Abstract:Background
Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM).
Methods
For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapse… Show more
“…These studies suggest that strategies to reduce 9-O-Ac-GD3 could be employed together with apoptosis-inducing drugs for the treatment of cancer. Conversely, high SIAE expression has been indicated as poor prognostic marker in patients with multiple myeloma (103). Clearly, more studies are needed to understand the effects of CASD1 and SIAE activity in cancer.…”
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
“…These studies suggest that strategies to reduce 9-O-Ac-GD3 could be employed together with apoptosis-inducing drugs for the treatment of cancer. Conversely, high SIAE expression has been indicated as poor prognostic marker in patients with multiple myeloma (103). Clearly, more studies are needed to understand the effects of CASD1 and SIAE activity in cancer.…”
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
“…In recent years, aberrant expression of PAFAH1B3 has been detected as a metabolic oncogene in different kinds of tumors, including gastric cancer [38], hypopharyngeal squamous cell carcinoma [39], and osteosarcoma [40]. When analyzed using pan-cancer TCGA data, upregulated PAFAH1B3 was strongly associated with poor prognosis in a variety of tumors, including HCC [41]. Consistent with previous studies, we found that PAFAH1B3 expression levels were signi cantly higher in HCC tissues compared to normal tissues and were independently associated with patient prognosis, and that reducing PAFAH1B3 with siRNA signi cantly inhibited the proliferative and migratory properties of Hep3B cells.…”
BackgroundComplex crosstalk between tumor cells and platelets is closely related to the development, relapse, and drug resistance of hepatocellular carcinoma (HCC). Therefore, an intensive analysis of the relationship between platelet-related genes and the effectiveness of immunotherapy is necessary for improving the poor prognosis of HCC patients. MethodsGenes associated with platelets in the GeneCards database were collected and were used to identified molecular subtypes using a non-negative matrix decomposition algorithm (NMF) and constructed a platelet-related genes-based prognostic stratification model by the LASSO-Cox regression and stepwise Cox regression analysis. The effect of this feature on the immune microenvironment of HCC and the response to immune checkpoint inhibitors was also explored.ResultsAfter identifying two molecular subtypes, we constructed a platelet-related genes-based prognostic stratification model that can be effectively used for immune checkpoint inhibitor (PD1, PD-L1, PD-L2, and CTLA4) efficacy and prognosis prediction in HCC patients, which was subsequently validated using patient samples from ICGC, GSE14520 and a small sample size clinical cohort. We also found downregulation of PAFAH1B3 remarkably inhibited the proliferation and migration ability of Hep3B cells. ConclusionsIn conclusion, we constructed a prognostic classifier based on platelet-related genes that could effectively classify HCC patients for prognostic prediction provide new light on the selection of optimal individualized antiplatelet therapy for HCC patients in future clinical practice.
“…Finally, the study of esterase expression in MM is becoming of increasing interest due to the development of melflufen, which utilizes not only intracellular aminopeptidases but also and esterases to release a L-PAM cytotoxic payload in neoplastic MM cells. 37,45,47 Thus, because of the fast melflufen transport rate into cells and, conversely, the gradual exit of L-PAM-free outside cells, a high intracellular-free L-PAM concentration is achieved due to the intracellular cleavage. In other words, treatment with melflufen efficiently results in the intracellular trapping of L-PAM.…”
Section: Pharmacology and Pharmacokineticsmentioning
confidence: 99%
“…Finally, the study of esterase expression in MM is becoming of increasing interest due to the development of melflufen, which utilizes not only intracellular aminopeptidases but also and esterases to release a L-PAM cytotoxic payload in neoplastic MM cells. 37 , 45 , 47 Figure 1 Chemical structure and metabolism of melflufen (melphalan flufenamide) hydrochloride, a dipeptide prodrug of melphalan. Melflufen is metabolized into melphalan and p-Fluorophenylalanine by aminopeptidases (AP) inside myeloma cells.…”
Section: Pharmacology and Pharmacokineticsmentioning
Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptideconjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased offtarget cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third-or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.
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