The Experts below are selected from a list of 33204 Experts worldwide ranked by ideXlab platform

Suzanne George - One of the best experts on this subject based on the ideXlab platform.

  • Gastrointestinal Stromal Tumor challenges and opportunities for a new decade
    Clinical Cancer Research, 2020
    Co-Authors: Cesar Serrano, Suzanne George
    Abstract:

    Gastrointestinal Stromal Tumor (GIST) provides a paradigm to evaluate new molecularly targeted therapies and to identify structural and functional mechanisms for drug response and resistance. Drug development in GIST has successfully exploited the high reliance on KIT/PDGFRA oncogenic signaling as a therapeutic vulnerability. The recent arrival of avapritinib and ripretinib to the GIST arena has aimed to further improve on precision kinase inhibition and address Tumor heterogeneity in imatinib-resistant GIST. The two main clinical challenges for the forthcoming years entail Tumor eradication in patients with early-stage GIST, and maximization of Tumor response in late-stage disease. To succeed, we will need to better understand the mechanisms behind adaptation to KIT inhibition and apoptosis evasion, Tumor evolution after successive lines of treatment, and to explore clinically novel creative therapeutic strategies, with the overarching goal to tackle the intrinsic oncogenic complexity while minimizing adverse events.

  • intrigue phase iii study of ripretinib versus sunitinib in advanced Gastrointestinal Stromal Tumor after imatinib
    Future Oncology, 2020
    Co-Authors: Margaret Von Mehren, John Nemunaitis, Sebastian Bauer, Jeanyves Blay, Khalil Choucair, Hans Gelderblom, Suzanne George, Patrick Schoffski, John Zalcberg
    Abstract:

    Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of Gastrointestinal Stromal Tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced Gastrointestinal Stromal Tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.

  • translational insights into Gastrointestinal Stromal Tumor and current clinical advances
    Annals of Oncology, 2018
    Co-Authors: Matthew L Hemming, Sebastian Bauer, Michael Heinrich, Suzanne George
    Abstract:

    Gastrointestinal Stromal Tumor (GIST) is the most common soft tissue sarcoma of the Gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.

  • mechanisms of resistance to imatinib and sunitinib in Gastrointestinal Stromal Tumor
    Cancer Chemotherapy and Pharmacology, 2011
    Co-Authors: Wei Lien Wang, Suzanne George, Anthony Paul Conley, David Reynoso, Laura K Nolden, Alexander J Lazar, Jonathan C. Trent
    Abstract:

    Gastrointestinal Stromal Tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase. It is becoming increasingly apparent that the binding affinity of imatinib for the receptor is dependent on the type and location of mutation. Within KIT, patients whose Tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.

John Nemunaitis - One of the best experts on this subject based on the ideXlab platform.

  • intrigue phase iii study of ripretinib versus sunitinib in advanced Gastrointestinal Stromal Tumor after imatinib
    Future Oncology, 2020
    Co-Authors: Margaret Von Mehren, John Nemunaitis, Sebastian Bauer, Jeanyves Blay, Khalil Choucair, Hans Gelderblom, Suzanne George, Patrick Schoffski, John Zalcberg
    Abstract:

    Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of Gastrointestinal Stromal Tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced Gastrointestinal Stromal Tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.

Jonathan C. Trent - One of the best experts on this subject based on the ideXlab platform.

  • switch control inhibition of kit and pdgfra in patients with advanced Gastrointestinal Stromal Tumor a phase i study of ripretinib
    Journal of Clinical Oncology, 2020
    Co-Authors: Filip Janku, Jonathan C. Trent, Margaret Von Mehren, Hans Gelderblom, Albiruni R A Razak, Ping Chi, Michael Heinrich, Robin L Jones, Kristen N Ganjoo, Neeta Somaiah
    Abstract:

    PURPOSEIn advanced Gastrointestinal Stromal Tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is ...

  • mechanisms of resistance to imatinib and sunitinib in Gastrointestinal Stromal Tumor
    Cancer Chemotherapy and Pharmacology, 2011
    Co-Authors: Wei Lien Wang, Suzanne George, Anthony Paul Conley, David Reynoso, Laura K Nolden, Alexander J Lazar, Jonathan C. Trent
    Abstract:

    Gastrointestinal Stromal Tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase. It is becoming increasingly apparent that the binding affinity of imatinib for the receptor is dependent on the type and location of mutation. Within KIT, patients whose Tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.

  • An unusual site of metastasis from Gastrointestinal Stromal Tumor.
    Rare tumors, 2010
    Co-Authors: Carolina Cauchi, Jonathan C. Trent, Kristin Edwards, Monica Davey, Massimo Lopez, Margaret Von Mehren
    Abstract:

    Gastrointestinal Stromal Tumors are mesenchymal Tumors of the Gastrointestinal tract. They commonly metastasize within the abdominal cavity, particularly to the liver. Less commonly, metastases can be found in the lung or bone. This report describes the first two cases of metastasis to the left ventricle in patients with advanced Gastrointestinal Stromal Tumor.

  • New developments in Gastrointestinal Stromal Tumor.
    Current opinion in oncology, 2006
    Co-Authors: Jonathan C. Trent, Robert S. Benjamin
    Abstract:

    Purpose of review This review will provide an update of important studies in Gastrointestinal Stromal Tumor with an emphasis on those published over the past 2 years. Recent findings Over the past 60 years basic scientists, pathologists and clinical investigators have studied Gastrointestinal Stromal Tumor with no major advances in patient care until the late 1990s. Discovery at that time of the critical biological role of Kit in Gastrointestinal Stromal Tumor led to the development of one of the most exciting examples of targeted therapy to date. The success of the Kit tyrosine kinase inhibitor, imatinib mesylate (Gleevec, formerly STI-571), has caught the attention of the medical community. With the use of targeted therapy in a targetable disease, new developments in our understanding of epidemiology, genetics, histopathology, radiographic imaging and the biology of Gastrointestinal Stromal Tumor have become apparent. Recent findings are discussed herein. Summary Continued intense study of Gastrointestinal Stromal Tumor may lead to new paradigms that could revolutionize all of oncology.

John Zalcberg - One of the best experts on this subject based on the ideXlab platform.

  • intrigue phase iii study of ripretinib versus sunitinib in advanced Gastrointestinal Stromal Tumor after imatinib
    Future Oncology, 2020
    Co-Authors: Margaret Von Mehren, John Nemunaitis, Sebastian Bauer, Jeanyves Blay, Khalil Choucair, Hans Gelderblom, Suzanne George, Patrick Schoffski, John Zalcberg
    Abstract:

    Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of Gastrointestinal Stromal Tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced Gastrointestinal Stromal Tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.

Margaret Von Mehren - One of the best experts on this subject based on the ideXlab platform.

  • switch control inhibition of kit and pdgfra in patients with advanced Gastrointestinal Stromal Tumor a phase i study of ripretinib
    Journal of Clinical Oncology, 2020
    Co-Authors: Filip Janku, Jonathan C. Trent, Margaret Von Mehren, Hans Gelderblom, Albiruni R A Razak, Ping Chi, Michael Heinrich, Robin L Jones, Kristen N Ganjoo, Neeta Somaiah
    Abstract:

    PURPOSEIn advanced Gastrointestinal Stromal Tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is ...

  • intrigue phase iii study of ripretinib versus sunitinib in advanced Gastrointestinal Stromal Tumor after imatinib
    Future Oncology, 2020
    Co-Authors: Margaret Von Mehren, John Nemunaitis, Sebastian Bauer, Jeanyves Blay, Khalil Choucair, Hans Gelderblom, Suzanne George, Patrick Schoffski, John Zalcberg
    Abstract:

    Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of Gastrointestinal Stromal Tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced Gastrointestinal Stromal Tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.

  • An unusual site of metastasis from Gastrointestinal Stromal Tumor.
    Rare tumors, 2010
    Co-Authors: Carolina Cauchi, Jonathan C. Trent, Kristin Edwards, Monica Davey, Massimo Lopez, Margaret Von Mehren
    Abstract:

    Gastrointestinal Stromal Tumors are mesenchymal Tumors of the Gastrointestinal tract. They commonly metastasize within the abdominal cavity, particularly to the liver. Less commonly, metastases can be found in the lung or bone. This report describes the first two cases of metastasis to the left ventricle in patients with advanced Gastrointestinal Stromal Tumor.