1. P856 : a single-cell functional precision medicine landscape of multiple myelomaKlara Kropivšek, Paul Kachel, Sandra Goetze, Rebekka Wegmann, Yannik Severin, Benjamin D. Hale, Yasmin Festl, Julien Mena, Audrey Van Drogen, Nadja Dietliker, 2022, published scientific conference contribution abstract Abstract: Multiple myeloma (MM) is a cancer of plasma cells, defined by complex genetics and extensive intra- and inter-patient heterogeneity. Despite improved patient survival driven by a plethora of treatment options, the disease remains incurable.
Molecularly-guided precision medicine to individualize treatment strategies in MM has had limited success, in part due to the genetic and molecular complexity of the disease. Functional precision medicine, a complementary approach in which patient treatment is guided by the ex vivo drug response of patient cells, has not yet been evaluated for MM systematically.
Keywords: mutliple myeloma, hematology, precision medicine, microscopy, deep learning, phenotyping, oncology, proteotype
Published in RUNG: 11.11.2024; Views: 374; Downloads: 2
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2. Postnatal dynamics of Zeb2 expression in rat brain : analysis of novel 3′ UTR sequence reveals a miR-9 interacting siteKlara Kropivšek, Jasmine Pickford, David A. Carter, 2014, original scientific article Abstract: ZEB2 is a transcription factor with established roles in neurogenesis but no defined function in postnatal brain despite extensive neuronal expression in telencephalic structures. Multiple, incompletely annotated transcripts derive from the Zeb2 locus; the purpose of the present study was to structurally characterize rat brain Zeb2 transcripts with respect to 3′ untranslated (UTR) sequence in order to understand Zeb2 transcript regulation including possible interactions with regulatory molecules such as neuronal miRNAs. We cloned a 5054-nucleotide Zeb2 3′ UTR that is included in the most abundant Zeb2 transcript in neonatal rat brain. Unique features of the distal 3′ UTR region included a number of brain-specific miRNA target sites; a highly conserved miR-9 target site at 3′ UTR position 4097 was selected for functional verification in transfection experiments. Parallel analysis of Zeb2 transcript, ZEB2 protein and miR-9 levels across postnatal brain cortical development revealed a significant accumulation of ZEB2 protein levels only between postnatal days P2 and P5 that was associated with an acute loss of postnatal miR-9 expression in cortex. These studies demonstrate novel features of Zeb2 gene expression in postnatal rat brain and highlight the importance of full transcript annotation for identifying the complement of potential transcript-interacting regulators.
Keywords: transcription factor, RNA, untranslated region, miRNA, brain, rat
Published in RUNG: 11.11.2024; Views: 308; Downloads: 3
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3. A novel dual-cytokine-antibody fusion protein for the treatment of CD38-positive malignanciesRoberto De Luca, Paul Kachel, Klara Kropivšek, Berend Snijder, Markus G. Manz, Dario Neri, 2018, original scientific article Abstract: A novel dual-cytokine–antibody fusion protein, consisting of an antibody directed against CD38 [a tumor-associated antigen mainly expressed on the surface of multiple myeloma (MM) cells], simultaneously fused to both tumor necrosis factor ligand superfamily member 10 (TRAIL) and interleukin-2 (IL2), was designed, expressed and purified to homogeneity. The novel fusion protein, termed IL2-αCD38-αCD38-scTRAIL, was able to selectively recognize its cognate antigen expressed on the surface of MM and lymphoma cell lines, as evidenced by flow cytometry analysis. Moreover, the targeted version of TRAIL was able to induce cancer cell death in vitro, both with MM cell lines and with fresh isolates from the bone marrow of MM patients. The experiments provide a rationale for possible future applications of IL2-αCD38-αCD38-scTRAIL for the treatment of patients with MM or other CD38-positive malignancies.
Keywords: antibodies, dual-cytokine-antibody, CD38, multiple myeloma, TRAIL, IL2
Published in RUNG: 11.11.2024; Views: 336; Downloads: 1
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4. A roadmap of therapeutic strategies for patients with multiple myelomaBerend Snijder, Klara Kropivšek, 2023, other scientific articles Abstract: Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.
Keywords: multiple myeloma, multiomics, deep learning, imaging, ex vivo drug screening
Published in RUNG: 11.11.2024; Views: 376; Downloads: 3
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5. Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myelomaKlara Kropivšek, Paul Kachel, Sandra Goetze, Rebekka Wegmann, Yasmin Festl, Yannik Severin, Benjamin D. Hale, Julien Mena, Audrey Van Drogen, Nadja Dietliker, 2023, original scientific article Abstract: Abstract
Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
Keywords: ultiple myeloma, precision medicine, ex-vivo, pharmacoscopy, proteotyping, oncology, hematology, microscopy, drug score
Published in RUNG: 11.11.2024; Views: 382; Downloads: 4
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