Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma

Muz, Barbara; Azab, Feda; Puente, Pilar de la; Landesman, Yosef; Azab, Abdel Kareem

doi:10.1016/j.tranon.2017.04.010

Cited by 25 publications

(25 citation statements)

References 44 publications

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“…Inhibitors that target CRM1 export pathway have already begun phase I and II clinical trials with encouraging results. In one trial, the first generation CRM1 inhibitor selinexor (KPT-330) has yielded positive results in patients with refractory multiple myeloma [ 21 ] and ovarian cancer [ 22 ]. In patients with advanced solid tumors, Selinexor treatment achieved stable disease in 17% of patients for greater than 4 months [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity

et al. 2018

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CRM1/XPO1 (CRM1) is a nuclear export chaperone that mediates the export of proteins essential to growth regulation and tumor suppression. Its overexpression in tumors was found to be associated with poor prognosis. Selective inhibitors of nuclear export are in phase I and II clinical trials for several tumor types. Our aim was to investigate CRM1 expression in pancreatic adenocarcinoma (PAC) and its relationship to survivin expression and the proliferative activity. Sections of tissue microarray containing 76 formalin fixed and paraffin embedded PAC were stained by immunohistochemistry (IHC) for CRM1, survivin, and Cyclin A. Expression levels of CRM1 and survivin and the proliferative activity, the S-phase fraction (SPF) in tumor cells, were determined using a quantitative digital image analysis solution (OTMIAS). Sixty-six of the 76 (86%) PAC showed positive staining for CRM1, and 10 (14%) were completely negative. The mean CRM1 expression levels ranged from 0.3 to 53 units and the median from 0.3 to 45 units. There was significant positive correlation between the mean and median expression levels of CRM1 in tumor cells and the mean and median levels of survivin (p<0.001). Moreover, there was positive correlation between the mean and median CRM1 levels in tumor cells and the SPF (p=0.013). Our results show that CRM1 is expressed in a significant proportion of PAC, and increased CRM1 levels correlates with increased survivin levels and increased proliferative activity.

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Section: Discussionmentioning

confidence: 99%

CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity

et al. 2018

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“… 19 , 20 Selinexor was effective in inducing apoptosis in cells from established AML cell lines that are in the G0/G1 phase of the cell cycle, 21 and targeting it also abrogated hypoxia-induced drug resistance in multiple myeloma cells. 22 These results suggest that targeting XPO1 with selinexor may have potent anti-proliferative effects against non-proliferating or slowly proliferating leukemia-initiating cells in primary AML unlike the limitation observed when using FLT3 inhibitors. 19 In addition, the recent results of phase I/II trials using selinexor as monotherapy (e.g.…”

Section: Introductionmentioning

confidence: 88%

Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial

Zhang

Ishizawa

et al. 2018

Haematologica

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Targeted therapies against FLT3-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (e.g., XPO1) and FLT3 concomitantly may be therapeutically effective. Here we report on the combinatorial inhibition of XPO1 using selinexor and FLT3 using sorafenib. Selinexor exerted marked cell killing of human and murine FLT3-mutant acute myeloid leukemia cells, including those harboring internal tandem duplication and/or tyrosine kinase domain point mutations. Interestingly, selinexor treatment of murine FLT3-mutant acute myeloid leukemia cells activated FLT3 and its downstream MAPK or AKT signaling pathways. When combined with sorafenib, selinexor triggered marked synergistic pro-apoptotic effects. This was preceded by elevated nuclear levels of ERK, AKT, NFκB, and FOXO3a. Five days of in vitro combination treatment using low doses (i.e., 5 to 10 nM) of each agent promoted early myeloid differentiation of MOLM13 and MOLM14 cells without noticeable cell killing. The combinatorial therapy demonstrated profound in vivo anti-leukemia efficacy in a human FLT3-mutated xenograft model. In an ongoing phase IB clinical trial the selinexor/sorafenib combination induced complete/partial remissions in six of 14 patients with refractory acute myeloid leukemia, who had received a median of three prior therapies (ClinicalTrials.gov: NCT02530476). These results provide pre-clinical and clinical evidence for an effective combinatorial treatment strategy targeting XPO1 and FLT3 in FLT3- mutated acute myeloid leukemias.

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“…These findings suggested that SINEs may be selective specifically for myeloma cells, unlike LMB in prior studies. The sensitization of myeloma cells to doxorubicin, bortezomib, and carfilzomib in the presence of selinexor was further supported in later studies [35][36][37][38]. In 2014, Tai et al demonstrated that not only do SINEs induce apoptosis but they also block receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced nuclear factor (NF)-kB and NFATc1, key osteoclast differentiation regulators [39].…”

Section: Selinexormentioning

confidence: 89%

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

2020

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Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/ XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.

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Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma

Cited by 25 publications

References 44 publications

CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity

CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity

Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

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