[{"_id":"project:7898","_type":"project","abstract":{"sv":"Vi avser att utveckla en metod för att bättre kunna välja och följa upp behandling vid maligniteter. Kunskaper om kritiska genetiska förändringar i tumörer har ökat dramatiskt under senare år och kan utläsas genom DNA sekvensning som blir allt viktigare kliniskt. Det finns också en snabbt ökande repertoar av läkemedel att ta till som riktas mot effekter av dessa genetiska förändringar. Emellertid behövs betydligt bättre metoder för att välja rätt behandling för varje patient bland alla som nu står till buds, samt för att undersöka om tumörer utvecklar resistensmekanismer som kräver byte av behandlingsupplägg. För att förstå detta krävs metoder att utläsa hur cellens signalvägar påverkas på proteinnivå av maligniteter och vid behandling av dessa. Vi har tidigare utvecklat en teknik som erbjuder unika möjligheter att följa proteiners aktivitetsnivåer i patientprover, och tekniken är nu i bruk in flera tusen laboratorium i världen, men den har krävt en hel del arbete av användaren för att tillämpa metoden, och normalt studeras ett protein i taget. Vi tänker nu använda en förbättrad version av tekniken för att bygga färdiga paneler av tester som kan ge användaren en samlad bild av om ett läkemedel har önskad effekt på tumörceller jämfört med effekter på normala celler i ett patientprov. I ett första skede tänker vi använda dessa paneler i samarbete med kliniska kollegor som forskar på solida tumörer respektive på leukemier. Vi avser att senare också göra dessa paneler brett tillgängliga via den svenska SciLifeLab organisationen. I ett längre perspektiv är det vår förhoppning att testerna skall komma att användas i rutinsjukvården för att välja rätt behandling år varje patient, och för att följa upp terapisvar i form av precisionsmedicin. ","en":"Cellular activity states are manifested by changes in protein concentration and distribution, but importantly, also by factors such as posttranslational modifications or dynamic interactions among the proteins. The latter is information that has been difficult to capture for patient samples. Building on our long tradition of constructing DNA-assisted protein assays in solution and in situ, along with a series of recent developments, we will now establish dedicated panels for multiplex in situ detection of protein activity states to monitor responses to single or combinations of drugs. The assay panels will target critical sets of protein interactions and phosphorylations. In the same assays we will also be able to characterize individual cells according to whether they carry specific mutations, or according to the target engagement of clinical drugs. Armed with these panels we will collaborate with clinical colleagues to investigate drug responses by leukemic and solid tumor cells. We plan to make the panels broadly available via SciLifeLab, and in a perspective beyond the present project these analyses can become an important means of therapy selection and follow-up in precision medicine."},"project_id":"2022-00570_VR","identifier_short":"2022-00570","dates":{"start_date":"2023-01-01","end_date":"2026-12-31"},"organizations":[{"funding":[{"_id":2,"id":"202100-5208","sv":"Vetenskapsrådet","en":"Swedish Research Council"}]},{"coordinating":[{"_id":978,"id":"202100-2932","sv":"Uppsala universitet","en":"Uppsala University"}]}],"people":[{"project_leaders":[{"_id":"authority-person:11830","orcid":"0000-0002-7820-1000","name":"Landegren, Ulf","role":"principal_investigator","affiliation":[{"_id":7706,"sv":"Institutionen för immunologi, genetik och patologi","en":"Department of Immunology, Genetics and Pathology","parent":[{"_id":1326,"sv":"Medicinska fakulteten","en":"Faculty of Medicine","parent":[{"_id":1311,"sv":"Medicinska och farmaceutiska vetenskapsområdet","en":"Disciplinary Domain of Medicine and Pharmacy","parent":[{"_id":978,"sv":"Uppsala universitet","en":"Uppsala University"}]}]}]}]}]},{"other_personnel":[{"_id":"authority-person:17902","name":"Löf, Liza","role":"co_investigator","affiliation":[{"_id":7706,"sv":"Institutionen för immunologi, genetik och patologi","en":"Department of Immunology, Genetics and Pathology","parent":[{"_id":1326,"sv":"Medicinska fakulteten","en":"Faculty of Medicine","parent":[{"_id":1311,"sv":"Medicinska och farmaceutiska vetenskapsområdet","en":"Disciplinary Domain of Medicine and Pharmacy","parent":[{"_id":978,"sv":"Uppsala universitet","en":"Uppsala University"}]}]}]}]}]}],"tags":[{"_id":11658,"id":"30108","sv":"Cell- och molekylärbiologi","en":"Cell and Molecular Biology"}],"titles":{"sv":"Functional proteomics for precision medicine","en":"Funktionell proteomik för precisionsmedicin"},"total_funding":"4800000","type_of_awards":{"sv":"Projektbidrag","en":"Project grant"},"publications":[{"id":"diva2:1843942","type":"article-journal","status":"Published","issued":{"date-parts":[[2024]]},"title":"Sensitive and Specific Analyses of Colorectal Cancer Recurrence through Multiplex superRCA Mutation Detection in Blood Plasma","language":"eng","author":[{"family":"Sandberg","given":"Emma","ORCID":"0009-0003-5681-4417","localId":"emmsa387","affiliation":[{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"},{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"}]},{"family":"Nunes","given":"Luís","ORCID":"0000-0002-3391-1607","localId":"luinu972","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"}]},{"family":"Edqvist","given":"Per-Henrik","ORCID":"0000-0002-8330-0134","localId":"peedq227","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"}]},{"family":"Mathot","given":"Lucy","ORCID":"0000-0002-2990-2038","localId":"lucma494","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"}]},{"family":"Chen","given":"Lei","ORCID":"0000-0002-5226-1427","localId":"leich344","affiliation":[{"name":"Rarity Biosci AB, SE-75237 Uppsala, Sweden"},{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887405","name":"Uppsala universitet, Molekylära verktyg och funktionsgenomik"}]},{"family":"Edgren","given":"Tomas","affiliation":[{"name":"Rarity Biosci AB, SE-75237 Uppsala, Sweden."}]},{"family":"Al Nassralla","given":"Shahed","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"7706","name":"Uppsala universitet, Institutionen för immunologi, genetik och patologi"}]},{"family":"Glimelius","given":"Bengt","ORCID":"0000-0002-5440-791x","localId":"bengglim","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"}]},{"family":"Landegren","given":"Ulf","ORCID":"0000-0002-7820-1000","localId":"ulfland","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887405","name":"Uppsala universitet, Molekylära verktyg och funktionsgenomik"}]},{"family":"Sjöblom","given":"Tobias","ORCID":"0000-0001-6668-4140","localId":"tobisjob","affiliation":[{"id":"9051","name":"Uppsala universitet, Science for Life Laboratory, SciLifeLab"},{"id":"887404","name":"Uppsala universitet, Cancerprecisionsmedicin"}]}],"abstract":"Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10<sup>−5</sup>, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10<sup>−4</sup> or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.","DOI":"10.3390/cancers16030549","PMID":"38339300","NBN":"urn:nbn:se:uu:diva-524607","issue":"3","volume":"16","number":"549","container-title":"Cancers","ISSN":"2072-6694","keyword":"colorectal cancer; recurrence; cfDNA; ctDNA","publisher":"MDPI","published":[{"raw":"2024-03-12T12:10:13.850+01:00"}],"created":[{"raw":"2024-03-12T12:10:13.926+01:00"}],"updated":[{"raw":"2024-03-12T12:10:13.850+01:00"}],"URL":"https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524607"}],"links":[{"type":"pid","link":"https://uu.diva-portal.org/smash/api/project/swecris/project:7898"}]}]