Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC

Bauer, Todd M.; Besse, Benjamin; Martinez-Martí, Alex; Trigo, José; Moreno, Víctor; Garrido, P.; Ferron‐Brady, Geraldine; Wu, Yuehui; Park, Jennifer; Collingwood, Therese S.; Kruger, Ryan G.; Mohammad, Helai P.; Ballas, Marc; Dhar, Arindam; Govindan, Ramaswamy

doi:10.1016/j.jtho.2019.06.021

Cited by 57 publications

(32 citation statements)

References 25 publications

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“…A major issue noted in early clinical trials of LSD1 inhibitors is development of dose-dependent thrombocytopenia (44). Although we did not observe hematologic toxicity in healthy mice treated with GSK2879552 either alone or in combination with ruxolitinib and the combination was also well tolerated in leukemic mice, this remains a serious concern.…”

Section: Discussioncontrasting

confidence: 58%

Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Braun

Coblentz

Curtiss

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

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Section: Discussioncontrasting

confidence: 58%

Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Braun

Coblentz

Curtiss

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…LSD1 inhibitors (ORY1001, GSK2879552, tranylcypromine) induce cell cycle arrest and apoptosis by regulating the hexokinase 2 expression and increase the expression of the transcriptional repressor GFI1 as well as the transcription factor PU.1, thus inducing differentiation [44,45]. However, a recent phase I open-label trial of the LSD1 inhibitor GSK2879552 was terminated early due to poor disease control and an unfavourable sideeffect profile [46]. JmjC domain-containing protein inhibitors (GSK-J1, GSK-J4) induce apoptosis and inhibit tumour growth by increasing global levels of repressive trimethylated H3K27 and downregulating cancerpromoting HOX genes [47,48].…”

Section: Figure 5: Mechanism Of Action Of Hdacismentioning

confidence: 99%

Advances in Epigenetic Cancer Therapeutics

Hillyar¹,

Rallis²,

Varghese³

2020

Cureus

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Cancer has traditionally been hailed a genetic disease, dictated by successive genetic aberrations which alter gene expression. Yet, recent advances in molecular sequencing technologies, enabling the characterisation of cancer patient phenotypes on a large scale, have highlighted epigenetic changes as a hallmark of cancer. Epigenetic modifications, including DNA methylation and demethylation and histone modifications, have been found to play a key role in the pathogenesis of a wide variety of cancers through the regulation of chromatin state, gene expression and other nuclear events. Targeting epigenetic aberrations offers remarkable promise as a potential anti-cancer therapy given the reversible nature of epigenetic changes. Hence, epigenetic therapy has emerged as a rapidly advancing field of cancer research. A plethora of epigenetic therapies which inhibit enzymes of post-translational histone modifications, so-called 'writers', 'erasers' and 'readers', have been developed, with several epigenetic inhibitor agents approved for use in routine clinical practice. Epigenetic therapeutics inhibit the methylation or demethylation and acetylation or deacetylation of DNA and histone proteins. Their targets include writers (DNA methyltransferases [DNMT], histone acetyltransferases [HAT] and histone deacetylases [HDAC]) and erasers (histone demethylases [HDM] and histone methylases [HMT]). With new epigenetic mechanisms increasingly being elucidated, a vast array of targets and therapeutics have been brought to the fore. This review discusses recent advances in cancer epigenetics with a focus on molecular targets and mechanisms of action of epigenetic cancer therapeutics.

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“…Unfortunately, Notch signaling inhibition with Rova-T and tarextumab have failed, but combination therapies studies are ongoing that could potentially yield positive results. Lysine demethylase 1 (LSD1) is implicated in maintaining stemness properties and hence, has emerged as a potential target for inhibiting lung CSCs [124]. A phase II trial (CLEPSIDRA) investigating the LSD1 inhibitor iadademstat in combination with standard-of-care in relapsing SCLC patients showed remarkable response rates (up to 75%).…”

Section: Stem Cell Therapymentioning

confidence: 99%

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research

Subbiah

Nam

Garg

et al. 2020

JCM

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Small cell lung cancer (SCLC) is an aggressive, complex disease with a distinct biology that contributes to its poor prognosis. Management of SCLC is still widely limited to chemotherapy and radiation therapy, and research recruitment still poses a considerable challenge. Here, we review the current standard of care for SCLC and advances made in utilizing immunotherapy. We also highlight research in the development of targeted therapies and emphasize the importance of a team-based approach to make clinical advances. Building an integrative network between an academic site and community practice sites optimizes biomarker and drug target discovery for managing and treating a difficult disease like SCLC.

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Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC

Cited by 57 publications

References 25 publications

Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Advances in Epigenetic Cancer Therapeutics

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research

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