Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL).

Clonal competition assays identify fitness signatures in cancer progression and resistance in multiple myeloma.

Multiple myeloma (MM) is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. alterations are established high-risk markers and are included in the current disease staging criteria. is the most frequently mutated gene affecting around 20% of MM patients.

Real-world experience with letermovir for cytomegalovirus-prophylaxis after allogeneic hematopoietic cell transplantation: A multi-centre observational study.

Objectives: Efficacy and safety of letermovir as prophylaxis for clinically significant cytomegalovirus infections (csCVMi) was evaluated in randomised controlled trials while most of the real-world studies are single-centre experiences.

Methods: We performed a retrospective, multi-centre case-control study at six German university hospitals to evaluate clinical experiences in patients receiving CMV prophylaxis with letermovir (n = 200) compared to controls without CMV prophylaxis (n = 200) during a 48-week follow-up period after allogeneic hematopoietic cell transplantation (aHCT).

Results: The incidence of csCMVi after aHCT was significantly reduced in the letermovir (34%, n = 68) compared to the control group (56%, n = 112; p < 0.

Functional Investigation of Mutations in Multiple Myeloma.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor () and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of mutations is so far unknown, we investigated the functional impact of mutations on survival signaling, viability/proliferation and survival response to therapy.

The Route of the Malignant Plasma Cell in Its Survival Niche: Exploring "Multiple Myelomas".

Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses.

Ga-Pentixafor PET/CT for Detection of Chemokine Receptor CXCR4 Expression in Myeloproliferative Neoplasms.

C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic malignancies. This study investigated the feasibility of CXCR4-directed imaging with PET/CT using Ga-pentixafor to visualize and quantify disease involvement in myeloproliferative neoplasms (MPNs). Twelve patients with MPNs (4 with primary myelofibrosis, 6 with essential thrombocythemia, and 2 with polycythemia vera) and 5 controls underwent Ga-pentixafor PET/CT.

RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS.

Oncogenic RAS provides crucial survival signaling for up to half of multiple myeloma cases, but has so far remained a clinically undruggable target. RAL is a member of the RAS superfamily of small GTPases and is considered to be a potential mediator of oncogenic RAS signaling. In primary multiple myeloma, we found RAL to be overexpressed in the vast majority of samples when compared with pre-malignant monoclonal gammopathy of undetermined significance or normal plasma cells.

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression.

Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls.

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines.

Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in . However, there is still no final consent on whether -mutations are associated with disease outcome. Specifically, no data exist on whether -mutations have an impact on survival of MM patients at diagnosis in the era of novel agents.

Protocol for MP: A Comprehensive and Clinical Oriented Targeted Sequencing Panel for Routine Molecular Analysis in Multiple Myeloma.

Over the past 10 years next generation sequencing (NGS) approaches deciphered a large number of genomes from a wide variety of tumor types. However, despite most relevant findings, this technology has not yet been implemented into standard diagnostic workflows. Broad access to NGS technology is still limited, sequencing/analysis times exceed clinically relevant timeframes and despite huge cuts, costs remain significant.

Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma.

Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom".

A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.

Efficient transient transfection of human multiple myeloma cells by electroporation--an appraisal.

Cell lines represent the everyday workhorses for in vitro research on multiple myeloma (MM) and are regularly employed in all aspects of molecular and pharmacological investigations. Although loss-of-function studies using RNA interference in MM cell lines depend on successful knockdown, no well-established and widely applied protocol for efficient transient transfection has so far emerged. Here, we provide an appraisal of electroporation as a means to introduce either short-hairpin RNA expression vectors or synthesised siRNAs into MM cells.

PI3K-dependent multiple myeloma cell survival is mediated by the PIK3CA isoform.

Constitutive phosphatidylinositide 3-kinase (PI3K) signalling has been implicated in multiple myeloma (MM) pathophysiology and is regarded as an actionable target for pharmacological intervention. Isoform-specific PI3K inhibition may offer the most focused treatment approach and could result in greater clinical efficacy and reduced side effects. We therefore performed isoform-specific knockdown of PIK3CA, PIK3CB, PIK3CD, and PIK3CG to analyse their individual contributions to MM cell survival and downstream signalling.

The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma.

Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising preclinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition.

Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma.

So-called RAS-dependent pathways, such as those signalling via mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/Akt, are implicated in proliferation and survival of multiple myeloma (MM) cells. However, the effects of their combined blockade and its potential therapeutic utility for the treatment of RAS-mutated MM have not systematically been analysed. Here, we tested the functional consequences of single versus combined inhibition of the MEK/MAPK and PI3K/Akt pathways in a large series of primary MM samples (n = 55) and MM cell lines (n = 11).

Integrin-linked kinase is dispensable for multiple myeloma cell survival.

We investigated the utility of integrin-linked kinase (ILK) as a target for therapeutic intervention in multiple myeloma (MM). ILK (over-)expression was assessed in primary samples and MM cell lines, and the molecular and physiological consequences of siRNA-mediated ILK ablation were compared to treatment with the small molecule inhibitor QLT0267. Whereas ILK expression was ubiquitous, overexpression was only rarely observed in patient biopsies.

Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival.

We have recently shown that approximately half of primary multiple myeloma (MM) samples display constitutive Akt activity, which disposes them for sensitivity to Akt inhibition. The Akt pathway counts among the signaling conduits for oncogenic RAS and activating mutations of K- and N-RAS frequently occur in MM. We therefore analyzed the relation between RAS mutation and Akt dependency in biopsies and CD138-purified cells from MM patients (n = 65) and the function of oncogenic RAS for MM cell survival in a range of MM cell lines with differing RAS status.