Publications by authors named "Sharon Shacham"

Article Synopsis
  • The nuclear export receptor XPO1 is commonly overexpressed in cancer cells, leading to mislocalization of important proteins; the inhibitor selinexor reverses this effect by blocking XPO1-cargo binding.
  • Selinexor triggers the degradation of XPO1 through a specific mechanism involving the cullin-RING E3 ubiquitin ligase (CRL) system and its substrate receptor ASB8.
  • Research using cryogenic electron microscopy revealed that selinexor stabilizes XPO1 in a unique conformation, allowing ASB8 to bind effectively and facilitate ubiquitination, showcasing a new method of protein degradation that differs from previously known molecular glue strategies.
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Purpose: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC.

Patients And Methods: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries.

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Article Synopsis
  • * Data from 11 heavily pretreated patients indicate that selinexor (X) regimens show strong effectiveness and produce lasting responses, even when used later in treatment.
  • * X-containing regimens resulted in better overall response rates and longer progression-free survival compared to previous anti-BCMA treatments, highlighting their potential in addressing an ongoing treatment gap.
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Chordoma is a rare cancer that grows in the base of the skull and along the mobile spine from remnants of embryonic notochord tissue. The cornerstone of current treatments is surgical excision with adjuvant radiation therapy, although complete surgical removal is not always possible. Chordomas have high rates of metastasis and recurrence, with no approved targeted agents.

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NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations.

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Article Synopsis
  • Patients with higher-risk myelodysplastic syndromes (MDS) who don't respond to standard treatments face limited options and a short survival expectancy of 3-5 months.
  • Eltanexor, an investigational oral drug showing promise in preclinical studies, was evaluated in a clinical trial for its effectiveness and safety in these patients, demonstrating an overall response rate of 53.3%.
  • The trial found that eltanexor was generally well tolerated, with manageable side effects like nausea and diarrhea, and the median overall survival for treated patients was approximately 9.86 months.
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Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies.

Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort.

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Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study.

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Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease.

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Article Synopsis
  • Proteasome inhibitors, such as carfilzomib, enhance the effectiveness of selinexor, a new oral treatment, in battling multiple myeloma (MM) based on preclinical studies.
  • A clinical trial involving 32 patients assessed the safety, maximum-tolerated dose (MTD), and efficacy of selinexor combined with carfilzomib and dexamethasone, finding significant adverse effects but manageable under supportive care.
  • The combination treatment led to an impressive 78% overall response rate, with a median progression-free survival of 15 months, indicating that weekly XKd is both effective and well-tolerated for relapsed refractory MM patients.
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Purpose: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma.

Patients And Methods: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled.

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Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring mutations.

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Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor.

Patients And Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate.

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Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM).

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Selinexor, a selective inhibitor of nuclear export, has demonstrated promising activity in patients with acute myeloid leukemia (AML). This randomized, phase II study evaluated selinexor 60 mg twice weekly ( = 118) physician's choice (PC) treatment ( = 57) in patients aged ≥60 years with relapsed/refractory (R/R) AML. The primary outcome was overall survival (OS).

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Article Synopsis
  • Patients with relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL) have poor treatment options and an expected survival of less than 6 months, but the SADAL study showed that the oral medication selinexor achieved an overall response rate of 29.1% and a median duration of response of 9.3 months.
  • In the study, the median overall survival (OS) was 9.0 months overall, with patients responding to selinexor experiencing even better outcomes, particularly those under 70 years of age.
  • Further research is planned to explore the use of selinexor in combination with other therapies for DLBCL, given its promising results for patients with limited alternatives
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The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways.

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Article Synopsis
  • - In the phase 3 BOSTON study, patients with multiple myeloma (MM) received either weekly selinexor combined with bortezomib-dexamethasone (XVd) or the standard twice-weekly bortezomib-dexamethasone (Vd), with XVd showing significant improvements in progression-free survival (PFS) and overall response rate (ORR).
  • - Results indicated that patients with high-risk MM had a median PFS of 12.91 months with XVd compared to 8.61 months with Vd, and ORRs were 78.6% for XVd versus 57.7% for Vd.
  • - The study
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The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis.

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Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size).

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Article Synopsis
  • Therapeutic options for previously treated multiple myeloma have limited effectiveness and can cause serious side effects, like peripheral neuropathy.
  • In the Phase 3 BOSTON study, the combination of selinexor, bortezomib, and dexamethasone (XVd) significantly outperformed the standard treatment (Vd) in terms of progression-free survival, response rates, and severity of side effects.
  • XVd showed the most benefits for patients with fewer previous treatments, especially those who hadn't received a proteasome inhibitor or prior stem cell transplant, suggesting it may be a better option for early treatment phases.
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