Tyrosine kinase inhibitors in sarcoma treatment

Abstract

Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.