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Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives.

ABSTRACT: Selective inhibitors of nuclear export (SINE) are emerging as a potentially efficacious therapeutic strategy for overcoming resistance to conventional chemotherapy for acute myeloid leukemia. SINE specifically block the protein Exportin 1, also known as chromosomal region maintenance 1, leading to nuclear retention of cargo proteins, including several tumor suppressor proteins. Selinexor, a first generation SINE, is currently in early phase clinical studies in various combinations with promising antileukemic and pro-apoptotic activity. Here we discuss the mechanism of action of SINEs and further elaborate on the clinical data available from the various trials in acute myeloid leukemia.

SUBMITTER: Talati C

PROVIDER: S-EPMC6219429 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives.

Talati Chetasi C Sweet Kendra L KL

International journal of hematologic oncology 20180911 3

Selective inhibitors of nuclear export (SINE) are emerging as a potentially efficacious therapeutic strategy for overcoming resistance to conventional chemotherapy for acute myeloid leukemia. SINE specifically block the protein Exportin 1, also known as chromosomal region maintenance 1, leading to nuclear retention of cargo proteins, including several tumor suppressor proteins. Selinexor, a first generation SINE, is currently in early phase clinical studies in various combinations with promising ...[more]

PMID: 30405902

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Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

Dataset Information

Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives.

Publications

Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives.

Similar Datasets

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