Selinexor and dexamethasone in multiple myeloma

Burki, Talha

doi:10.1016/s1470-2045(18)30089-5

Cited by 6 publications

(4 citation statements)

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“…More than 1000 patients have been exposed to selinexor in these trials combined. The published results of several of these trials have shown evaluable response in patients and support the safety and efficacy of selinexor for the treatment of cancer [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ].…”

Section: Chemical Inhibition Of Nuclear Exporter Function In Cancementioning

confidence: 82%

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Muqbil

Azmi

Mohammad

2018

Cancers

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Pancreatic cancer is a deadly disease that is resistant to most available therapeutics. Pancreatic cancer to date has no effective drugs that could enhance the survival of patients once their disease has metastasized. There is a need for the identification of novel actionable drug targets in this unusually recalcitrant cancer. Nuclear protein transport is an important mechanism that regulates the function of several tumor suppressor proteins (TSPs) in a compartmentalization-dependent manner. High expression of the nuclear exporter chromosome maintenance region 1 (CRM1) or exportin 1 (XPO1), a common feature of several cancers including pancreatic cancer, results in excessive export of critical TSPs to the incorrect cellular compartment, leading to their functional inactivation. Small molecule inhibitors of XPO1 can block this export, retaining very important and functional TSPs in the nucleus and leading to the effective killing of the cancer cells. This review highlights the current knowledge on the role of XPO1 in pancreatic cancer and how this serves as a unique and clinically viable target in this devastating and by far incurable cancer.

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Section: Chemical Inhibition Of Nuclear Exporter Function In Cancementioning

confidence: 82%

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Muqbil

Azmi

Mohammad

2018

Cancers

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“…Although the treatment effects of KPT on multiple myeloma and lymphoma have been proved, , and there are currently available preparations on the market, whether it has an inhibitory effect on 4T1 tumor cells has not been reported. Our results showed that KPT and its nanoparticles could inhibit 4T1 cell proliferation in a concentration-dependent manner (Figures A,B and S4).…”

Section: Resultsmentioning

confidence: 99%

“…At present, KPT preparation (Selinexor) has been used for clinical treatment of multiple myeloma and diffuse large B-cell lymphoma. Clinical studies have shown that the use of KPT has good efficacy and controllable safety. − It was reported that KPT treatment allows for normal CD8 T-cell functioning and development of antitumor immunity . Therefore, it is speculated that KPT may not promote the transformation of TAMs to M2 TAMs either.…”

Section: Introductionmentioning

confidence: 99%

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Yao

Tao

Lyu

et al. 2023

ACS Appl. Mater. Interfaces

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Mitochondria-targeting damage has become a popular therapeutic option for tumor metastasis; however, its efficacy is limited by the adaptive rescue capacity of nuclei. There is an urgent need for a dual mitochondrial and nuclear targeting strategy that can also increase the antitumor capacity of macrophages. In this study, XPO1 inhibitor KPT-330 nanoparticles were combined with mitochondria-targeting lonidamine (TPP-LND) nanoparticles. The combination of nanoparticles with a 1:4 ratio of KPT and TL demonstrated the best synergistic effect in restraining the proliferation and metastasis of 4T1 breast cancer cells. Investigating the mechanisms both in vitro and in vivo, it was found that KPT nanoparticles not only directly impede tumor growth and metastasis by controlling the expression of associated proteins but also indirectly facilitate mitochondrial damage. The two nanoparticles synergistically decreased the expression of cytoprotective factors, such as Mcl-1 and Survivin, causing mitochondrial dysfunction and thus inducing apoptosis. Additionally, it downregulated metastasis-related proteins like HIF-1α, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2 (MMP-2) and reduced endothelial-to-mesenchymal transition. Significantly, their combination increased the ratio of M1 tumor-associated macrophages (TAMs)/M2 TAMs both in vitro and in vivo and increased the phagocytosis of tumor cells by macrophages, thus suppressing tumor growth and metastasis. In summary, this research revealed that nuclear export inhibition can synergistically enhance the prevention of mitochondrial damage to tumor cells, heightening the antitumor properties of TAMs, thereby providing a viable and safe therapeutic approach for the treatment of tumor metastasis.

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“…The efficacy of carfilzomib/panobinostat was studied in a phase I/II clinical trial setting and shown to be beneficial for relapsed/refractory MM patients [42]. The combination of selinexor/dexamethasone has recently shown encouraging activity in a phase II trial involving highly refractory MM patients, leading to its FDA approval [43]. Further, adding liposomal doxorubicin to the combination of selinexor/ dexamethasone for relapsed and refractory MM patients is being currently studied as a phase I trial [44].…”

Section: Discussionmentioning

confidence: 99%

A pharmacodynamic model of clinical synergy in multiple myeloma

et al. 2020

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Background: Multiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires highthroughput combination screening tools to better allocate treatment, and facilitate personalized therapy. Methods: A second-order drug response model was employed to fit patient-specific ex vivo responses of 203 MM patients to single-agent models. A novel pharmacodynamic model, developed to account for twoway combination effects, was tested with 130 two-drug combinations. We have demonstrated that this model is sufficiently parameterized by single-agent and fixed-ratio combination responses, by validating model estimates with ex vivo combination responses for different concentration ratios, using a checkerboard assay. This new model reconciles ex vivo observations from both Loewe and BLISS synergy models, by accounting for the dimension of time, as opposed to focusing on arbitrary time-points or drug effect. Clinical outcomes of patients were simulated by coupling patient-specific drug combination models with pharmacokinetic data. Findings: Combination screening showed 1 in 5 combinations (21.43% by LD50, 18.42% by AUC) were synergistic ex vivo with statistical significance (P < 0.05), but clinical synergy was predicted for only 1 in 10 combinations (8.69%), which was attributed to the role of pharmacokinetics and dosing schedules. Interpretation: The proposed framework can inform clinical decisions from ex vivo observations, thus providing a path toward personalized therapy using combination regimens.

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Selinexor and dexamethasone in multiple myeloma

Cited by 6 publications

References 0 publications

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

A pharmacodynamic model of clinical synergy in multiple myeloma

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