A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies

Ho, Jingshan; Heong, Valerie; Yong, Wei Peng; Soo, Ross A.; Chee, Cheng Ean; Wong, Andrea Li‐Ann; Sundar, Raghav; Thian, Yee Liang; Gopinathan, Anil; Pang, Mei Yan; Koe, Priscillia; Jeraj, Santhiay Nathan; Soe, Phyu Pyar; Soe, Mu Yar; Tang, Tiffany; Ng, Matthew; Tai, David; Tan, Tira J.; Xu, Hongmei; Chang, Hua; Landesman, Yosef; Shah, Jatin J.; Shacham, Sharon; Lee, Soo‐Chin; Tan, Daniel Shao-Weng; Goh, Boon Cher; Tan, David S.P.

doi:10.1177/17588359221087555

Cited by 5 publications

(2 citation statements)

References 34 publications

(49 reference statements)

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“…In 2019 FDA approved Selinexor for hematological malignancies such as Multiple myeloma and lymphoma (25). However, Selinexor has also shown promising results against solid tumors in preclinical animal models and clinical trials (42)(43)(44). Selinexor is delivered orally, and thus it has the potential to be combined with OV delivered either intratumorally or systemically.…”

Section: Discussionmentioning

confidence: 99%

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Rahman¹,

Oosterom²,

Enow³

et al. 2022

Preprint

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Oncolytic viruses exploited for cancer therapy are developed to selectively infect, replicate, and kill cancer cells to stop tumor growth. However, in some cancer cells, oncolytic viruses are often limited in completing their full replication cycle, making progeny virions, and/or spread in the tumor bed due to the heterogeneous cell types within the tumor bed. Here we report that nuclear export pathway regulates oncolytic myxoma virus (MYXV) infection and cytoplasmic viral replication in a subclass of human cancer cell types where virus replication is restricted. Inhibition of CRM1/XPO-1 nuclear export pathway with nuclear export inhibitors can overcome this restriction by trapping restriction factors in the nucleus and allow significantly enhanced virus replication and killing of human cancer cells. Furthermore, knockdown of CRM1/XPO-1 significantly enhanced MYXV replication in restrictive human cancer cells and reduced the formation of anti-viral granules associated with RNA helicase DHX9. Both in vitro and in vivo, we demonstrate that the approved CRM1 inhibitor drug Selinexor enhances the replication of MYXV and cell killing of diverse human cancer cells. In the xenograft tumor model in NSG mice, combination therapy with Selinexor plus MYXV significantly reduced tumor burden and enhanced the survival of animals. Additionally, we performed global scale proteomic analysis of nuclear and cytosolic proteins in human cancer cells to identify the host and viral proteins that are upregulated or downregulated by different treatments. These results for the first time indicate that Selinexor in combination with oncolytic MYXV can be used as potential new anti-cancer therapy.

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Section: Discussionmentioning

confidence: 99%

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Rahman¹,

Oosterom²,

Enow³

et al. 2022

Preprint

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“…For advanced and metastatic malignancies, Selinexor has demonstrated a promising safety and efficacy profile. A Phase 1 study underscored its tolerability in patients with a range of advanced cancers, suggesting a potential for broader applicability (15).…”

Section: Selinexor In Nonhematologic Malignanciesmentioning

confidence: 99%

Beyond oncology: Selinexor’s journey into anti-inflammatory treatment and long-term management

Li,

Fang,

Zhang

et al. 2024

Front. Immunol.

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Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor’s dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug’s impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson’s Disease. The review emphasizes the criticality of managing Selinexor’s side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor’s long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders.

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Nuclear transport proteins: structure, function, and disease relevance

Yang,

Guo,

Chen

et al. 2023

Sig Transduct Target Ther

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Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport. Many of these nuclear transport proteins play additional and essential roles in mitosis, biomolecular condensation, and gene transcription. Dysregulation of nuclear transport is linked to major human diseases such as cancer, neurodegenerative diseases, and viral infections. Selinexor (KPT-330), an inhibitor targeting the nuclear export factor XPO1 (also known as CRM1), was approved in 2019 to treat two types of blood cancers, and dozens of clinical trials of are ongoing. This review summarizes approximately three decades of research data in this field but focuses on the structure and function of individual nuclear transport proteins from recent studies, providing a cutting-edge and holistic view on the role of nuclear transport proteins in health and disease. In-depth knowledge of this rapidly evolving field has the potential to bring new insights into fundamental biology, pathogenic mechanisms, and therapeutic approaches.

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A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies

Cited by 5 publications

References 34 publications

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Beyond oncology: Selinexor’s journey into anti-inflammatory treatment and long-term management

Nuclear transport proteins: structure, function, and disease relevance

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