Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase

Currie, Kevin S.; Kropf, Jeffrey E.; Lee, Tong; Blomgren, Peter; Xu, Jianjun; Zhao, Zheng; Gallion, Steve; Whitney, J. Andrew; Maclin, Deborah; Lansdon, E.B.; Maciejewski, Patrícia; Rossi, Ann Marie; Rong, Hong; Macaluso, Jennifer; Barbosa, James A.; Paolo, Julie A. Di; Mitchell, Scott A.

doi:10.1021/jm500228a

Cited by 139 publications

(120 citation statements)

References 50 publications

(102 reference statements)

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“…The SYK (spleen tyrosine kinase) gene is a member of the family of non-receptor type tyrosine protein kinases and high SYK expression is believed to play a role in cell migration and invasion and is significantly correlated with worse survival in HNSCC [56,57]. This target may be selectively targeted using GS-9973 [58]. PDGFA is a member of the platelet-derived growth factor family and is a mitogenic factor for cells of mesenchymal origin.…”

Section: Discussionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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The role of molecular methods in the diagnosis of head and neck cancer is rapidly evolving and holds great potential for improving outcomes for all patients who suffer from this diverse group of malignancies. However, there is considerable debate as to the best clinical approaches, particularly for Next Generation Sequencing (NGS). The choices of NGS methods such as whole exome, whole genome, whole transcriptomes (RNA-Seq) or multiple gene resequencing panels, each have strengths and weakness based on data quality, the size of the data, the turnaround time for data analysis, and clinical actionability. There have also been a variety of gene expression signatures established from microarray studies that correlate with relapse and response to treatment, but none of these methods have been implemented as standard of care for oropharyngeal squamous cell carcinoma (OPSCC). Because many genomic methodologies are still far from the capabilities of most clinical laboratories, we chose to explore the use of a combination of off the shelf targeted mutation analysis and gene expression analysis methods to complement standard anatomical pathology methods. Specifically, we have used the Ion Torrent AmpliSeq cancer panel in combination with the NanoString nCounter Human Cancer Reference Kit on 8 formalin-fixed paraffin embedded (FFPE) OPSCC tumor specimens, (4) HPVpositive and (4) HPV-negative. Differential expression analysis between HPV-positive and negative groups showed that expression of several genes was highly likely to correlate with HPV status. For example, WNT1, PDGFA and OGG1 were all over-expressed in the positive group. Our results show the utility of these methods with routine FFPE clinical specimens to identify potential therapeutic targets which could be readily applied in a clinical trial setting for clinical laboratories lacking the instrumentation or bioinformatics infrastructure to support comprehensive genomics workflows. To the best of our knowledge, these preliminary experiments are among the earliest to combine both mutational and gene expression profiles using Ion Torrent and NanoString technologies. This reports serves as a proof of principle methodology in OPSCC.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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“…Broad kinase panel screening revealed a greater selectivity of entospletinib vs R406. 12 Dissociation constant (K d ) determinations of the strongest hits from the broad panel KINOMEscan (DiscoveRx Corporation, San Diego, CA) showed that aside from Syk itself, only 1 kinase, TNK1, had a K d , 100 nM for entospletinib, whereas 79 kinases had K d , 100 nM for R406 (Figure 1). In healthy volunteers, entospletinib at BID doses higher than 200 mg demonstrated inhibition of Syk activity, as measured by CD63 expression and phospho-Syk.…”

Section: Introductionmentioning

confidence: 99%

“…13 Because of its excellent selectivity profile, entospletinib was hypothesized to provide high levels of Syk inhibition with potentially fewer off-target adverse effects (AEs) than observed with fostamatinib. 12 In this phase 2 trial, the safety and efficacy of entospletinib was tested in separate cohorts of subjects with CLL, indolent nonHodgkin lymphoma, mantle cell lymphoma (MCL), or diffuse large B-cell lymphoma (DLBCL). In this article, we report the efficacy of entospletinib in the cohort of subjects with relapsed or refractory CLL and the initial safety results from all patients enrolled in the study.…”

Section: Introductionmentioning

confidence: 99%

An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia

Sharman

Hawkins

Kolibaba

et al. 2015

Blood

153

131

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• Entospletinib is a selective inhibitor of spleen tyrosine kinase, which is implicated in the pathobiology of B-cell lymphoid malignancies.• Entospletinib shows clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity.Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n 5 41) or nonHodgkin lymphoma (n 5 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n 5 41) and safety outcomes in all cohorts (N 5 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889. (Blood. 2015;125(15):2336-2343

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“…57 Ongoing combination studies of lenalidomide include those with obinutuzumab (NCT02225275, Syk is therefore a viable target and GS-9973 (entospletinib) is under development as a selective Syk inhibitor. 75,76 A phase II study in R/R CLL showed an ORR of 61%, and serious adverse events included dyspnea, pneumonia, fever and febrile neutropenia76 CD37 is a cell surface marker seen on mature B cells and is expressed on CLL cells at a high level. 74 Otlertuzumab (TRU-016), a novel humanized anti-CD37 protein has been studied in a phase I study in R/R CLL and also in combination with rituximab.…”

Section: Immunomodulators and Other Immune Based Treatments In Cllmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

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U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapyDisclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del [17p]).This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general tr...

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Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase

Cited by 139 publications

References 50 publications

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

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