Browsing by Subject "Multiple Myeloma"
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(2021)Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.
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Identifying Gene Expression Biomarkers for Venetoclax and Bortezomib Resistance in Multiple Myeloma (Helsingin yliopisto, 2020)Multiple Myeloma (MM) is the second most common hematologic malignancy. Despite the advancements in treatment approaches in the last decade, the prevalence of refractory disease leading to relapsed cases has been a major challenge. A wide range of intricate genetic heterogeneity demonstrated by myeloma patients is a credible explanation for the diverse treatment responses observed in patients sharing the same treatment regimens. Pertaining to this, the study aims to identify predictive gene expression biomarkers that forecast response to BCL2 inhibitor venetoclax and treatment outcome to proteasome inhibitor bortezomib. In this study, samples from MM patients were characterized into sensitive and resistant, (1) based on ex vivo response to venetoclax treatment (Resistant n=21; Sensitive n=21), and (2) based on their bortezomib treatment outcome in clinical profiles (Resistant n=12; Sensitive n=15). Associations between the different gene expressions and drug responses were studied using statistical and bioinformatic tools. As a result, we identified that significant (p-value <0.05) overexpression of 36 genes and downregulation of 38 genes appeared to confer resistance to venetoclax drug response in MM patients. Additionally, the functional association of these genes with pathways was determined using a pathway enrichment tool. Furthermore, the study provided evidence that cytogenetic alterations t(11;14) and t(4;14) are significantly (p-value <0.05) associated with differing venetoclax response in MM patients. These findings demonstrated that gene expression biomarkers and chromosomal translocations play a significant role in regulating venetoclax drug response in MM, which can be further utilized to personalize treatments for patients. The knowledge obtained from this work best applies in personalized medicine; whereby fitting treatments to an individual patient’s genomic landscape will enhance patient outcome.
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(2022)• Myelooman vuosittainen ilmaantuvuus on pysynyt vakaana, mutta kehittyneiden hoitojen ansiosta potilaiden elinikä pitenee. Siksi hoidossa olevien potilaiden määrä kasvaa. • Kliinisen hematologian erikoislääkärien määrän huomattava vaje voi vaarantaa hoidon yhdenvertaisen toteutumisen. • Hoidon kustannukset kasvavat pääasiassa lääkekustannusten nousun vuoksi. Lääkekustannuksia pyritään hallitsemaan erilaisilla riskinjako- sopimuksilla. • Kliiniset lääketutkimukset tarjoavat arvokasta varhaisvaiheen käyttö- kokemusta ja konkreettista säästöä sairaaloiden lääkebudjetteihin. Niiden toteuttaminen sujuvasti rinnakkain rutiinihoidon kanssa tulisi mahdollistaa.
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(2020)Autologisella kantasolusiirrolla tuetulla intensiivihoidolla on keskeinen rooli etenkin multippelia myeloomaa sekä tietyissä tilanteissa lymfoomaa sairastavien potilaiden hoidossa. Huono tai epäonnistunut kantasolujen mobilisaatio ja keräys on tärkeä autologisen kantasolusiirron saatavuutta rajoittava tekijä. Noin vuosikymmenen ajan käytössä olleella pleriksaforilla voidaan usein auttaa potilaita, joiden kantasolut mobilisoituvat huonosti vaikuttamatta siirronjälkeiseen ennusteeseen. Pleriksaforin käytön on todettu vaikuttavan kerättyjen kantasolusiirteiden solukoostumukseen sekä potilaiden siirronjälkeiseen hematologiseen ja immunologiseen toipumiseen. Näiden löydösten kliininen merkitys vaatii vielä lisäselvityksiä, kuten optimaalisen autologisen kantasolusiirteen koostumuskin. Pleriksaforin optimaalisen ja etenkin kustannustehokkaan käytön kannalta on keskeistä tunnistaa oikeat potilasryhmät esimerkiksi tutkimuksissa varmennetuin algoritmein.
