Carfilzomib boosted combination therapy for relapsed multiple myeloma

Steiner, Raphaël; Manasanch, Elisabet E.

doi:10.2147/ott.s102756

Cited by 16 publications

(14 citation statements)

References 60 publications

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“…The panobinostat EC 50 was in the 12th percentile or better for all of the t4;14 multiple myeloma lines tested, and notably the EC 50 of panobinostat against KMS26 was less than the first percentile at 3.7 nM. The insight provided by the negative connection of these lines to HDAC inhibitors is further supported by the fact that HDAC inhibitors have proved to be potent elements in the treatment of multiple myeloma, especially in combination with other agents ( Laubach et al, 2017 ; Steiner and Manasanch, 2017 ).…”

Section: Resultsmentioning

confidence: 90%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

et al. 2018

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SUMMARYAlthough the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs 3 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the “connectivity” framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.

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Section: Resultsmentioning

confidence: 90%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

et al. 2018

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“…The panobinostat EC 50 was in the 12th percentile or better for all of the t4;14 multiple myeloma lines tested, and notably the EC 50 of panobinostat against KMS26 was less than the first percentile at 3.7 nM. The insight provided by the negative connection of these lines to HDAC inhibitors is further supported by the fact that HDAC inhibitors have proven to be potent elements in the treatment of multiple myeloma, especially in combination with other agents (Laubach et al, 2017;Steiner and Manasanch, 2017).…”

Section: Proteomic Connectivity Links Genetics To Function and Identimentioning

confidence: 90%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Litichevskiy

Peckner

Abelin

et al. 2017

Preprint

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Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL).

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“…It was designed in an effort to address resistance to BTZ as well as to try to avoid some of its side effects, though CFZ does have side effects of its own. Indeed, carfilzomib does show efficacy in BTZ-refractory multiple myeloma patients [64]. However, a recent trial suggests that CFZ may not be as effective when used alone compared to when used in combination with dexamethasone [65].…”

Section: Proteasome Inhibitors In Clinical Studiesmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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Carfilzomib boosted combination therapy for relapsed multiple myeloma

Cited by 16 publications

References 60 publications

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

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