFUHHQV,QWKHVHVFUHHQVWKH+16&&FHOOOLQH SDQHOVWHVWHGZHUHH[WHQGHGDQGLQFOXGHGDOVRQRUPDOSULPDU\ÀEUREODVWVWRDOORZ GLUHFW H[FOXVLRQ RI FRUH HVVHQWLDO JHQHV 7KHVH VWXGLHV LGHQWLÀHG Wee1, RRM1 and

RRM2DVSRWHQWLDOWDUJHWPROHFXOHVDQGWKHVHVKRXOGEHFRQVLGHUHGDVSRWHQWLDOKLWV

IRUWDUJHWHGFKHPRSUHYHQWLRQDVZHOO

In Chapter 6 ZHVKRZHGWKDWEHVLGHVWKHPRUHFODVVLFDOJHQHWDUJHWVPL51$PLPLFV DUHDOVRVXLWDEOHIRUWDUJHWLQJSUHFDQFHUFHOOVin vitro:HSHUIRUPHGDKLJKWKURXJKSXW VFUHHQZLWKPLPLFVRQDSUHFDQFHUFHOOOLQHWZRFDQFHUFHOOOLQHVDQGQRUPDO SULPDU\ ÀEUREODVWV $QDO\VLV RI WKH GDWD UHVXOWHG LQ  PL51$ PLPLF FDQGLGDWHV ZLWKDSUHFDQFHUVSHFLÀFOHWKDOHͿHFWLQWHUHVWLQJIRUIXUWKHUYDOLGDWLRQH[SHULPHQWV 2YHUDOO WKLV ZRUN IRFXVHG RQ WKH GHYHORSPHQW RI WDUJHWHG FKHPRSUHYHQWLRQ VWUDWHJLHV IRU SUHFDQFHURXV ÀHOGV LQ +16&& SDWLHQWV WR SUHYHQW SULPDU\ WXPRUV DQGORFDOUHODSVHV%\GHYHORSLQJFHOOXODUPRGHOVIROORZHGE\WDUJHWLGHQWLÀFDWLRQ DQG YDOLGDWLRQ VHYHUDO SURPLVLQJ GUXJJDEOH WDUJHWV DQG VPDOO PROHFXOH LQKLELWRUV KDYH EHHQ LGHQWLÀHG DQG DUH DYDLODEOH IRU IXWXUH FOLQLFDO WHVWLQJ LQ SDWLHQWV ZLWK SUHFDQFHURXVFKDQJHVDWKLJKULVNIRU+16&&

SUMMARY

+HDGDQGQHFNVTXDPRXVFHOOFDUFLQRPDV+16&&VGHYHORSLQWKHPXFRVDOOLQLQJ RI WKH XSSHU DHURGLJHVWLYH WUDFW +16&& LV D YHU\ KHWHURJHQHRXV GLVHDVH ZKLFK RQWKHRQHKDQGUHODWHVWRWKHGLͿHUHQFHVLQDQDWRPLFDOORFDWLRQDVZHOODVHWLRORJ\ DQGRQWKHRWKHUKDQGWRWKHODUJHYDULHW\LQPROHFXODUDOWHUDWLRQV7KHODVWGHFDGHV QHZ GLDJQRVWLF WRROV DQG WUHDWPHQW VWUDWHJLHV KDYH EHHQ GHYHORSHG EXW WKHVH GLG QHLWKHUWUDQVODWHLQDVLJQLÀFDQWGHFOLQHRIUHFXUUHQWGLVHDVHQRULQDQLQFUHDVHRIWKH \HDUVVXUYLYDOUDWHV\HW7RLPSURYHWKHFOLQLFDORXWFRPHRISDWLHQWVGLDJQRVHGZLWK +16&&PXOWLSOHHͿRUWVWRGHYHORSQHZWKHUDSHXWLFVWUDWHJLHVDUHUHTXLUHG6HYHUDO \HDUVDJR7KH&DQFHU*HQRPH$WODV7&*$FRQVRUWLXPSXEOLVKHGDFRPSUHKHQVLYH RYHUYLHZRIWKHJHQRPLFVRI+16&&+RZHYHUWKHGHWDLOHGLQVLJKWVLQWKHPROHFXODU ODQGVFDSHRI+16&&GLGQRWSURYLGHQHZWKHUDSHXWLFRSWLRQV$PDMRUFRQFOXVLRQ RIWKHVHVWXGLHVZDVWKDW+16&&LVGULYHQE\WXPRUVXSSUHVVRUJHQHLQDFWLYDWLRQ FRPSOLFDWLQJWKHLGHQWLÀFDWLRQRIGUXJJDEOHWDUJHWV 6LQFHSUHYHQWLRQLVJHQHUDOO\PRUHHͿHFWLYHWKDQFXUHZHIRFXVHGZLWKRXUUHVHDUFK GHVFULEHGLQWKLVWKHVLVRQWKHSUHFDQFHURXVÀHOGVLQWKHKHDGDQGQHFNPXFRVDOOLQLQJ 7KHVHÀHOGVFRQVLVWRIHSLWKHOLDOFHOOVFRQWDLQLQJWKHHDUOLHVWFDQFHUDVVRFLDWHGJHQHWLF FKDQJHVEXWGRQRWVKRZWKHLQYDVLYHEHKDYLRURIWXPRUFHOOV6HYHUDOW\SHVRIWKHVH ÀHOGVDUHNQRZQWRRFFXUVRPHDUHYLVLEOHWRWKHQDNHGH\HDVOHVLRQVVRPHFDQEH GHWHFWHG XVLQJ D PLFURVFRSH DQG RWKHUV FDQ RQO\ EH GHWHFWHG E\ JHQHWLF DQDO\VLV 7KHVHSUHFXUVRUÀHOGVIRUPDQLPSRUWDQWULVNIDFWRUIRUWKHGHYHORSPHQWRISULPDU\ +16&& EXW DOVR IRU ORFDO UHODSVHV LQ WUHDWHG SDWLHQWV 7KHVH SUHFDQFHURXV ÀHOGV VKRXOG EH GLDJQRVHG DQG WUHDWHG EXW WUHDWPHQW LV D FKDOOHQJH 7DUJHWHG WUHDWPHQW VHHPVPRVW SURPLVLQJ EHFDXVH RI WKH JHQHUDOO\ ORZ WR[LFLW\ ZKLOH WKH FHOOV FDQ EH VSHFLÀFDOO\KLWDWWKHLUYXOQHUDELOLWLHVFDXVHGE\WKHJHQHWLFFKDQJHV

$V D ÀUVW VWHS GHVFULEHG LQ Chapter 2 ZH JHQHUDWHG VHYHUDO FHOOXODU PRGHOV RI SUHFDQFHURXVÀHOGVGLUHFWO\IURPSDWLHQWPDWHULDO:HFROOHFWHGELRSVLHVRIQRUPDO DSSHDULQJ PXFRVD VXUURXQGLQJ WKH WXPRU IURP SDWLHQWV XQGHUJRLQJ VXUJHU\ WR UHPRYHWKHLUSULPDU\+16&&7KHWLVVXHFROOHFWHGZDVFXOWXUHGDQGSUROLIHUDWLQJ NHUDWLQRF\WHV ZHUH DQDO\]HG IRU WKH SUHVHQFH RI JHQHWLF DOWHUDWLRQV 7KHVH UHVXOWV FRQÀUPHGWKHSUHVHQFHRIJHQHWLFDOWHUDWLRQVLQDSSUR[LPDWHO\KDOIRIWKHFXOWXUHV 7KH REVHUYHG FKDQJHV W\SLFDOO\ RFFXU HDUO\ LQ FDUFLQRJHQHVLV VXFK DV ORVV RI D SDUWLFXODUUHJLRQRIFKURPRVRPHDUPSDQGPXWDWLRQVLQTP53. :HIXUWKHUQRWHG WKDW PXWDWLRQV LQ NOTCH1 VRPHWLPHV RFFXU DV HDUO\ FKDQJHV LQ WKH FXOWXUHG NHUDWLQRF\WHV 7KHVH GDWD SURYLGHG XV ZLWK FHOOXODU PRGHOV RI SUHFDQFHURXV ÀHOGV WKDWZHUHXVHGVXEVHTXHQWO\IRULGHQWLÀFDWLRQDQGYDOLGDWLRQRIGUXJJDEOHWDUJHWV DQGHYDOXDWLRQRISURPLVLQJVPDOOPROHFXOHLQKLELWRUV