Pathway-Directed Therapy in Multiple Myeloma

John, Lukas; Krauth, Maria Theresa; Podar, Klaus; Raab, Marc-Steffen

doi:10.3390/cancers13071668

Cited by 23 publications

(18 citation statements)

References 150 publications

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“…It is believed that IGH rearrangement may affect the prognosis of MM not straightforwardly; however, to some extent, the disease progression is achieved by affecting the sensitivity of drug treatment (21,22). For high-risk MM with p53 gene mutation, some new drugs can improve the prognosis of these relapsed MM by inhibiting p53 pathway (27,28). In the continuous research progress, the survival status of MM patients with different types of gene variants is expected to be improved.…”

Section: Discussionmentioning

confidence: 99%

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently

et al. 2022

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BackgroundDiffusion-weighted whole-body MRI (DW-MRI) is increasingly used to evaluate bone diseases of multiple myeloma (MM), but there is lack of quantitative indicator for DW-MRI to reflect the prognosis of MM. Apparent diffusion coefficient (ADC) values in DW-MRI has potential correlations between some indexes of MM, but the influence of ADC on MM survival needs to be further verified.MethodsA total of 381 newly diagnosed MM patients were enrolled in the study to analyze the effect of ADC values in DW-MRI on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method was used to perform univariate survival analysis, and the Cox proportional hazards model was used for multivariate analysis. In addition to the ADC value, genetic and serological indexes were also included.ResultsThe survivals were observed in univariate ADC stratification with median PFS of 52.0, 45.0, 34.0, and 26.0 months (the unit of ADC value was 10−3 mm2/s; the ADC ranges were ADC < 0.4886, 0.4886 ≤ ADC < 0.6545, 0.6545 ≤ ADC < 0.7750, and ADC ≥ 0.7750; 95% CI, 43.759–62.241, 46.336–53.664, 39.753–46.247, and 27.812–32.188). The OS were 81.0, 61.0, 47.0, and 36.0 months (p < 0.001; 95% CI, 71.356–82.644, 67.630–70.370, 57.031–60.969, and 36.107–43.893). In Cox proportional hazards model, the ADC value was considered to be an independent risk factor affecting PFS and OS of MM (both p < 0.001).ConclusionsThis study supports that ADC in DW-MRI may independently stratify MM patients and better predict their prognosis. The combined use of DW-MRI and other parameters allows more accurate evaluation of MM survival.Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=49012, ChiCTR2000029587.

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Section: Discussionmentioning

confidence: 99%

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently

et al. 2022

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“…The high levels of genetic and clonal heterogeneity and the lack of a unifying driver event represent essential challenges in the management of MM and potential explanations for the failure of the therapies directed to a specific set of mutations or more genetic lesions [ 141 ]. A more effective strategy could be to target a pathway to which MM shows addiction, irrespective of the mutations present in every single clone, somehow in line with the non-oncogene addiction paradigm [ 6 ].…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Botrugno

Tonon

2021

Cancers

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Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

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“…Although several PKIs have reached phase II of clinical trials for treatment of MM, none have reached the market yet [ 46 ]. This is somewhat remarkable given that both myelomagenesis and development of therapy resistance are, at least in part, associated with perturbations in protein phosphorylation [ 47 ]. Both hyperactivation of the PI3K/AKT/mTOR and JAK/STAT signaling pathways, for example, are associated with poor prognosis and MM tumor proliferation, and are actively being explored in preclinical drug research as potential drug targets [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Logie

Pérez-Novo

Driesen

et al. 2021

IJMS

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Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.

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Pathway-Directed Therapy in Multiple Myeloma

Cited by 23 publications

References 150 publications

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

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