4 results on '"Maiju-Emilia Huppunen"'
Search Results
2. The Novel Peptide Drug Conjugate OPDC3 Is Highly Active in Different Hematological Malignancies
- Author
-
Juho J. Miettinen, Tanja Ruokoranta, Vilma Ikonen, Maiju-Emilia Huppunen, Klara Acs, Fredrik Lehmann, and Caroline A. Heckman
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Single Cell RNA Sequencing Identifies Potential Molecular Indicators of Response to Melflufen in Multiple Myeloma
- Author
-
Ana Slipicevic, Caroline A. Heckman, Sadiksha Adhikari, Nina N. Nupponen, Philipp Sergeev, Minna Suvela, Fredrik Lehmann, Maiju-Emilia Huppunen, and Juho J. Miettinen
- Subjects
0303 health sciences ,Immunology ,Cell ,RNA ,Cell Biology ,Hematology ,Computational biology ,Biology ,medicine.disease ,Biochemistry ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Multiple myeloma ,030304 developmental biology ,030215 immunology - Abstract
Introduction Melphalan flufenamide (melflufen), is a novel peptide-drug conjugate that targets aminopeptidases and selectively delivers alkylating agents in tumors. Melflufen was recently FDA approved for the treatment of relapsed/refractory multiple myeloma (MM) patients. Considering the challenges in treating this group of patients, and the availability of several new drugs for MM, information that can support treatment selection is urgently needed. To identify potential indicators of response and mechanism of resistance to melflufen, we applied a multiparametric drug sensitivity assay to MM patient samples ex vivo and analyzed the samples by single cell RNA sequencing (scRNAseq). Ex vivo drug testing identified MM samples that were distinctly sensitive or resistant to melflufen, while differential gene expression analysis revealed pathways associated with response. Methods Bone marrow (BM) aspirates from 24 MM patients were obtained after written informed consent following approved protocols in compliance with the Declaration of Helsinki. BM mononuclear cells from 12 newly diagnosed (ND) and 12 relapsed/refractory (RR) patients were used for multi-parametric flow cytometry-based drug sensitivity and resistance testing (DSRT) evaluation to melflufen and melphalan, and for scRNAseq. Based on the results from the DSRT tests and drug sensitivity scores (DSS), we divided the samples into three groups - high sensitivity (HS, DSS > 40 (melflufen) or DSS > 16 (melphalan)), intermediate sensitivity (IS, 31 ≤ DSS ≤ 40 (melflufen) or 10 ≤ DSS ≤ 16 (melphalan)), and low sensitivity (LS, DSS < 31 (melflufen) or DSS < 10 (melphalan)). To identify genes, responsible for the general sensitivity to melphalan-based drugs we conducted differential gene expression (DGE) analyses separately for melphalan and melflufen focusing on the plasma cell populations, comparing gene expression between HS and LS samples for both drugs ("HS vs. LS melphalan" and "HS vs. LS for melflufen", respectively). In addition, to explain the increased sensitivity of RR samples, we conducted the DGE analysis for ND vs. RR samples and searched for similarities between these three datasets. Results DSRT data indicated that samples from RRMM patients were significantly more sensitive to melflufen compared to samples from NDMM (Fig. 1A). In addition, we observed that samples with a gain of 1q (+1q) were more sensitive to melflufen while those with deletion of 13q (del13q) appeared to be less sensitive, although these results lacked significance (Fig. 1A). After separating the samples into different drug sensitivity groups (HS, IS, LS), DGE analysis showed significant downregulation of the drug efflux and multidrug resistance protein family member ABCB9 in the melflufen HS group opposed to the LS group (2.2-fold, p < 0.001). A similar pattern was detected for the melphalan HS vs. LS comparison suggesting that this alteration might be a common indicator of sensitivity to melphalan-based drugs. Furthermore, in the melflufen HS group we observed downregulation of the matrix metallopeptidase inhibitors TIMP1 and TIMP2 (3-fold and 1.6-fold, p < 0.001, respectively), and cathepsin inhibitors CST3 and CSTB (3.2-fold and 1.3-fold, p < 0.001, respectively) (Fig. 1B). This effect was observed in both "ND vs. RR" and "HS vs. LS for melflufen" comparisons, but not for melphalan, suggesting that these changes are associated with disease progression and specific indicators of sensitivity to melflufen. Moreover, gene set enrichment analysis (GSEA) showed activation of pathways related to protein synthesis, as well as amino acid starvation for malignant and normal cell populations in the HS group. Conclusion In summary, our results indicate that melflufen is more active in RRMM compared to NDMM. In addition, samples from MM patients with +1q, which is considered an indicator of high-risk disease, tended to be more sensitive to melflufen. Based on differential GSEA and pathway enrichment, several synergizing mechanisms could potentially explain the higher sensitivity to melflufen, such as decreased drug efflux and increased drug uptake. Although these results indicate potential indicators of response and mechanisms of drug efficacy, further validation of these findings is required using data from melflufen treated patients. Figure 1 Figure 1. Disclosures Slipicevic: Oncopeptides AB: Current Employment. Nupponen: Oncopeptides AB: Consultancy. Lehmann: Oncopeptides AB: Current Employment. Heckman: Orion Pharma: Research Funding; Oncopeptides: Consultancy, Research Funding; Novartis: Research Funding; Celgene/BMS: Research Funding; Kronos Bio, Inc.: Research Funding.
- Published
- 2021
4. Abstract 1843: Melflufen efficacy in multiple myeloma with TP53 aberrations
- Author
-
Caroline A. Heckman, Thorsten Stühmer, Juho J. Miettinen, Maria-Victoria Mateos, Johan Aschan, Paul G. Richardson, Nina N. Nupponen, Ralf C. Bargou, Paula Rodriguez Otero, Maiju-Emilia Huppunen, Fredrik Lehmann, Ana Slipicevic, and Umair Munawar
- Subjects
0301 basic medicine ,Melphalan ,Cancer Research ,medicine.diagnostic_test ,business.industry ,Cancer ,Phases of clinical research ,Plasma cell ,medicine.disease ,3. Good health ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Ex vivo ,Multiple myeloma ,medicine.drug - Abstract
Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal evolution and heterogeneous genetic abnormalities. Deletion of the short arm of chromosome 17 (del17p) harboring TP53 is a high-risk abnormality associated with aggressive disease and therapy resistance. Here, we tested in vitro and ex vivo efficacy of a peptide-drug conjugate melflufen, currently in phase 3 clinical trials for relapsed/refractory multiple myeloma (RRMM), in an isogenic myeloma p53-abrogated cell line model and patient samples. Methods Efficacy of melflufen versus melphalan was tested in the AMO-1 cell line, which displays biallelic wildtype TP53 and retains aspects of a functional p53 system, and AMO-1 clones with either complete loss of p53 or expressing point-mutated p53 protein (R282W hotspot mutation), created using the CRISPR/Cas9 system and modified via Sleeping Beauty vectors. We assessed toxicity and apoptosis using Annexin V and Alamar blue assays. Ex vivo sensitivity to the drugs was examined by flow cytometry in CD138+ plasma cells isolated from MM patients with confirmed del17p or TP53 mutations. We also analyzed response rates in a subpopulation of patients with confirmed del17p from OP-106 HORIZON, an ongoing phase 2 study evaluating the efficacy of melflufen plus dexamethasone in patients with RRMM (NCT02963493). Results Whereas loss of p53 functionality strongly impaired melphalan induced cytotoxicity in the AMO-1 MM cell line model system, treatment with melflufen showed superior efficacy in the parental cells, and was effective independent of the respective TP53 status. Although at low dosages wild-type cells were still more sensitive, in contrast to melphalan this effect was overcome by slight dose increases of melflufen, due to the much steeper dose-effect relationships in the p53 deficient sublines. In contrast to melphalan, the melflufen effect was only partially blocked by combined pre-treatment with inhibitors of apoptosis and necroptosis. Similar results were observed in patient-derived material with melflufen displaying superior activity towards TP53 mutated plasma cells. Analysis of OP-106 HORIZON trial data showed comparable ORR of 20% (CI 95% 4.3-48.1) in the del17p subpopulation (n=15) to 26.2% (CI 95% 18.8-34.6) in the total population (n=136). Conclusions Melflufen is able to trigger myeloma cell death regardless of p53 status, and thus overcome p53-deficiency-mediated melphalan resistance. It demonstrates better ex vivo efficacy in MM patient derived plasma cells harboring del17p or TP53 mutations. Melflufen response rates in the del17p Citation Format: Ana Slipicevic, Umair Munawar, Thorsten Stühmer, Johan Aschan, Fredrik Lehmann, Nina N. Nupponen, Juho Miettinen, Maiju-Emilia Huppunen, Caroline A. Heckman, María-Victoria Mateos, Paula Rodríguez Otero, Paul Richardson, Ralf Bargou. Melflufen efficacy in multiple myeloma with TP53 aberrations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1843.
- Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.