Drug targets and resistance mechanisms in multiple myeloma

Naß, Janine; Efferth, Thomas

doi:10.20517/cdr.2018.04

Cited by 27 publications

(21 citation statements)

References 240 publications

(250 reference statements)

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“…The BM microenvironment provides the ideal niche for myeloma cell survival and is known to contribute to drug resistance in the treatment of MM, so it is crucial to assess potential therapeutics for myeloma in this context (15). Using this model, we found that the BM niche did not protect cells from immunotoxin action and that both LMB-70 and LMB-75 caused complete and durable tumor regressions lasting more than 90 d. Tumor regressions required targeting the toxin to the myeloma cells with an anti-BCMA Fv as well as an active toxin.…”

Section: Discussionmentioning

confidence: 99%

Anti-BCMA immunotoxins produce durable complete remissions in two mouse myeloma models

Shancer

Liu

Nagata

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Multiple myeloma (MM) is a B cell malignancy for which new treatments are urgently needed. The B cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed on myeloma. Recombinant immunotoxins (RITs) are proteins composed of the Fv or Fab portion of an antibody fused to a bacterial toxin. We previously treated H929 myeloma s.c. tumors with anti-BCMA immunotoxins, very active on killing cultured cells, and observed tumor growth inhibition but not complete tumor responses. To determine if immunotoxins were more active against cells growing in the bone marrow (BM), the normal location of myeloma cells, we developed a BM mouse model that is more relevant to human disease. H929 cells were transfected with luciferase and GFP, enriched by flow, recycled through the BM of a mouse, and injected IV into nonobese diabetic scid γ mice (NSG) mice. A second myeloma mouse model used the MM.1S-GFP-luc cell line. Mice were treated IV with immunotoxins, and the tumor burden was assessed using bioluminescence imaging. We achieved complete durable remissions when treating mice with H929-GFP-luc cells with anti-BCMA RITs both leptomycin B-75 (LMB-75) [anti-BCMA-disulfide-stabilized (ds)-Fv-PE24] (where PE represents Pseudomonas exotoxin A) or LMB-70 (anti-BCMA-Fab-PE24) given every other day for 5-d (QOD×5) doses beginning on day 4 or day 8. Mice were disease free at 3 months; untreated mice became moribund around day 40. We also achieved long-term responses using the MM.1S-GFP-luc myeloma cell line. Treatment with an 1.5 mg/kg LMB-75 QOD×5 anti-BCMA RIT beginning on day 4 caused the complete disappearance of tumors for 80 days. To summarize, LMB-75 and LMB-70, our anti-BCMA RITs, induced complete durable responses in two myeloma models.

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Section: Discussionmentioning

confidence: 99%

Anti-BCMA immunotoxins produce durable complete remissions in two mouse myeloma models

Shancer

Liu

Nagata

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The genetic, cytogenetic and epigenetic changes related to the MM pathogenesis are associated with predisposition to drug resistance and, eventually, relapse [116,160,161].…”

Section: Genetic Alterations Influencing Drug Resistance In MMmentioning

confidence: 99%

“…In MM, hypomethylation is associated to disease progression, poor prognosis and drug resistance, by upregulation of the ABCG2 gene and, consequently, increased drug efflux [195]. On the other hand, hypermethylation of tumor suppressor genes was also shown to interfere on cell cycle, DNA repair, apoptosis and signaling pathways regulation [161].…”

Section: Epigenetic Alterations and Micrornas Responsible For Drug Rementioning

confidence: 99%

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

Pinto

Bergantim

Caires

et al. 2020

Cancers

142

138

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Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.

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“…Мы предположили, что одним из механизмов, объясняющих низкую ОВ пациентов с ММ, может являться IGF-1-зависимая гиперэкспрессия гена ABC-транспортера MDR1 / ABCB1. Известно, что этот ген у многих больных ММ гиперэкспрессируется и приводит к развитию множественной лекарственной устойчивости (МЛУ), которая становится основной причиной потери ответа на лечение и, как следствие, причиной смертности [8][9][10] Данные, полученные по экспрессии мРНК гена IGF-1 в группах A и B, мы сопоставили с показателем ОВ больных ММ в этих группах (рис. 4).…”

Section: Introductionunclassified

The overexpression of IGF-1 is a poor prognostic factor in multiple myeloma

Шушанов

Кравцова

Vaiman

et al. 2019

Rossijskij bioterapevtičeskij žurnal

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Introduction . Insulin-like growth factors (IGF) are one of the widely studied factors in oncology. For tumors with a high expression level of IGF typical postoperative relapse, they are invasive and give distant metastases. There are also data on the participation of IGF in the emergence of resistance to anticancer drugs. The mechanisms that determine the influence of insulin-like growth factors on the progression of a number of malignant neoplasms remain undisclosed and carrying out fundamental research in this direction is relevant. Objective: to study the role of IGF type 1 (IGF-1) in multiple myeloma (MM).Materials and methods . 26 samples of bone marrow aspirates received from 26 patients – 14 men and 12 women – were studied in the work. All patients were diagnosed with stage III ММ. The age of patients ranged from 52 to 72 years. From the obtained bone marrow aspirates, using centrifugation in the Ficoll gradient, a mononuclear fraction of bone marrow cells containing plasma cells was obtained. Then we carried out the procedure of extracting RNA and using polymerase chain reaction with reverse transcription, we studied the expression of mRNA of the genes of IGF-1 and MDR1/ABCB1.Results . The paper analyzes the overall survival (OS) of patients with MM depending on the expression of the gene IGF-1. It is shown that for patients with MM who have a high level of IGF-1 expression, a decrease in OS is characteristic and, conversely, with a weak expression of IGF-1 or in the absence of its expression, an increase in OS is observed. Studies of expression of IGF-1 gene and MDR1/ABCB1 gene responsible for the occurrence of multiple drug resistance showed that these genes are co-expressed in patients with MM. Conclusion . The obtained results indicate that the high level of IGF-1 gene expression may be a poor prognostic factor in ММ. IGF-1 may participate in regulation of the mechanisms of emergence of multiple drug resistance in patients with MM.

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Drug targets and resistance mechanisms in multiple myeloma

Cited by 27 publications

References 240 publications

Anti-BCMA immunotoxins produce durable complete remissions in two mouse myeloma models

Anti-BCMA immunotoxins produce durable complete remissions in two mouse myeloma models

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

The overexpression of IGF-1 is a poor prognostic factor in multiple myeloma

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