Name: ex vivo treatment response of primary tumors and/or associated metastases for preclinical and clinical development of therapeutics
Uploaded: 2014-10-02T15:00:00
Description: Watch this Scientific Journal Video about Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics at JoVE.com

The authors would like to thank the MSKCC Tissue Procurement Service Team (TPS), specifically, Maria Corazon Mariano, Priscilla McNeil, Anas Idelbi, Daniel Navarrete and Katrina Allen, in all of their efforts in the successful pursuit of this project and funding from the following sources: 5 R21 CA158609-02 and the Conquer Cancer Foundation and the Breast Cancer Research Foundation. In addition, the authors would like to thank Eric Cottington PhD, Vice President of the Office of Research and Project Administration, the Office of Technology Development, Research Outreach and Compliance and RTM Information Systems Support, in the support of the submission of this manuscript.

OBS: Patient vävnaden har blivit godkänt genom institutionell översyn ombord (IRB) -godkända Biospecimen och kliniska protokoll (IP-numren 09-121 och 11-041, respektive) vid Memorial Sloan Kettering Cancer Center. 1 Tissue Upphandling <ol><li> Upphandling av patientens primärtumör / metastas OBS: Hittills har protokollet utförts på opererats bort bukspottkörteln, mag och brösttumörtyper samt, lymfommetastaser. <ol><li> Rikta kirurgerna att leverera bladet med bud eller pn...

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Cancer biologer står inför stora utmaningar när man försöker att utveckla effektiva behandlingsstrategier. Testa läkemedel under utveckling på etablerade cancercellinjer kan inte korrekt återspeglar in vivo respons och in vivo experiment på PDX modeller är arbetskrävande och mycket dyra. Med hänsyn till ovanstående, att tillämpa ex vivo tekniker för primär patientens tumörer 14, 15 är nu placerad bredvid molekylär analys av etablerade cancercelllinjer och patientg...

Utveckla effektiva cancerterapi har visat sig vara mycket utmanande. Cancer cellinjer och tumör explants - samt xenografter har använts i cancerforskningen i över ett halvt sekel 1,2,3. Hittills är den molekylära analyser av läkemedelskänslighet och motstånd i både etablerade cancer cellinjer och patientgenererade xenotransplantat (PDX) oumbärlig. Emellertid är testning av föreningar i etablerade cancercellinjer inte ofta förutsägande för effektivitet in vivo, och motsvarande in vivo-studier i djur, speciellt i PDX modeller, är mycket dyr och tidskrävande. Begränsningarna av dessa modellsystem, nämligen oförmågan att informera om inverkan av den infödda mikromiljö i tumörprogression och svar på terapeutiska strategier har lett forskningen för att utveckla ytterligare metoder som förgyller dessa analyser. Av nyligen, är förhöjd uppmärksamhet mot ex vivo analys av patientens tumeller explantat 4, 5 på grund av den större förståelse att cancer terapeutiskt svar är inte exklusivt för den inneboende molekylära sammansättningen av cancerceller, utan i hög grad påverkas av tumörcellsmikro 6, 7 en funktion som inte kan rekapituleras genom traditionella odlingsmetoder och / eller PDX. Ex vivo-analys i ovanstående sammanhang (dvs., påverkan av närliggande omgivande tumörcellmikromiljö) innebär bedömning av livskraftiga primära tumör / metastas sektioner, snarare än ex vivo analys av cellulära isolat 8, 9. Vi rapporterar här på en ex vivo-teknik (dvs.., Precisions skivad färsk vävnadssnitt) av såväl patientens primära tumörer och tillhörande metastaser (dvs, lymfkörtlar) som troget informerar på svar (IC50), off-target effekter och medger molekylär analys av resistens och återkopplingsmekanismer. Dessutom kan en korrelativ analys av therapeUTIC känslighet / resistans-biomarkör och genuttryck profil kan utföras i ett försök att identifiera patienter mer benägna att svara på den experimentella drogen av intresse (dvs., matchar höga läkemedelssvar patient med speciell biologisk profil). Tillämpning av ex vivo tekniken och bedömning i en multiparameter mode är rörelse mot patientens val och övergripande förbättring av kliniska resultat. Ex vivo-behandling responsanalys skulle kunna bli ett standardverktyg i preklinisk och klinisk utveckling av cancerterapi och är tänkt som ett steg mot en personlig medicin tillvägagångssätt i terapeutiska utvecklingsstrategier.

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ex vivo treatment response of primary tumors and/or associated metastases for preclinical and clinical development of therapeutics

The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.

För denna studie var ex vivo teknik som används i en motsvarande analys av terapeutisk känslighet / resistens av en värmechockprotein 90 inhibitor (Hsp90i). I en preklinisk utvärdering av denna Hsp90i, bröstcancer primärtumör, en ER + invasiv duktal cancer (IDC), och tillhörande lymfkörtelmetastaser analyserades ex vivo för behandlingssvar &#160; (Figur 1). Flera 200 um seriella sektioner behandlades med fordons bara och ökande doser (0,25, 0,50, 1,0 och 2,...

Watch this Scientific Journal Video about Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics at JoVE.com

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

Etablerade cancer cellinjer och xenotransplantat varit stöttepelaren i cancerforskning under de senaste decennierna. Dock tyder nya bevis som terapeutiskt svar i hög grad påverkas av tumörcellsmikromiljö. Därför har vi tagit fram en ex vivo analys av primära tumörprover för drogutvecklingsändamål.

Ex vivo Behandling svar av primära tumörer och / eller associerade Metastaser för preklinisk och klinisk utveckling av Therapeutics

The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both ...

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Medicine

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

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Spontaneously contracting syncytia of cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CM) are a useful model of human cardiac ...