A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

Wang, Amy; Weiner, Howard; Green, Margaret; Chang, Hua; Fulton, Noreen; Larson, Richard A.; Odenike, Olatoyosi; Artz, Andrew S.; Bishop, Michael; Godley, Lucy A.; Thirman, Michael J.; Kosuri, Satyajit; Churpek, Jane E.; Curran, Emily; Pettit, Kristen; Stock, Wendy; Liu, Hongtao

doi:10.1186/s13045-017-0550-8

Cited by 58 publications

(37 citation statements)

References 35 publications

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“…The authors concluded that Selinexor is a safe therapy in AML patients, and established the RP2D at 35 mg/m 2 (60 mg flat dose) given twice weekly. Another phase I doseescalation trial in AML evaluated the combination of Selinexor with high-dose cytarabine and mitoxantrone in 20 patients [198] . Selinexor doses of 60 mg or 80 mg were administered.…”

Section: In Vitromentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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Section: In Vitromentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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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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“…Formalin-fixed paraffin-embedded sections (5 μm) were cut from untreated BALB/cJ mouse RENCA tumors. Immunohistochemistry was performed as previously described (31) using the following antibodies, Ki67 (Cell Marque, 275R-18), PD-L1 (Cell Signaling Technology, 13684) and PD-L2 (Cell Signaling Technology, 82723).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer

et al. 2020

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Background Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the US and is increasing in incidence. Despite new therapies, including targeted and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. While we have previously shown efficacy of the dual PAK4/NAMPT inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer. Methods In this study we utilize the RENCA model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal sacrifice for subsequent studies. Results We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors. Conclusion This study highlights the potential of the RENCA model for evaluating immunological responses to KPT-9274 and CPI and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.

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A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

Cited by 58 publications

References 35 publications

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Nuclear Export Inhibition for Pancreatic Cancer Therapy

Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer

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