Tyrosine kinase inhibitors in sarcoma treatment (Review)

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. Contents 1. Introduction 2. Methods 3. Results of the literature meta-analysis 4. Discussion 5. Conclusion

Head and Neck Mesenchymal Tumors with Kinase Fusions

“…Recently, TRK inhibitors, larotrectinib, and entrectinib, have been approved by the Food and Drug Administration (FDA) to treat advanced or metastatic NTRK- rearranged cancers, including sarcoma 44. Other tyrosine kinase inhibitors are also used in treating mesenchymal tumors with kinase fusions in clinical trials 45…”

Effectiveness and Tolerability of Anlotinib Plus PD-1 Inhibitors for Patients with Previously Treated Metastatic Soft-Tissue Sarcoma

“…22 Noteworthily, although the development of targeted drugs was scanty own to the heterogeneity of STS and the absence of driver mutation, some previous work had explored that the angiogenetic pathway might be one of the promising targets clinically. 23 Patients included in the present study were the metastatic STS who had received at least first-line systemic chemotherapy treatment, similar as the baseline characteristics of ALTER0203 clinical trial, which suggested that the combination administration of anlotinib plus PD-1 blockades was reasonable and ethical, given that anlotinib had the indication for patients with previously treated metastatic STS in China. To our knowledge, the ORR and DCR of anlotinib monotherapy for patients with previously treated metastatic STS was 13% and 74%, respectively.…”

“… 22 Noteworthily, although the development of targeted drugs was scanty own to the heterogeneity of STS and the absence of driver mutation, some previous work had explored that the angiogenetic pathway might be one of the promising targets clinically. 23 …”

Locally advanced undifferentiated small round cell sarcoma of the lung with novel SDCCAG8-AKT3 fusion and type II tumor immunity in the microenvironment: a rare case report

“…For unresectable and metastatic STS, chemotherapy including doxorubicin and cyclophosphamide has recommended for decades, although with limited efficacy (1). Some clinical trials of small sample size on advanced sarcoma have indicated that anlotinib (10,11) or immunotherapy (12,13) are potential treatment options in chemotherapy-resistant patients and the objective response rate (ORR) ranges from 13% to 40%. However, a standard treatment for USRCS is still unavailable.…”