Therapeutic Potential of Directed Tyrosine Kinase Inhibitor Therapy
Therapeutic Potential of Directed Tyrosine Kinase Inhibitor Therapy
Background: Sarcomas are rare mesenchymally derived tumors for which there are limited treatment options. This paper discusses the current therapeutic potential of directed tyrosine kinase inhibitors (TKIs) in sarcoma.
Methods: The authors review antibody-based strategies and small molecular inhibitors of TKIs, with specific emphasis placed on the potential use of these targeted agents as therapeutic options for the treatment of sarcomas that are not gastrointestinal stromal tumors.
Results: Many TKs have been shown to be mutated or overexpressed in human sarcoma tumors and cell lines and may serve as potential targets for promising new sarcoma therapies. Furthermore, the novel mechanism of targeting TKs may complement the antitumor activity of existing sarcoma treatment options.
Conclusions: TKIs such as imatinib, sunitinib, and sorefanib are promising new therapeutic options for the management of patients with soft tissue sarcoma.
Sarcomas are rare and diverse malignancies that arise from mesenchymally derived connective tissues. They are a heterogeneous group of malignancies with more than 50 different types that vary in their clinical presentation, disease course, histology grade, growth rate, and metastatic potential. With approximately 12,000 new cases diagnosed each year nationwide, sarcomas account for a small fraction of all newly diagnosed cancers in the United States. Sarcomas, however, represent more than 20% of newly diagnosed pediatric malignancies and are among the cancers that confer the greatest risk of mortality and morbidity in children and young adults.
Surgical management remains the mainstay of treatment of localized disease. Anthracycline-based chemotherapy is an option for advanced disease; however, effective treatment of advanced soft tissue remains a challenge. Various combinations and dosages of conventional chemotherapeutic agents have not achieved significant improvements in overall survival.
Advances in understanding the genetic nature of cancer have led to the development of new treatment options for sarcoma. For example, gastrointestinal stromal tumors (GISTs) that harbor activating mutations in the c-kit gene are sensitive to treatment with imatinib mesylate, a tyrosine kinase inhibitor (TKI), whereas those without c-kit mutations are less sensitive. Evidence presented at the 2004 meeting of the American Society of Clinical Oncology (ASCO) demonstrated that patients with liposarcoma, leiomyosarcoma, and fibrosarcoma had objective response rates to imatinib despite absence of a c-kit mutation. Patients with advanced GIST who have progressed on imatinib treatment have a partial response rate of 8% and a stable disease rate of 70% when treated with sunitinib malate. This is a broad-spectrum, orally available, multitargeted TKI of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, and FLT-3 kinase. Sunitinib was approved by the US Food and Drug Administration for imatinib-refractory or intolerant GIST in January 2006. A plethora of novel drugs are in various stages of clinical development for GISTs. The example of GIST is encouraging and might become a model for developing new agents for the other sarcoma subtypes.
Abstract and Introduction
Abstract
Background: Sarcomas are rare mesenchymally derived tumors for which there are limited treatment options. This paper discusses the current therapeutic potential of directed tyrosine kinase inhibitors (TKIs) in sarcoma.
Methods: The authors review antibody-based strategies and small molecular inhibitors of TKIs, with specific emphasis placed on the potential use of these targeted agents as therapeutic options for the treatment of sarcomas that are not gastrointestinal stromal tumors.
Results: Many TKs have been shown to be mutated or overexpressed in human sarcoma tumors and cell lines and may serve as potential targets for promising new sarcoma therapies. Furthermore, the novel mechanism of targeting TKs may complement the antitumor activity of existing sarcoma treatment options.
Conclusions: TKIs such as imatinib, sunitinib, and sorefanib are promising new therapeutic options for the management of patients with soft tissue sarcoma.
Introduction
Sarcomas are rare and diverse malignancies that arise from mesenchymally derived connective tissues. They are a heterogeneous group of malignancies with more than 50 different types that vary in their clinical presentation, disease course, histology grade, growth rate, and metastatic potential. With approximately 12,000 new cases diagnosed each year nationwide, sarcomas account for a small fraction of all newly diagnosed cancers in the United States. Sarcomas, however, represent more than 20% of newly diagnosed pediatric malignancies and are among the cancers that confer the greatest risk of mortality and morbidity in children and young adults.
Surgical management remains the mainstay of treatment of localized disease. Anthracycline-based chemotherapy is an option for advanced disease; however, effective treatment of advanced soft tissue remains a challenge. Various combinations and dosages of conventional chemotherapeutic agents have not achieved significant improvements in overall survival.
Advances in understanding the genetic nature of cancer have led to the development of new treatment options for sarcoma. For example, gastrointestinal stromal tumors (GISTs) that harbor activating mutations in the c-kit gene are sensitive to treatment with imatinib mesylate, a tyrosine kinase inhibitor (TKI), whereas those without c-kit mutations are less sensitive. Evidence presented at the 2004 meeting of the American Society of Clinical Oncology (ASCO) demonstrated that patients with liposarcoma, leiomyosarcoma, and fibrosarcoma had objective response rates to imatinib despite absence of a c-kit mutation. Patients with advanced GIST who have progressed on imatinib treatment have a partial response rate of 8% and a stable disease rate of 70% when treated with sunitinib malate. This is a broad-spectrum, orally available, multitargeted TKI of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, and FLT-3 kinase. Sunitinib was approved by the US Food and Drug Administration for imatinib-refractory or intolerant GIST in January 2006. A plethora of novel drugs are in various stages of clinical development for GISTs. The example of GIST is encouraging and might become a model for developing new agents for the other sarcoma subtypes.