Next Article in Journal
Natural History and Prognostic Factors at First Relapse in Multiple Myeloma
Next Article in Special Issue
A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas
Previous Article in Journal
Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy
Previous Article in Special Issue
Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 12
Issue 7
10.3390/cancers12071758
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma

by
Shinji Miwa
*,
Norio Yamamoto
,
Katsuhiro Hayashi
,
Akihiko Takeuchi
,
Kentaro Igarashi
and
Hiroyuki Tsuchiya
Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1758; https://doi.org/10.3390/cancers12071758
Submission received: 27 May 2020 / Revised: 22 June 2020 / Accepted: 30 June 2020 / Published: 2 July 2020
(This article belongs to the Special Issue Bone and Soft Tissue Tumors)
Review Reports Versions Notes

Abstract

:
Rhabdomyosarcoma, the most common soft tissue sarcoma noted in childhood, requires multimodality treatment, including chemotherapy, surgical resection, and/or radiation therapy. The majority of the patients with localized rhabdomyosarcoma can be cured; however, the long-term outcomes in patients with metastatic rhabdomyosarcoma remain poor. The standard chemotherapy regimen for patients with rhabdomyosarcoma is the combination of vincristine, actinomycin, and cyclophosphamide/ifosfamide. In recent clinical trials, modifications of the standard chemotherapy protocol have shown improvements in the outcomes in patients with rhabdomyosarcoma. In various type of malignancies, new treatments, such as molecular targeted drugs and immunotherapies, have shown superior clinical outcomes compared to those of standard treatments. Therefore, it is necessary to assess the benefits of these treatments in patients with rhabdomyosarcoma. Moreover, recent basic and clinical studies on rhabdomyosarcoma have reported promising therapeutic targets and novel therapeutic approaches. This article reviews the recent challenges and advances in the management of rhabdomyosarcoma.

1. Introduction

Rhabdomyosarcoma (RMS) arises from immature cells with the ability to differentiate into skeletal muscle cells in the future. RMS can arise from soft tissues, such as the skeletal muscle, connective tissue, bone, bladder, prostate, testis, nose, orbit, and anus [1]. Approximately 70% of the patients with RMS are diagnosed before the age of 10 years; however, RMS can also develop in adolescents and adults. It is a relatively rare cancer that accounts for only 5–8% of all childhood malignancies but is the most commonly noted type of soft tissue sarcoma in childhood. RMS is classified as embryonal RMS (ERMS), alveolar RMS (ARMS), pleomorphic RMS (PRMS), and spindle cell/sclerosing RMS (SRMS), based on the histological features [2,3,4]. Chromosomal translocations of t(2;13)(q35;q14) or t(1;13)(q36;q14) are detected in most patients with ARMS. Approximately 60% of the patients with ARMS express PAX3-FOXO1 and 20% of those express PAX7-FOXO1 [5,6]. The PAX-FOXO1 chimeric protein functions as an active transcription factor, leading to oncogenic transformation by inducing the expression of abnormal genes. Previous studies have reported that PAX-FOXO1 fusion proteins have oncogenic potential and function as dominant oncogenes in promoting tumorigenesis in fusion-positive RMS [7,8]. In contrast, specific chimeric genes are not associated with ERMS and the other types of RMS; however, these tumors are often associated with various chromosomal abnormalities, which, in turn, lead to the inactivation of the tumor suppressor gene p53 pathway [9,10]. Skapek et al. reported that positivity for PAX3-FOXO1 or PAX7-FOXO1 significantly correlated with worse event-free survival (EFS) and overall survival (OS) [11]. Based on these reports, PAX-FOXO1 may be considered a strong potential therapeutic target and biomarker predicting prognosis in RMS patients with PAX-FOXO1 translocation.
Standard treatment of RMS comprises chemotherapy (vincristine, actinomycin D, and cyclophosphamide/ifosfamide), radiation therapy, and surgical tumor excision. Although most patients with localized RMS can be cured, the outcomes in those with metastatic or recurrent RMS remain poor [12,13]. Approximately 15% of the patients with RMS have metastatic lesions at diagnosis [14], and long-term EFS in patients with metastatic RMS is <20% [15,16,17]. Therefore, there is a need to develop systemic treatments, which have better oncological and functional outcomes with long-term safety, for patients with RMS. Several basic and clinical studies have been carried out on various treatment strategies, including modified or novel chemotherapy protocols, molecular targeted drug therapy, immunotherapy, and new therapeutic approaches for RMS. In this review article, the recent challenges and advancements in the treatment of RMS are discussed.

2. Chemotherapy

Patients with RMS require multidisciplinary treatment, including chemotherapy, surgical resection and radiation therapy (RT). Multi-drug chemotherapy regimens significantly improved the outcome in patients with localized RMS, although no marked improvement has been observed in patients with metastatic RMS [18]. Standard chemotherapy regimens for RMS in North America include vincristine, actinomycin D, and cyclophosphamide (VAC), whereas those in Europe include ifosfamide, vincristine, and actinomycin D (IVA) [19,20,21]. In a randomized trial comparing the VAC and IVA regimens, significant differences in the clinical outcomes were not observed [22]. In contrast, high-dose chemotherapy was thought to improve the outcomes compared to standard chemotherapy in patients with metastatic RMS. However, it was reported that a significant improvement was not observed in patients treated with high-dose chemotherapy compared to that in those treated with standard chemotherapy, although an increased incidence of treatment-related adverse events (AEs) was observed in patients with high-dose chemotherapy [23]. Furthermore, high-dose chemotherapy with stem-cell rescue did not show a significant advantage for the treatment of metastatic RMS [24]. In contrast, doxorubicin has been widely used for the treatment of soft tissue sarcomas. However, its role in the treatment of RMS remains controversial. To evaluate the efficacy of the addition of doxorubicin in the standard multidrug regimen, a multicenter randomized controlled phase 3 trial was conducted by the European pediatric Soft tissue sarcoma Study Group (EpSSG; Table 1) [25]. In the study, 484 patients with RMS were randomly assigned to the IVA group and IVA with doxorubicin group. The three-year EFS rates of the IVA group and IVA with doxorubicin group were 63% and 68%, respectively (p = 0.33). Severe AEs, including leukopenia, anemia, thrombocytopenia, gastrointestinal disorder, and infection were more commonly noted in the IVA with doxorubicin group. Furthermore, two treatment-related deaths were reported in the IVA with doxorubicin group. Based on the results, the authors concluded that addition of doxorubicin in the standard chemotherapy regimen did not lead to a significant improvement in the clinical outcome of RMS. These studies indicated that the chemotherapy regimen for RMS should be based on the VAC or IVA regimens, and that addition of doxorubicin or high-dose chemotherapy was thought to have little benefit for patients with RMS.
In the pooled analysis of a phase 2 study conducted by the Intergroup Rhabdomyosarcoma Study Group (IRSG) and the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee, the clinical outcomes of multiagent regimens were compared in patients with high-risk RMS [26]. The overall response rates were 52% for patients who received ifosfamide/doxorubicin (ID); 41%, those who received ifosfamide/etoposide (IE); 55%, those who received vincristine/melphalan (VM); 49% those who received topotecan; 50%, those who received topotecan/cyclophosphamide (TC); and 45%, those who received irinotecan. The disease control rates in the ID, IE, and VM group were higher than those in the topotecan, TC, and irinotecan group. These results indicated that the addition of topotecan or irinotecan to the chemotherapy regimen had no benefit for the management of RMS.
Recently, it was reported that the addition of low-dose maintenance chemotherapy after standard chemotherapy improved the outcome in patients with RMS (Table 1). In a phase 3 clinical trial, 371 patients with high-risk RMS were randomly assigned to standard chemotherapy group and standard chemotherapy with maintenance chemotherapy (low-dose of vinorelbine and cyclophosphamide) group (NCT00339118) [27]. The five-year disease-free survival (DFS) rates were 78% for the patients with maintenance chemotherapy and 70% for the patients without maintenance chemotherapy. The five-year OS rates for the patients with and without maintenance chemotherapy were 87% and 74%, respectively (p < 0.001). This study indicated that the addition of maintenance chemotherapy to standard chemotherapy can improve the outcome in patients with high-risk RMS.
A clinical trial was conducted to assess the efficacy of a modified chemotherapy regimen for reducing treatment-associated toxicity in RMS patients. In a phase 3 study conducted by the COG, the efficacy of substituting VAC by vincristine and irinotecan (VI) for half of the duration of chemotherapy was assessed in 448 patients with intermediate-risk RMS (Table 1) [28]. In that study, the cumulative doses of cyclophosphamide in the VAC group and VAC/VI group were 16.8 g/m2 and 8.4 g/m2, respectively. Although a significant improvement in the oncological outcome in VAC/VI group was not observed, the VAC/VI group showed less severe hematologic toxicity. These results of the study suggest that the VAC/VI regimen is a candidate for alternative standard therapy in patients with intermediate-risk RMS.
Trabectedin, a synthetic alkaloid isolated from the marine ascidian, Ecteinascidia turbinate, reduces disease progression and mortality rates for various types of soft tissue sarcoma [29]. In a phase 2 study of trabectedin conducted by the COG, 23 patients with RMS, 16 with Ewing’s sarcoma, and 11 with other soft tissue sarcomas underwent trabectedin treatment [30]. Among the 40 evaluable patients, one patient had a partial response (PR), three patients had stable disease (SD), and 36 patients had progressive disease (PD). This result suggested that trabectedin monotherapy was not sufficient to control recurrent sarcomas in patients with RMS, Ewing sarcoma, and other sarcomas. However, trabectedin is commonly used as a second-line and subsequent chemotherapeutic agent for soft tissue sarcoma, and additional clinical research is required to assess its usefulness in patients with RMS.
Although these recent clinical trials did not report significant improvements in the outcomes of RMS, gradual improvement has been noted on modification of the standard chemotherapy regimens. Additional clinical studies are required to improve the outcomes in patients with RMS, especially in patients with metastatic RMS.

3. Molecular Targeted Drugs

While conventional anticancer drugs destroy not only cancer cells, but also normal cells, molecular targeted drugs are thought to specifically attack cells with target molecules involved in growth and proliferation of cancer cells. These molecules, including insulin-like growth factor 1 receptor (IGF-1R), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor (VEGF), anaplastic lymphoma kinase (ALK), mesenchymal-epithelial transition factor (MET), and mammalian target of rapamycin (mTOR), are considered the candidates for molecular targets in patients with RMS [18]. To reduce the incidence of treatment-related AEs and to improve outcomes in patients with soft tissue sarcomas, including RMS, clinical trials for various molecular targeted drugs had been conducted (Table 2).
Pazopanib, a multitargeted tyrosine kinase inhibitor, specifically inhibits VEGF receptor (VEGFR), PDGFR, and c-kit [31]. In a phase 2 trial of pazopanib in patients with soft tissue sarcomas conducted by the European Organization for Research and Treatment of Cancer-soft tissue and bone sarcoma group (EORTC), prolonged progression-free survival (PFS) and OS were observed compared to those for the controls [31]. Based on the results, the EORTC conducted a phase 3 trial in 372 patients with STS (NCT00753688) [32]. The study patients with advanced soft tissue sarcomas were randomly assigned into the pazopanib (800 mg, once daily) and placebo groups. In the study, mean PFS was 4.6 months in the pazopanib group and 1.6 months in the placebo group (p < 0.0001). However, the OS was 12.5 months in the pazopanib group and 10.7 months in the placebo group, and there was no statistically significant difference between the two groups (p = 0.25). Currently, pazopanib has been widely used for the treatment of soft tissue sarcomas, including RMS, although the efficacy in patients with RMS remains unclear. To assess the efficacy of pazopanib for the treatment of RMS, further clinical studies in RMS patients are needed.
VEGF plays an important role in regulating physiologic angiogenesis, and tumor cells induce pathologic angiogenesis via production of VEGF [33]. Therefore, VEGF is considered a therapeutic target in cancer. The efficacy of the anti-VEGF monoclonal antibody, bevacizumab, has been investigated in various malignancies [34,35,36]. In a phase 1 study of bevacizumab in combination with topoisomerase 1 inhibitor, irinotecan, for recurrent/refractory pediatric solid tumors, the PR, SD, and PD rates were 30% (3/10), 30% (3/10), and 40% (4/10), respectively [37]. In the study, one of nine assessable patients (11%) had grade 4 toxicity involving neutropenia and thrombocytopenia. These results suggest that bevacizumab combined with irinotecan seems to be well-tolerated and has an antitumor effect in a proportion of patients with pediatric malignancies.
Sorafenib is a multiple kinase inhibitor of the C-, B-RAF, VEGF-2,3, PDGFR-β, FLT3, and c-KIT signaling pathways [38]. Maruwge et al. reported that sorafenib inhibited tumor growth in an in vitro study and that sorafenib inhibited tumor growth and angiogenesis in a xenograft model of RMS [39]. In a phase 1 trial of sorafenib (200 mg/m2) for childhood solid tumors, including RMS and Wilms tumor (NCT01502410), an objective response was not observed [40]. Another phase 2 study on sorafenib (200 mg/m2, twice a day) conducted by the COG in 21 patients with refractory solid tumors did not report an objective response in the study patients [40]. In contrast, a phase 2 trial of sorafenib (400 mg, twice a day) involving 101 patients with soft tissue sarcomas showed that 14% of the patients had PR and 33% of those had SD [41]. Although sorafenib showed clinical benefits in adult patients, clinical effects were not observed in pediatric patients. Reconsideration of the dose and frequency of sorafenib may improve the outcomes in pediatric patients.
Crizotinib is a tyrosine kinase inhibitor targeting ALK, MET, ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and RON [42,43,44]. In a multinational phase 2 clinical study of crizotinib for advanced ARMS (EORTC90101, NCT01524926), the disease control rate was 14%; median PFS, 1.3 months; and median OS, 5.6 months [45]. In the study, the AEs noted were fatigue (39%), nausea (31%), anorexia (31%), vomiting (15%), and constipation (15%). The results of the study indicated that the clinical benefits of crizotinib can be expected in only a small proportion of the patients with ARMS.
Since Akt and mammalian target of rapamycin (mTOR) regulate cell metabolism, growth, proliferation, and survival [46,47,48], these molecules are considered candidates for therapeutic targets for cancers. Temsirolimus, a specific inhibitor of mTOR, can regulate cell growth, proliferation, and survival in cancer cells [49,50,51]. In a basic research study, mTOR inhibitor showed antitumor activity by inhibition of angiogenesis in xenograft models of RMS [52]. In a phase 2 study of temsirolimus, 52 patients with glioma, neuroblastoma, or RMS were treated with 75 mg/m2 temsirolimus once weekly [53]. In the study, the disease control rates in patients with high-grade glioma, neuroblastoma, and RMS were 41% (7 of 17 patients), 32% (6 of 19 patients), and 6% (1 of 16 patients), respectively. In another phase 1 study on combination therapy using perifosine and temsirolimus in patients with pediatric solid tumors, 8 of 19 patients had SD and 11 patients had no objective response [54]. In the study, the most commonly noted treatment-related toxicities (grade 3 or 4) were thrombocytopenia (38%), neutropenia (24%), lymphopenia (24%), and hypercholesterolemia (19%). Although these studies suggested that temsirolimus-based treatments are feasible and safe, the response to the treatment is limited in patients with RMS.
IGF-1R, which is strongly expressed in RMS and is associated with tumor initiation and progression [55,56], is considered a potential therapeutic target. In basic studies, cixutumumab, a human monoclonal antibody against IGF-1R, showed antitumor activity in vitro and in vivo [57,58]. In a phase 2 study of cixutumumab conducted by the COG, patients with refractory solid tumors underwent treatment with cixutumumab (9 mg/kg, intravenous, weekly) (NCT00831844) [59]. The study included 102 patients with osteosarcoma, RMS, neuroblastoma, Wilms tumor, adrenocortical carcinoma, hepatoblastoma, and synovial sarcoma. Among these patients, 4 of 20 patients with neuroblastomas and 1 of 20 patients with RMS showed PR, and SD was observed in 14 patients (six patients with neuroblastomas, three patients with RMS, two patients with synovial sarcoma, one patient with Wilms tumor, one patient with osteosarcoma, and one patient with adrenocortical carcinoma). Another study conducted by the COG investigated the efficacy of adding cixutumumab or temozolomide to the standard chemotherapy regimen in 168 patients with metastatic RMS [60]. In this study, an improvement in the outcome in response to the added cixutumumab or temozolomide was not observed. In another phase 2 study on combination treatment with cixutumumab and temsirolimus in 43 patients with recurrent or refractory sarcoma, an objective response was not observed [61]. These results indicated that cixutumumab seems to have only a small effect on the oncological outcomes in patients with advanced RMS. Because RMS is only a small population of these studies, it is difficult to assess the efficacies of the agents in patients with RMS. To assess the safety and efficacy of these treatment in patients with RMS, further clinical trials dedicated to RMS are demanded.
As PAX-FOXO1 is expressed in 80% of the tissues with ARMS but not in the normal tissues, the chimeric transcription factor is considered a promising target in patients with ARMS. In a basic research, lipid-prostamine-siRNA (LPR) nanoparticles targeting PAX-FOXO1 inhibited the production of the fusion transcript and proliferation of RMS cells [62], and the LPR nanoparticles targeting PAX-FOXO1 significantly inhibited tumor growth in a xenograft model of ARMS. In contrast, Bharathy et al. reported that entinostat, a class-I specific histone deacetylase inhibitor, inhibited production of the PAX3-FOXO1 fusion protein [63], and that entinostat induced sensitization to chemotherapy by destabilization of PAX3-FOXO1 mRNA in RMS cells in vitro and in vivo. These basic studies reported the potential of PAX-FOXO1 as a therapeutic target in RMS. Further preclinical studies on PAX-FOXO1-targeting treatment are needed to assess the usefulness of PAX-FOXO1 as a therapeutic target for RMS.

4. Radiation Therapy

RT is one of the standard treatment modalities used in the management of RMS [64,65]. Patients with RMS are stratified into the low, intermediate, and high-risk groups according to the tumor location, size, histological subtype, involvement of lymph node, metastatic lesion, and surgical margin [66]. Although patients with low-risk RMS who undergo excision with wide margins do not require RT, most RMS patients require RT, and the radiation doses are determined according to the risk. Patients with low-risk RMS with gross tumor excision and positive surgical margins require a radiation dose 36 Gy during RT, whereas those with positive nodes require 41.4 Gy and those with gross residual tumor require 50.4 Gy. Wolden et al. investigated local control after standard chemotherapy and RT in patients with RMS [67]. In their study, the clinical outcomes in 423 patients with ARMS (group I-II: n = 41; group III: n = 102) and group III ERMS (n = 280) were analyzed. The five-year EFS and local failure rates in patients with group I/II ARMS were 69% and 10%, whereas the five-year EFS and local failure rates in patients with group III RMS were 70% and 19%, respectively. This study indicated that excellent local control could be achieved with chemotherapy combined with RT in patients with intermediate-risk RMS.
RT induces various complications, such as dermatitis and secondary cancer caused by normal tissue damage; therefore, long-term safety of the treatment is essential in pediatric patients with malignancies. Recently, intensity modulated radiation therapy (IMRT) and proton RT have been commonly performed to concentrate the radiation on the target lesion and to avoid irradiation of the normal cells. Lin et al. investigated the effect of IMRT and three-dimensional conformal radiotherapy (3D-CRT) in 375 patients with intermediate-risk RMS [68]. The study showed that IMRT improved the target coverage compared with 3D-CRT, although no improvement was observed with respect to local control in the study patients. In contrast, a physical characteristic of the proton beam is that it emits most of the energy near the end of its reach. This characteristic makes it possible to concentrate the proton beam on the target lesion. Since proton RT can reduce the toxicity of RT by prevention of damage to normal tissues [69,70], proton RT can be expected to reduce the incidence of the RT-related complications. A phase 2 study comparing proton RT and IMRT in pediatric RMS showed that the integral dose in IMRT was 1.8 times higher than in proton RT, and significant normal tissue sparing was noted with proton RT, such that 87% of essential structures were spared [71]. The results suggest that proton RT can reduce the incidence of RT-related AEs. In a phase 2 study on proton RT in 57 patients with metastatic ERMS treated with chemotherapy, the five-year EFS, OS, and local control rates were 69%, 78%, and 81%, respectively [72]. In the study, 11 of 57 (13%) patients presented with acute grade 3 treatment-related toxicities, including odynophagia, dermatitis, dry eye, mucositis, otitis, and hepatopathy. In contrast, 3 of 43 (7%) patients presented with late treatment-related toxicities, including cataract, chronic otitis, and retinopathy. Proton RT is considered beneficial for pediatric patients with malignancies. Additional investigations of the clinical outcomes and long-term safety of proton RT in patients with RMS are warranted to determine the efficacy of proton RT.

5. Immunotherapy

5.1. Immune Checkpoint Inhibitors

According to several basic and clinical studies, the immune checkpoint axis is considered a strong therapeutic target in various malignancies. Although the clinical benefits of immune checkpoints as therapeutic targets in soft tissue sarcomas are unclear [73,74,75,76,77], studies have reported on the importance of immune checkpoints in sarcomas. Pollack et al. investigated the expression of programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD-1) in sarcomas, including undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, well-differentiated/dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and synovial sarcoma [78]. In the study, the expression of PD-L1 and PD-1 was high in UPS and leiomyosarcoma, while the expression was low in myxoid/round cell liposarcoma and synovial sarcoma. In contrast, Kim et al. investigated the association of PD-L1 expression with prognosis in patients with soft tissue sarcomas, including 32 RMS, 19 synovial sarcomas, 18 Ewing sarcomas, seven epithelioid sarcomas, and six mesenchymal chondrosarcomas [79]. Among the study patients, 38% of those with RMS, 53% of those with synovial sarcoma, 33% of those with Ewing sarcoma, 100% of those with epithelioid sarcoma, and 0% of those with mesenchymal chondrosarcoma showed positive PD-L1 expressions. In the study, the five-year OS rates in patients with PD-L1(+) sarcomas and PD-L1(-) sarcomas were 48% and 68%, respectively (p = 0.015). Multivariate analysis revealed a significant association between PD-L1 expression and poor OS. Therefore, the immune checkpoints are considered promising therapeutic targets in patients with RMS.
Only a few clinical studies have investigated the efficacy of immune checkpoint inhibitors for patients with RMS. Davis et al. investigated the efficacy and safety of nivolumab in a phase 1/2 trial in patients with solid tumors and lymphoma (NCT02304458) [80]. In the study, 85 patients (22 neuroblastomas, 22 lymphomas, 12 RMSs, 11 Ewing sarcomas, 13 osteosarcomas, and one melanoma, two epithelioid sarcomas, two other sarcomas) were enrolled. Four of 20 (20%) patients with lymphoma showed an objective response, while none of the 74 patients with solid tumors showed an objective response. Among the patients with solid tumors, 33% (11 of 33 patients) of those with sarcomas and 50% (5 of 10 patients) of those with neuroblastomas showed SD. In another phase 1 study of ipilimumab in pediatric patients with solid tumors, the safety and efficacy of ipilimumab were assessed in patients with solid tumors, solid tumors, including 12 patients with melanoma, eight patients with osteosarcoma, three patients with clear cell sarcoma, three patients with carcinoma, two patients with synovial sarcoma, two patients with RMS, one patient with pleomorphic sarcoma, one patient with neuroblastoma, and one patient with undifferentiated sarcoma [81]. In the study, immune-related AEs, including pneumonitis, pancreatitis, endocrinopathies, colitis, and transaminitis were observed at 5 mg/kg and 10 mg/kg dose levels. Among these patients, six patients had SD (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma), and none of the patients presented with PR or complete response (CR). Because these clinical trials enrolled only a small number of RMS patients, it is difficult to assess efficacies of the treatments for RMS.
Currently, only a few clinical studies have reported the efficacy of immune checkpoint inhibitors in patients with RMS. According to the limited number of clinical studies, immune checkpoint inhibitors seem to have little clinical benefit in RMS patients. As the sample population was small, additional studies with a large number of study patients are needed to evaluate the efficacy of immune checkpoint inhibitors.

5.2. Cellular Immunotherapy

Although anti-cancer immunity and cancer immunotherapy have recently attracted attention [82], cancer immunotherapy has been administered for a long time. Coley’s toxin, including live or inactivated bacteria, including Serratia marcescens and Streptococcus pyogenes, was the first immunotherapy reported in 1891 [83]. In that study, 10% of the patients with inoperable sarcoma showed tumor regression after the injection of Coley’s toxin. However, several studies have investigated various immune stimulators, including muramyl tripeptide, Bacillus Calmette-Guerin (BCG), and allogenic tumor cells, and have reported no significant improvement in patients with sarcomas [84,85,86,87]. In contrast, recent studies on the tumor microenvironment and antitumor immune system have contributed to the development of immunotherapy [88]. Dendritic cells (DCs), a type of antigen presenting cells (APCs), phagocytize apoptotic cancer cells, process them, and present tumor-associated antigens (TAAs) via major histocompatibility complexes (MHCs). T lymphocytes recognize the TAAs presented on the surface of the DCs. Cytotoxic T lymphocytes detect cancer cells by identifying TAAs and eliminate cancer cells. The antitumor immune responses are induced by delivering co-stimulatory signals among the APCs and effector cells. In normal immune condition, tumor cells with TAA are eliminated by the antitumor immune system. In contrast, early stage of cancer is associated with insufficient functioning of the immune system because of the suppression of immune checkpoints and recruitment of immune-suppressive cells, such as myeloid-derived suppressor cells and regulatory T cells. Based on the immune response and the escape system, these systems are considered promising therapeutic targets for various type of cancers. As DCs play a central role in the antitumor immune system, clinical studies on DC-based immunotherapy for various malignancies have been conducted. In a clinical study on immunotherapy using DCs in combination with standard chemotherapy in 43 patients with metastatic and/or recurrent pediatric sarcomas, 29 patients underwent immunotherapy (Table 3) [89]. In the study, T-cell responses to tumor lysates were observed in 62% (16 of 26 patients) of the patients treated with immunotherapy, and significantly higher survival rates were observed for patients with an immune response than in those without an immune response (73% vs. 37%, p = 0.017) [89]. In contrast, Krishnadas et al. conducted a phase 1/2 study on decitabine and DC vaccine targeting the melanoma-associated gene (MAGE) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) in children with advanced solid tumors (NCT01241162). In the study, patients with relapsed/refractory solid tumors (neuroblastoma, Ewing’s sarcoma, osteosarcoma, and RMS) underwent decitabine treatment with autologous DCs pulsed with NY-ESO-1, MAGE-A1, and MAGE-A3 (Table 3) [90]. The study reported that one of the eight evaluable patients presented with CR, one patient presented with PR, and six presented with PD; the patient with CR presented with complete remission 3.5 years after the treatment. These studies suggest that a proportion of the patients showed a response to DC-based immunotherapy and that T-cell response seems to be important for the clinical outcomes. Adjuvant treatment activating T-cell response may enhance the effect of DC-based immunotherapy. These studies included only a small population of RMS patients, and further studies are demanded to assess the immunotherapies for RMS.
Recently, adoptive T-cell therapy (ACT) has been considered a promising treatment for cancer [88,91,92,93,94]. In a basic research study, T cells were engineered to express chimeric receptors composed of the antigen-binding domain of a human anti-fetal acetylcholine receptor (fAChR) antibody. In the study, the interaction between fAchR-transduced T cells and fAchR-positive RMS cell lines induced T-cell activation by IFN-γ secretion, and delayed lysis of tumor cells was observed [95]. Huang et al. reported that IGF-1R and tyrosine kinase-like orphan receptor 1 (ROR1) were strongly expressed in Ewing sarcoma, osteosarcoma, ARMS, ERMS, and fibrosarcoma cell lines [92]. Furthermore, the adoptive transfer of chimeric antigen receptor (CAR) T cells targeting the IGF-1R and ROR1 significantly reduced tumor growth in xenograft models [92]. In a clinical trial of ACT using T-cells engineered with T-cell receptor (TCR) directed against NY-ESO-1 in patients with melanoma or synovial sarcoma, objective responses were observed in four of six patients with synovial sarcoma and 5 of 11 patients with melanoma [96]. In another phase 1/2 clinical study on T cells expressing human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor in patients with HER2-positive sarcomas, 4 of 17 showed SD (Table 3) [91]. Three of four patients with SD underwent tumor resection, and one of the resected specimens showed ≥90% necrosis. Although only a few clinical studies on ACT have included RMS patients, ACT is considered a promising treatment due to the specificity for TAAs.

6. Basic Studies of Novel Therapeutic Approaches

Recent basic studies have reported promising therapeutic approaches, including ferroptotic agents, oncolytic virus, and tumor-targeting bacterial therapy.
Ferroptosis is non-necrotic and non-apoptotic form of programmed cell death which requires abundant intracellular free iron to promote lipid peroxidation and accumulation of reactive oxygen species. Chen et al. reported that RMS had vulnerability to oxidative stress [97]. In the study, a genomic analysis showed that RMS samples had nucleotide mutations associating with oxidative stress, which indicates high levels of oxidative damage [97]. Furthermore, xenograft models of RMS showed sensitivity to several compounds which enhanced oxidative stress such as cerivastatin, auranofin, and carfilzomib. Oxidative damages in RMS suggest that RMS may be sensitive to oxidative stress inducers [98]. Dachert et al. reported that erastin, a glutathione-depleting agent, induced reactive oxygen species production, lipid peroxidation, and ferroptosis [99]. Based on these reports, ferroptotic agents may be promising treatments in RMS, although the further investigations for mechanisms of cell death by ferroptotic agents are demanded.
ERMS mainly develops in response to aberrant activation of receptor tyrosine kinase-mediated RAS signaling cascade. Phelps et al. investigated the function of RAS signaling in regulating the growth and differentiation of ERMS [100]. In the study, RAS knockout in ERMS xenograft models resulted in tumor regression and myogenic differentiation, and recombinant oncolytic myxoma virus targeting RAS significantly reduced tumor growth and improved OS in a xenograft model of ERMS. In another study, antitumor effects of telomerase-specific oncolytic adenovirus on bone and soft tissue sarcomas were observed [101]. These viruses are capable of tumor-specific replication due to induction of the expression of the adenoviral E1A and E1B genes under the control of the human telomerase reverse transcriptase-encoding gene (hTERT) promoter. Yano et al. reported that oncolytic viruses labelled by green fluorescent protein (GFP) enabled fluorescence-guided surgery based on the specificity for tumor cells [102]. In the study, telomerase-dependent, GFP-containing adenovirus was injected in an orthotopic mouse model of fibrosarcoma. The accumulation of GFP-expressing oncolytic viruses in the tumor tissues was visualized using fluorescence imaging, and fluorescence-guided surgery could be performed by visualization of the tumor tissues during surgical resection.
Zhao et al. developed tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R [103,104,105,106]. Auxotrophy for Leu-Arg in S. typhimusrium A1-R prevents infection in normal tissues; however, S. typhimusrium A1-R specifically accumulate in the tumor tissue and virulence. S. typhimurium A1-R concentrated and eradicated the primary and metastatic tumors in an in vivo study [105,106]. Igarashi et al. reported that S. typhimurium A1-R inhibited significantly regressed tumor growth compared with that in the untreated control in a mouse model of RMS [107]. To the best of our knowledge, although clinical studies have not reported the efficacy of bacterial therapy for RMS, bacterial therapy may potentially be used for the treatment of RMS in the clinical setting.
To minimize the incidence of treatment-related complications due to damage to normal cells, high specificity of tumor-targeting treatment is warranted. The tumor-specific viral or bacterial therapy may possibly reduce the incidence of complications associated with antitumor treatment. Additional studies investigating these treatments are required to evaluate the efficacy and safety of these treatments for patients with RMS.

7. Precision Medicine

Expression of some molecules may be associated with the therapeutic responses to the molecular targeted drugs. Therefore, studies addressing the correlation between expression of the target molecules and therapeutic responses to the molecular target drugs are warranted to predict the clinical responses in patients with soft tissue sarcoma.
It is difficult to conduct clinical trials of anticancer drugs for the treatment of RMS owing to the rarity of RMS, its various subtypes, and differences in gene mutations. Recently, genomic profiling has been used in various malignancies, and genomic profiling data have contributed to the determination of the optimal clinical treatment strategies in patients with malignancies [108]. Although genomic profiling is not commonly performed during the treatment of RMS, several studies have reported on the prediction of therapeutic response in patients with RMS.
Casey et al. reported that RMS patients with the PAX-FOXO1 fusion protein had a lower tumor mutational burden (TMB) than those without the fusion protein, and that high TMB was significantly associated with worse local control, DFS, and OS [109]. TMB is identified as a biomarker predicting response to immune checkpoint inhibitors [108]. However, assessment of TMB does not seem to be beneficial for predicting the response to immune checkpoint inhibitors in patients with STS since a low TMB has been reported in soft tissue sarcoma [110]. In contrast, microsatellite instability (MSI) can be also used as a biomarker to predict the response to pembrolizumab, an immune checkpoint inhibitor [111,112]. However, only 0.2% of the patients with soft tissue sarcomas reportedly showed high-MSI [113]. Further investigations of biomarkers predicting the response to molecular targeted drugs and immune checkpoint inhibitors are needed.
Several studies have reported on the prediction of the response to anticancer agents in patients using animal models of cancer. Although the mouse model of human malignant tumors has been used to investigate the mechanism of tumor progression and to evaluate response to anticancer agents, the mouse model created by subcutaneous injection of cancer cells cannot reflect on tumor progression and response to anticancer agents in the human body. In contrast, it was reported that a patient-derived orthotopic xenograft (PDOX) model created by orthotopic implantation of tumor tissues in immunocompromised mice can mimic the characteristics of cancer in patients [114]. In preclinical studies, PDOX models demonstrated characteristics similar to those of sarcoma in patients, including recurrence, metastasis, invasion, and response to anticancer agents [107]. Due to the similarity to cancer in patients, the PDOX model is considered useful in precision medicine for various malignancies, including RMS [107,114,115]. Further information and clinical studies regarding the correlation of response to anticancer agents between the PDOX models and human patients are needed to utilize the prediction of therapeutic response by PDOX model in patients with RMS.

8. Conclusions

Because there are only a small number of clinical trials dedicated to RMS, it is often difficult to discuss the efficacy and safety of new treatments for RMS. However, several clinical trials of molecular targeted drugs and immunotherapy showed efficacies in patients with soft tissue sarcomas, including RMS. On the other hand, the usefulness of modified chemotherapy regimens has been demonstrated in recent clinical trials on RMS. Furthermore, basic research including studies on RMS-specific tumor antigen, oncolytic virus and tumor-targeting bacterial therapy have shown the potential to contribute to the development of therapeutic strategies for patients with RMS. These promising treatments should be assessed in clinical studies in the future.

Author Contributions

Writing—original draft preparation, S.M.; writing-review, N.Y., K.H., A.T., K.I. and H.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ognjanovic, S.; Linabery, A.M.; Charbonneau, B.; Ross, J.A. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 2009, 115, 4218–4226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Xia, S.J.; Rajput, P.; Strzelecki, D.M.; Barr, F.G. Analysis of genetic events that modulate the oncogenic and growth suppressive activities of the PAX3-FKHR fusion oncoprotein. Lab. Investig. 2007, 87, 318–325. [Google Scholar] [CrossRef] [PubMed]
  3. Barr, F.G. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 2001, 20, 5736–5746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Fletcher, C.D.M.; Bridge, J.A.; Hogendoorn, P.; Mertens, F. Who Classification of Tumours of the Soft Tissues and Bone; IARC Press: Lyon, France, 2013. [Google Scholar]
  5. Barr, F.G.; Qualman, S.J.; Macris, M.H.; Melnyk, N.; Lawlor, E.R.; Strzelecki, D.M.; Triche, T.J.; Bridge, J.A.; Sorensen, P.H. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 2002, 62, 4704–4710. [Google Scholar] [PubMed]
  6. Wachtel, M.; Dettling, M.; Koscielniak, E.; Stegmaier, S.; Treuner, J.; Simon-Klingenstein, K.; Bühlmann, P.; Niggli, F.K.; Schäfer, B.W. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t (2;2) (q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res. 2004, 64, 5539–5545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Xia, S.J.; Pressey, J.G.; Barr, F.G. Molecular pathogenesis of rhabdomyosarcoma. Cancer Biol. Ther. 2002, 1, 97–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Fredericks, W.J.; Ayyanathan, K.; Herlyn, M.; Friedman, J.R.; Rauscher, F., Jr. An engineered PAX3-KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3-FKHR oncogene. Mol. Cell. Biol. 2000, 20, 5019–5031. [Google Scholar] [CrossRef] [Green Version]
  9. Parham, D.M.; Ellison, D.A. Rhabdomyosarcomas in adults and children: An update. Arch. Pathol. Lab. Med. 2006, 130, 1454–1465. [Google Scholar] [PubMed]
  10. Borden, E.C.; Baker, L.H.; Bell, R.S.; Bramwell, V.; Demetri, G.D.; Eisenberg, B.L.; Fletcher, C.D.; Fletcher, J.A.; Ladanyi, M.; Meltzer, P.; et al. Soft tissue sarcomas of adults: State of the translational science. Clin. Cancer Res. 2003, 9, 1941–1956. [Google Scholar]
  11. Skapek, S.X.; Anderson, J.; Barr, F.G.; Bridge, J.A.; Gastier-Foster, J.M.; Parham, D.M.; Rudzinski, E.R.; Triche, T.; Hawkins, D.S. PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: A children’s oncology group report. Pediatr. Blood Cancer 2013, 60, 1411–1417. [Google Scholar] [CrossRef] [Green Version]
  12. Dantonello, T.M.; Int-Veen, C.; Schuck, A.; Seitz, G.; Leuschner, I.; Nathrath, M.; Schlegel, P.G.; Kontny, U.; Behnisch, W.; Veit-Friedrich, I.; et al. Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr. Blood Cancer 2013, 60, 1267–1273. [Google Scholar] [CrossRef]
  13. Malempati, S.; Hawkins, D.S. Rhabdomyosarcoma: Review of the Children’s Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr. Blood Cancer 2012, 59, 5–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Hawkins, D.S.; Spunt, S.L.; Skapek, S.X.; COG Soft Tissue Sarcoma Committee. Children’s Oncology Group’s 2013 blueprint for research: Soft tissue sarcomas. Pediatr. Blood Cancer 2013, 60, 1001–1008. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Oberlin, O.; Rey, A.; Lyden, E.; Bisogno, G.; Stevens, M.C.; Meyer, W.H.; Carli, M.; Anderson, J.R. Prognostic factors in metastatic rhabdomyosarcomas: Results of a pooled analysis from United States and European cooperative groups. J. Clin. Oncol. 2008, 26, 2384–2389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Breneman, J.C.; Lyden, E.; Pappo, A.S.; Link, M.P.; Anderson, J.R.; Parham, D.M.; Qualman, S.J.; Wharam, M.D.; Donaldson, S.S.; Maurer, H.M.; et al. Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma—A report from the Intergroup Rhabdomyosarcoma Study IV. J. Clin. Oncol. 2003, 21, 78–84. [Google Scholar] [CrossRef]
  17. Weigel, B.J.; Lyden, E.; Anderson, J.R.; Meyer, W.H.; Parham, D.M.; Rodeberg, D.A.; Michalski, J.M.; Hawkins, D.S.; Arndt, C.A. Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J. Clin. Oncol. 2016, 34, 117–122. [Google Scholar] [CrossRef]
  18. Chen, C.; Dorado Garcia, H.; Scheer, M.; Henssen, A.G. Current and Future Treatment Strategies for Rhabdomyosarcoma. Front. Oncol. 2019, 9, 1458. [Google Scholar] [CrossRef]
  19. Maurer, H.M.; Crist, W.; Lawrence, W.; Ragab, A.H.; Raney, R.B.; Webber, B.; Wharam, M.; Vietti, T.J.; Beltangady, M.; Gehan, E.A.; et al. The intergroup rhabdomyosarcoma study-I.A final report. Cancer 1988, 61, 209–220. [Google Scholar] [CrossRef]
  20. Maurer, H.M.; Gehan, E.A.; Beltangady, M.; Crist, W.; Dickman, P.S.; Donaldson, S.S.; Fryer, C.; Hammond, D.; Hays, D.M.; Herrmann, J.; et al. The intergroup rhabdomyosarcoma study-II. Cancer 1993, 71, 1904–1922. [Google Scholar] [CrossRef]
  21. Koscielniak, E.; Harms, D.; Henze, G.; Jurgens, H.; Gadner, H.; Herbst, M.; Klingebiel, T.; Schmidt, B.F.; Morgan, M.; Knietig, R. Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J. Clin. Oncol. 1999, 17, 3706–3719. [Google Scholar] [CrossRef]
  22. Crist, W.M.; Anderson, J.R.; Meza, J.L.; Fryer, C.; Raney, R.B.; Ruymann, F.B.; Breneman, J.; Qualman, S.J.; Wiener, E.; Wharam, M.; et al. Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J. Clin. Oncol. 2001, 19, 3091–3102. [Google Scholar] [CrossRef] [PubMed]
  23. Carli, M.; Colombatti, R.; Oberlin, O.; Bisogno, G.; Treuner, J.; Koscielniak, E.; Tridello, G.; Garaventa, A.; Pinkerton, R.; Stevens, M. European intergroup studies (MMT4–89 and MMT4–91) on childhood metastatic rhabdomyosarcoma: Final results and analysis of prognostic factors. J. Clin. Oncol. 2004, 22, 4787–4794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Weigel, B.J.; Breitfeld, P.P.; Hawkins, D.; Crist, W.M.; Baker, K.S. Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J. Pediatr. Hematol. Oncol. 2001, 23, 272–276. [Google Scholar] [CrossRef]
  25. Bisogno, G.; Jenney, M.; Bergeron, C.; Gallego Melcón, S.; Ferrari, A.; Oberlin, O.; Carli, M.; Stevens, M.; Kelsey, A.; De Paoli, A.; et al. Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): A multicentre, open-label, randomised controlled, phase 3 trial. Lancet Oncol. 2018, 19, 1061–1071. [Google Scholar] [CrossRef]
  26. Soft Tissue Sarcoma Committee of the Children’s Oncology, G.; Lager, J.J.; Lyden, E.R.; Anderson, J.R.; Pappo, A.S.; Meyer, W.H.; Breitfeld, P.P. Pooled analysis of phase II window studies in children with contemporary high-risk metastatic rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J. Clin. Oncol. 2006, 24, 3415–3422. [Google Scholar] [CrossRef]
  27. Bisogno, G.; De Salvo, G.L.; Bergeron, C.; Gallego Melcón, S.; Merks, J.H.; Kelsey, A.; Martelli, H.; Minard-Colin, V.; Orbach, D.; Glosli, H.; et al. Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019, 20, 1566–1575. [Google Scholar] [CrossRef]
  28. Hawkins, D.S.; Chi, Y.Y.; Anderson, J.R.; Tian, J.; Arndt, C.A.S.; Bomgaars, L.; Donaldson, S.S.; Hayes-Jordan, A.; Mascarenhas, L.; McCarville, M.B.; et al. Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J. Clin. Oncol. 2018, 36, 2770–2777. [Google Scholar] [CrossRef]
  29. Kawai, A.; Araki, N.; Sugiura, H.; Ueda, T.; Yonemoto, T.; Takahashi, M.; Morioka, H.; Hiraga, H.; Hiruma, T.; Kunisada, T.; et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: A randomised, open-label, phase 2 study. Lancet Oncol. 2015, 16, 406–416. [Google Scholar] [CrossRef]
  30. Baruchel, S.; Pappo, A.; Krailo, M.; Baker, K.S.; Wu, B.; Villaluna, D.; Lee-Scott, M.; Adamson, P.C.; Blaney, S.M. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: A report from the Children’s Oncology Group. Eur. J. Cancer 2012, 48, 579–585. [Google Scholar] [CrossRef]
  31. Sleijfer, S.; Ray-Coquard, I.; Papai, Z.; Le Cesne, A.; Scurr, M.; Schoffski, P.; Collin, F.; Pandite, L.; Marreaud, S.; De Brauwer, A.; et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: A phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J. Clin. Oncol. 2009, 27, 3126–3132. [Google Scholar]
  32. van der Graaf, W.T.A.; Blay, J.-Y.; Chawla, S.P.; Kim, D.-W.; Bui-Nguyen, B.; Casali, P.G.; Schöffski, P.; Aglietta, M.; Staddon, A.P.; Beppu, Y.; et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012, 379, 1879–1886. [Google Scholar] [CrossRef]
  33. Ferrara, N.; Gerber, H.P.; LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 2003, 9, 669–676. [Google Scholar] [CrossRef] [PubMed]
  34. Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 2004, 350, 2335–2342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Escudier, B.; Pluzanska, A.; Koralewski, P.; Ravaud, A.; Bracarda, S.; Szczylik, C.; Chevreau, C.; Filipek, M.; Melichar, B.; Bajetta, E.; et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007, 370, 2103–2111. [Google Scholar] [CrossRef]
  36. Vredenburgh, J.J.; Desjardins, A.; Herndon, J.E., 2nd; Marcello, J.; Reardon, D.A.; Quinn, J.A.; Rich, J.N.; Sathornsumetee, S.; Gururangan, S.; Sampson, J.; et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 2007, 25, 4722–4729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Okada, K.; Yamasaki, K.; Tanaka, C.; Fujisaki, H.; Osugi, Y.; Hara, J. Phase I study of bevacizumab plus irinotecan in pediatric patients with recurrent/refractory solid tumors. Jpn. J. Clin. Oncol. 2013, 43, 1073–1079. [Google Scholar] [CrossRef] [Green Version]
  38. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 2006, 5, 835–844. [Google Scholar] [CrossRef]
  39. Maruwge, W.; D’Arcy, P.; Folin, A.; Brnjic, S.; Wejde, J.; Davis, A.; Erlandsson, F.; Bergh, J.; Brodin, B. Sorafenib inhibits tumor growth and vascularization of rhabdomyosarcoma cells by blocking IGF-1R-mediated signaling. Onco Targets Ther. 2008, 1, 67–78. [Google Scholar] [CrossRef] [Green Version]
  40. Kim, A.; Widemann, B.C.; Krailo, M.; Jayaprakash, N.; Fox, E.; Weigel, B.; Blaney, S.M. Phase 2 trial of sorafenib in children and young adults with refractory solid tumors: A report from the Children’s Oncology Group. Pediatr. Blood Cancer 2015, 62, 1562–1566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Santoro, A.; Comandone, A.; Basso, U.; Soto Parra, H.; De Sanctis, R.; Stroppa, E.; Marcon, I.; Giordano, L.; Lutman, F.R.; Boglione, A.; et al. Phase II prospective study with sorafenib in advanced soft tissue sarcomas after anthracycline-based therapy. Ann. Oncol. 2013, 24, 1093–1098. [Google Scholar] [CrossRef]
  42. Kwak, E.L.; Bang, Y.J.; Camidge, D.R.; Shaw, A.T.; Solomon, B.; Maki, R.G.; Ou, S.H.; Dezube, B.J.; Janne, P.A.; Costa, D.B.; et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 2010, 363, 1693–1703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Rodig, S.J.; Shapiro, G.I. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr. Opin. Invest. Drugs 2010, 11, 1477. [Google Scholar]
  44. Sahu, A.; Prabhash, K.; Noronha, V.; Joshi, A.; Desai, S. Crizotinib: A comprehensive review. South Asian J. Cancer 2013, 2, 91–97. [Google Scholar] [PubMed]
  45. Schoffski, P.; Wozniak, A.; Leahy, M.G.; Aamdal, S.; Rutkowski, P.; Bauer, S.; Richter, S.; Grunwald, V.; Debiec-Rychter, M.; Sciot, R.; et al. The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’. Eur. J. Cancer 2018, 94, 156–167. [Google Scholar]
  46. Chandarlapaty, S.; Sawai, A.; Scaltriti, M.; Rodrik-Outmezguine, V.; Grbovic-Huezo, O.; Serra, V.; Majumder, P.K.; Baselga, J.; Rosen, N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011, 19, 58–71. [Google Scholar] [CrossRef] [Green Version]
  47. Martini, M.; De Santis, M.C.; Braccini, L.; Gulluni, F.; Hirsch, E. PI3K/AKT signaling pathway and cancer: An updated review. Ann. Med. 2014, 46, 372–383. [Google Scholar] [CrossRef]
  48. Sims, D.; Maranyane, H.M.; Damerell, V.; Govender, D.; Isaacs, A.W.; Peres, J.; Prince, S. The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma. Cancers 2020, 12, 501. [Google Scholar] [CrossRef] [Green Version]
  49. Bjornsti, M.A.; Houghton, P.J. The TOR pathway: A target for cancer therapy. Nat. Rev. Cancer 2004, 4, 335–348. [Google Scholar] [CrossRef]
  50. Guertin, D.A.; Sabatini, D.M. Defining the role of mTOR in cancer. Cancer Cell 2007, 12, 9–22. [Google Scholar] [CrossRef] [Green Version]
  51. Gibbons, J.J.; Abraham, R.T.; Yu, K. Mammalian target of rapamycin: Discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin. Oncol. 2009, 36 (Suppl. 3), S3–S17. [Google Scholar] [CrossRef]
  52. Wan, X.; Shen, N.; Mendoza, A.; Khanna, C.; Helman, L.J. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia 2006, 8, 394–401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Geoerger, B.; Kieran, M.W.; Grupp, S.; Perek, D.; Clancy, J.; Krygowski, M.; Ananthakrishnan, R.; Boni, J.P.; Berkenblit, A.; Spunt, S.L. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur. J. Cancer 2012, 48, 253–262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Becher, O.J.; Gilheeney, S.W.; Khakoo, Y.; Lyden, D.C.; Haque, S.; De Braganca, K.C.; Kolesar, J.M.; Huse, J.T.; Modak, S.; Wexler, L.H.; et al. A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors. Pediatr. Blood Cancer 2017, 64, e26409. [Google Scholar] [CrossRef] [PubMed]
  55. Ayalon, D.; Glaser, T.; Werner, H. Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein. Growth Horm. IGF Res. 2001, 11, 289–297. [Google Scholar] [CrossRef] [PubMed]
  56. El-Badry, O.M.; Minniti, C.; Kohn, E.C.; Houghton, P.J.; Daughaday, W.H.; Helman, L.J. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ 1990, 1, 325–331. [Google Scholar]
  57. Burtrum, D.; Zhu, Z.; Lu, D.; Anderson, D.M.; Prewett, M.; Pereira, D.S.; Bassi, R.; Abdullah, R.; Hooper, A.T.; Koo, H.; et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res. 2003, 63, 8912–8921. [Google Scholar]
  58. Houghton, P.J.; Morton, C.L.; Gorlick, R.; Kolb, E.A.; Keir, S.T.; Reynolds, C.P.; Kang, M.H.; Maris, J.M.; Wu, J.; Smith, M.A. Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 2010, 54, 921–926. [Google Scholar] [CrossRef] [Green Version]
  59. Weigel, B.; Malempati, S.; Reid, J.M.; Voss, S.D.; Cho, S.Y.; Chen, H.X.; Krailo, M.; Villaluna, D.; Adamson, P.C.; Blaney, S.M. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: A report from the Children’s Oncology Group. Pediatr. Blood Cancer 2014, 61, 452–456. [Google Scholar] [CrossRef] [Green Version]
  60. Malempati, S.; Weigel, B.J.; Chi, Y.Y.; Tian, J.; Anderson, J.R.; Parham, D.M.; Teot, L.A.; Rodeberg, D.A.; Yock, T.I.; Shulkin, B.L.; et al. The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children’s Oncology Group. Cancer 2019, 125, 290–297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Wagner, L.M.; Fouladi, M.; Ahmed, A.; Krailo, M.D.; Weigel, B.; DuBois, S.G.; Doyle, L.A.; Chen, H.; Blaney, S.M. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the Children’s Oncology Group. Pediatr. Blood Cancer 2015, 62, 440–444. [Google Scholar] [CrossRef] [Green Version]
  62. Rengaswamy, V.; Zimmer, D.; Suss, R.; Rossler, J. RGD liposome-protamine-siRNA (LPR) nanoparticles targeting PAX3-FOXO1 for alveolar rhabdomyosarcoma therapy. J. Control. Release 2016, 235, 319–327. [Google Scholar] [CrossRef] [PubMed]
  63. Bharathy, N.; Berlow, N.E.; Wang, E.; Abraham, J.; Settelmeyer, T.P.; Hooper, J.E.; Svalina, M.N.; Ishikawa, Y.; Zientek, K.; Bajwa, Z.; et al. The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Sci. Signal. 2018, 11, eaau7632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Minn, A.Y.; Lyden, E.R.; Anderson, J.R.; Million, L.; Arndt, C.A.; Brown, K.; Hawkins, D.S.; Donaldson, S.S. Early treatment failure in intermediate-risk rhabdomyosarcoma: Results from IRS-IV and D9803—A report from the Children’s Oncology Group. J. Clin. Oncol. 2010, 28, 4228–4232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Wolden, S.L.; Anderson, J.R.; Crist, W.M.; Breneman, J.C.; Wharam, M.D., Jr.; Wiener, E.S.; Qualman, S.J.; Donaldson, S.S. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J. Clin. Oncol. 1999, 17, 3468–3475. [Google Scholar] [CrossRef]
  66. Raney, R.B.; Anderson, J.R.; Barr, F.G.; Donaldson, S.S.; Pappo, A.S.; Qualman, S.J.; Wiener, E.S.; Maurer, H.M.; Crist, W.M. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: A selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J. Pediatr. Hematol. Oncol. 2001, 23, 215–220. [Google Scholar] [CrossRef]
  67. Wolden, S.L.; Lyden, E.R.; Arndt, C.A.; Hawkins, D.S.; Anderson, J.R.; Rodeberg, D.A.; Morris, C.D.; Donaldson, S.S. Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children’s Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 2015, 93, 1071–1076. [Google Scholar] [CrossRef] [Green Version]
  68. Lin, C.; Donaldson, S.S.; Meza, J.L.; Anderson, J.R.; Lyden, E.R.; Brown, C.K.; Morano, K.; Laurie, F.; Arndt, C.A.; Enke, C.A.; et al. Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803—A report from the Children’s Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 2012, 82, 1764–1770. [Google Scholar] [CrossRef] [Green Version]
  69. Cotter, S.E.; McBride, S.M.; Yock, T.I. Proton radiotherapy for solid tumors of childhood. Technol. Cancer Res. Treat. 2012, 11, 267–278. [Google Scholar] [CrossRef] [Green Version]
  70. Ladra, M.M.; Yock, T.I. Proton radiotherapy for pediatric sarcoma. Cancers 2014, 6, 112–127. [Google Scholar] [CrossRef] [Green Version]
  71. Ladra, M.M.; Edgington, S.K.; Mahajan, A.; Grosshans, D.; Szymonifka, J.; Khan, F.; Moteabbed, M.; Friedmann, A.M.; MacDonald, S.M.; Tarbell, N.J.; et al. A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. Radiother. Oncol. 2014, 113, 77–83. [Google Scholar] [CrossRef] [Green Version]
  72. Ladra, M.M.; Szymonifka, J.D.; Mahajan, A.; Friedmann, A.M.; Yong Yeap, B.; Goebel, C.P.; MacDonald, S.M.; Grosshans, D.R.; Rodriguez-Galindo, C.; Marcus, K.J.; et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J. Clin. Oncol. 2014, 32, 3762–3770. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Sharma, P.; Allison, J.P. The future of immune checkpoint therapy. Science 2015, 348, 56–61. [Google Scholar] [CrossRef] [PubMed]
  74. Postow, M.A.; Callahan, M.K.; Barker, C.A.; Yamada, Y.; Yuan, J.; Kitano, S.; Mu, Z.; Rasalan, T.; Adamow, M.; Ritter, E.; et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 2012, 366, 925–931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Brahmer, J.; Reckamp, K.L.; Baas, P.; Crino, L.; Eberhardt, W.E.; Poddubskaya, E.; Antonia, S.; Pluzanski, A.; Vokes, E.E.; Holgado, E.; et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015, 373, 123–135. [Google Scholar] [CrossRef] [Green Version]
  76. Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Aren Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthelemy, P.; Porta, C.; George, S.; et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018, 378, 1277–1290. [Google Scholar] [CrossRef] [PubMed]
  77. Rizvi, N.A.; Mazières, J.; Planchard, D.; Stinchcombe, T.E.; Dy, G.K.; Antonia, S.J.; Horn, L.; Lena, H.; Minenza, E.; Mennecier, B.; et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 2015, 16, 257–265. [Google Scholar] [CrossRef] [Green Version]
  78. Pollack, S.M.; He, Q.; Yearley, J.H.; Emerson, R.; Vignali, M.; Zhang, Y.; Redman, M.W.; Baker, K.K.; Cooper, S.; Donahue, B.; et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer 2017, 123, 3291–3304. [Google Scholar] [CrossRef] [Green Version]
  79. Kim, C.; Kim, E.K.; Jung, H.; Chon, H.J.; Han, J.W.; Shin, K.H.; Hu, H.; Kim, K.S.; Choi, Y.D.; Kim, S.; et al. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer 2016, 16, 434. [Google Scholar] [CrossRef] [Green Version]
  80. Davis, K.L.; Fox, E.; Merchant, M.S.; Reid, J.M.; Kudgus, R.A.; Liu, X.; Minard, C.G.; Voss, S.; Berg, S.L.; Weigel, B.J.; et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol. 2020, 21, 541–550. [Google Scholar] [CrossRef]
  81. Merchant, M.S.; Wright, M.; Baird, K.; Wexler, L.H.; Rodriguez-Galindo, C.; Bernstein, D.; Delbrook, C.; Lodish, M.; Bishop, R.; Wolchok, J.D.; et al. Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Clin. Cancer Res. 2016, 22, 1364–1370. [Google Scholar] [CrossRef] [Green Version]
  82. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013, 342, 1432–1433. [Google Scholar] [CrossRef] [Green Version]
  83. Coley, W.B., II. Contribution to the Knowledge of Sarcoma. Am. Surg 1891, 14, 199–220. [Google Scholar] [CrossRef]
  84. Chou, A.J.; Kleinerman, E.S.; Krailo, M.D.; Chen, Z.; Betcher, D.L.; Healey, J.H.; Conrad, E.U., 3rd; Nieder, M.L.; Weiner, M.A.; Wells, R.J.; et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group. Cancer 2009, 115, 5339–5348. [Google Scholar] [CrossRef] [PubMed]
  85. Kleinerman, E.S.; Jia, S.F.; Griffin, J.; Seibel, N.L.; Benjamin, R.S.; Jaffe, N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: The cytokine cascade and monocyte activation following administration. J. Clin. Oncol. 1992, 10, 1310–1316. [Google Scholar] [CrossRef] [PubMed]
  86. Meyers, P.A.; Schwartz, C.L.; Krailo, M.D.; Healey, J.H.; Bernstein, M.L.; Betcher, D.; Ferguson, W.S.; Gebhardt, M.C.; Goorin, A.M.; Harris, M.; et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J. Clin. Oncol. 2008, 26, 633–638. [Google Scholar] [CrossRef] [PubMed]
  87. Larsson, S.E.; Lorentzon, R.; Boquist, L. Immunotherapy with irradiated tumour cells and BCG in experimental osteosarcoma. Acta Orthop. Scand. 1981, 52, 469–474. [Google Scholar] [CrossRef] [PubMed]
  88. Miwa, S.; Nishida, H.; Tsuchiya, H. Current status of immunotherapy for sarcomas. Immunotherapy 2017, 9, 1331–1338. [Google Scholar] [CrossRef] [Green Version]
  89. Merchant, M.S.; Bernstein, D.; Amoako, M.; Baird, K.; Fleisher, T.A.; Morre, M.; Steinberg, S.M.; Sabatino, M.; Stroncek, D.F.; Venkatasan, A.M.; et al. Adjuvant Immunotherapy to Improve Outcome in High-Risk Pediatric Sarcomas. Clin. Cancer Res. 2016, 22, 3182–3191. [Google Scholar] [CrossRef] [Green Version]
  90. Krishnadas, D.K.; Shusterman, S.; Bai, F.; Diller, L.; Sullivan, J.E.; Cheerva, A.C.; George, R.E.; Lucas, K.G. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol. Immunother. 2015, 64, 1251–1260. [Google Scholar] [CrossRef]
  91. Ahmed, N.; Brawley, V.S.; Hegde, M.; Robertson, C.; Ghazi, A.; Gerken, C.; Liu, E.; Dakhova, O.; Ashoori, A.; Corder, A.; et al. Human Epidermal Growth Factor Receptor 2 (HER2)-Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J. Clin. Oncol. 2015, 33, 1688–1696. [Google Scholar] [CrossRef]
  92. Huang, X.; Park, H.; Greene, J.; Pao, J.; Mulvey, E.; Zhou, S.X.; Albert, C.M.; Moy, F.; Sachdev, D.; Yee, D.; et al. IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas. PLoS ONE 2015, 10, e0133152. [Google Scholar] [CrossRef] [PubMed]
  93. Roberts, S.S.; Chou, A.J.; Cheung, N.K. Immunotherapy of Childhood Sarcomas. Front. Oncol. 2015, 5, 181. [Google Scholar] [CrossRef] [Green Version]
  94. Miwa, S.; Shirai, T.; Yamamoto, N.; Hayashi, K.; Takeuchi, A.; Igarashi, K.; Tsuchiya, H. Current and Emerging Targets in Immunotherapy for Osteosarcoma. J. Oncol 2019, 2019, 7035045. [Google Scholar] [CrossRef] [Green Version]
  95. Gattenlohner, S.; Marx, A.; Markfort, B.; Pscherer, S.; Landmeier, S.; Juergens, H.; Muller-Hermelink, H.K.; Matthews, I.; Beeson, D.; Vincent, A.; et al. Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor. Cancer Res. 2006, 66, 24–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Robbins, P.F.; Morgan, R.A.; Feldman, S.A.; Yang, J.C.; Sherry, R.M.; Dudley, M.E.; Wunderlich, J.R.; Nahvi, A.V.; Helman, L.J.; Mackall, C.L.; et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 2011, 29, 917–924. [Google Scholar] [CrossRef] [PubMed]
  97. Chen, X.; Stewart, E.; Shelat, A.A.; Qu, C.; Bahrami, A.; Hatley, M.; Wu, G.; Bradley, C.; McEvoy, J.; Pappo, A.; et al. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 2013, 24, 710–724. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Fanzani, A.; Poli, M. Iron Oxidative Damage and Ferroptosis in Rhabdomyosarcoma. Int J. Mol. Sci. 2017, 18, 1718. [Google Scholar] [CrossRef] [Green Version]
  99. Dachert, J.; Ehrenfeld, V.; Habermann, K.; Dolgikh, N.; Fulda, S. Targeting ferroptosis in rhabdomyosarcoma cells. Int. J. Cancer 2020, 146, 510–520. [Google Scholar] [CrossRef]
  100. Phelps, M.P.; Yang, H.; Patel, S.; Rahman, M.M.; McFadden, G.; Chen, E. Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma. Mol. Ther. Oncolytics 2018, 11, 52–61. [Google Scholar] [CrossRef] [Green Version]
  101. Tazawa, H.; Hasei, J.; Yano, S.; Kagawa, S.; Ozaki, T.; Fujiwara, T. Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy. Cancers 2020, 12, 478. [Google Scholar] [CrossRef] [Green Version]
  102. Yano, S.; Miwa, S.; Kishimoto, H.; Uehara, F.; Tazawa, H.; Toneri, M.; Hiroshima, Y.; Yamamoto, M.; Urata, Y.; Kagawa, S.; et al. Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma. Oncotarget 2015, 6, 13133–13148. [Google Scholar] [CrossRef] [PubMed]
  103. Zhao, M.; Geller, J.; Ma, H.; Yang, M.; Penman, S.; Hoffman, R.M. Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 10170–10174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Zhao, M.; Yang, M.; Li, X.M.; Jiang, P.; Baranov, E.; Li, S.; Xu, M.; Penman, S.; Hoffman, R.M. Tumor-Targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc. Natl. Acad. Sci. USA 2005, 102, 755–760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Miwa, S.; Yano, S.; Zhang, Y.; Matsumoto, Y.; Uehara, F.; Yamamoto, M.; Hiroshima, Y.; Kimura, H.; Hayashi, K.; Yamamoto, N.; et al. Tumor-Targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice. Oncotarget 2014, 5, 7119–7125. [Google Scholar] [CrossRef] [Green Version]
  106. Miwa, S.; Zhang, Y.; Baek, K.E.; Uehara, F.; Yano, S.; Yamamoto, M.; Hiroshima, Y.; Matsumoto, Y.; Kimura, H.; Hayashi, K.; et al. Inhibition of spontaneous and experimental lung metastasis of soft-tissue sarcoma by tumor-targeting Salmonella typhimurium A1-R. Oncotarget 2014, 5, 12849–12861. [Google Scholar] [CrossRef] [Green Version]
  107. Igarashi, K.; Kawaguchi, K.; Zhao, M.; Kiyuna, T.; Miyake, K.; Miyake, M.; Nelson, S.D.; Dry, S.M.; Li, Y.; Yamamoto, N.; et al. Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model. Transl. Oncol. 2020, 13, 393–400. [Google Scholar] [CrossRef] [PubMed]
  108. Nakano, K.; Takahashi, S. Precision Medicine in Soft Tissue Sarcoma Treatment. Cancers 2020, 12, E221. [Google Scholar] [CrossRef] [Green Version]
  109. Casey, D.L.; Wexler, L.H.; Pitter, K.L.; Samstein, R.M.; Slotkin, E.K.; Wolden, S.L. Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma. Clin. Cancer Res. 2020, 26, 1135–1140. [Google Scholar] [CrossRef] [Green Version]
  110. Lawrence, M.S.; Stojanov, P.; Polak, P.; Kryukov, G.V.; Cibulskis, K.; Sivachenko, A.; Carter, S.L.; Stewart, C.; Mermel, C.H.; Roberts, S.A.; et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013, 499, 214–218. [Google Scholar] [CrossRef] [PubMed]
  111. Marabelle, A.; Le, D.T.; Ascierto, P.A.; Di Giacomo, A.M.; De Jesus-Acosta, A.; Delord, J.P.; Geva, R.; Gottfried, M.; Penel, N.; Hansen, A.R.; et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J. Clin. Oncol. 2020, 38, 1–10. [Google Scholar] [CrossRef]
  112. Marcus, L.; Lemery, S.J.; Keegan, P.; Pazdur, R. FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin. Cancer Res. 2019, 25, 3753–3758. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Middha, S.; Zhang, L.; Nafa, K.; Jayakumaran, G.; Wong, D.; Kim, H.R.; Sadowska, J.; Berger, M.F.; Delair, D.F.; Shia, J.; et al. Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data. JCO Precis. Oncol. 2017, 1, 1–17. [Google Scholar] [CrossRef] [PubMed]
  114. Hoffman, R.M. Patient-Derived orthotopic xenografts: Better mimic of metastasis than subcutaneous xenografts. Nat. Rev. Cancer 2015, 15, 451–452. [Google Scholar] [CrossRef]
  115. Igarashi, K.; Kawaguchi, K.; Kiyuna, T.; Murakami, T.; Miwa, S.; Nelson, S.D.; Dry, S.M.; Li, Y.; Singh, A.S.; Kimura, H.; et al. Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 2017, 8, 75874–75880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Table
Table 1. Recent clinical trials on chemotherapy in patients with Rhabdomyosarcoma (RMS).
Table 1. Recent clinical trials on chemotherapy in patients with Rhabdomyosarcoma (RMS).
YearsPhaseChemotherapy RegimenNPatientsClinical SignificanceRef.
2019IIIIVA with or without maintenance chemotherapy (VC)371Non-metastatic RMSFive-year DFS:
77.6% with IVA/VC and 69.8% with IVA (p = 0.06)		[27]
Five-year OS:
86.5% with IVA/VC and 73.7% with IVA (p = 0.01)
2018IIIIVA with or without Dox484Non-metastatic RMSThree-year EFS:
67.5% with IVA/Dox and
63.3% with IVA (p = 0.33)		[25]
2018IIIVAC or VAC/VI (substitution for half of VAC course by VI)448Intermediate-risk RMSFour-year EFS:
63% with VAC and 59% with VAC/VI (p = 0.51)		[28]
Four-year OS:
73% with VAC and 72% with VAC/VI (p = 0.80)
less hematologic toxicities with VAC/VI
2012IITrabectedin50Recurrent sarcoma: RMS (23), EWS (16), and other sarcomas (11)PR 2.5%, SD 7.5%, and PD 90%[30]
IVA: ifosfamide, vincristine, and dactinomycin; VC: vinorelbine and cyclophosphamide; VAC: vincristine, dactinomycin, and cyclophosphamide; VI: vincristine and irinotecan; RMS, rhabdomyosarcoma; EWS, Ewing sarcoma; DFS: disease-free survival; OS: overall survival; EFS: event-free survival; Dox: doxorubicin; PR, partial response; SD, stable disease; PD, progressive disease.
Table
Table 2. Clinical trials of molecular targeting agents for sarcomas.
Table 2. Clinical trials of molecular targeting agents for sarcomas.
YearsPhaseTreatmentTarget MoleculeNPatientsClinical SignificanceRef.
2009IIPazopanib
(800 mg, daily)		PDGF-α, VEGF-1, 2, 3, c-kit142Advanced STS Disease control rate: 49% for SS, 44% for LMS, and 39% for other sarcomas[31]
2012IIIPazopanib
(800 mg, daily) or placebo		PDGF-α, VEGF-1, 2, 3, c-kit372Metastatic STSOS: 12.5 months with pazopanib and 10.7 months with placebo
PFS: 4.6 months with pazopanib and 1.6 months with placebo		[32]
2015IISorafenib
(200 mg/m2, oral)		PDGFRs, VEGFRs, MAPK, and c-kit20RMS (10) and Wilms tumor (10)Objective response: 0%[40]
2013IISorafenib
(400 mg, twice, daily for 28 days)		PDGFRs, VEGFRs, MAPK, and c-kit101Advanced STSPR, 14%; SD, 33%; PD, 49%, unevaluable 8%
Median PFS: four months
Median OS: 12 months		[41]
2018IICrizotinib
(250 mg, twice, daily)		MET, ALK,
ROS1 and RON		13Advanced/metastatic ARMSObjective response rate 14%, disease control rate: 14%[45]
2012IITemsirolimus (75 mg/m2)mTOR52High-grade glioma (17), neuroblastoma (19), and RMS (16)Disease control rate: 41% for glioma, 32% for neuroblastoma, and 6% for RMS[53]
2014IICixutumumab (9 mg/kg, weekly) IGF-1R114Relapsed or refractory solid tumors: osteosarcoma (11), RMS (20), neuroblastoma (30), Wilms tumor (10), Adrenocortical carcinoma (10), Hepatoblastoma (10), and synovial sarcoma (11)PR: 20% for neuroblastoma and 5% for RMS[59]
PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; MAPK, mitogen-activated protein kinases; ALK, anaplastic lymphoma kinase; ROS1, ROS proto-oncogene 1 receptor tyrosine kinase; RON, Recepteur d’Origine Nantais; IGF-1R, insulin-like growth factor 1 receptor; RMS, rhabdomyosarcoma; STS, soft tissue sarcoma; ARMS, alveolar rhabdomyosarcoma; LMS, leiomyosarcoma; OS, overall survival; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival.
Table
Table 3. Recent clinical studies on immunotherapy.
Table 3. Recent clinical studies on immunotherapy.
YearPhaseTreatmentNPatientsClinical SignificanceRef.
2016IIStandard therapy with or without immunotherapy using autologous lymphocytes, TL-pulsed DCs, with or without IL-743High-risk pediatric sarcomas: EWS (24), RMS (11), and others (8)T-cell responses toTL: 62%
Five-year OS:
73% in patients with T cell response and 37% in patients without T cell response		[89]
2015I/IIDecitabine followed by DC pulsed with MAGE-A1, MAGE-A3 and NY-ESO-1 peptides10 NB (8), EWS (1), and RMS (1)CR: 10%, SD 20%, PD 70%[90]
2015I/IIHER2-specific CAR T cells19HER2-positive tumors: Osteosarcoma (16), PNET (1), EWS (1), and DSRCT (1)SD 24%[91]
TL, tumor lysate; DC, dendritic cell, IL, interleukin; MAGE, melanoma-associated gene; NY-ESO-1, New York esophageal squamous cell carcinoma-1; HER2, human epidermal growth factor receptor 2; CAR, chimeric antigen receptor; EWS, Ewing’s sarcoma; RMS, rhabdomyosarcoma; NB, neuroblastoma; PNET, primitive neuroectodermal tumor; DSRCT, desmoplastic small round cell tumor; TL, tumor lysate; OS, overall survival; CR, complete response; SD, stable disease; PD, progressive disease.

Share and Cite

MDPI and ACS Style

Miwa, S.; Yamamoto, N.; Hayashi, K.; Takeuchi, A.; Igarashi, K.; Tsuchiya, H. Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma. Cancers 2020, 12, 1758. https://doi.org/10.3390/cancers12071758

AMA Style

Miwa S, Yamamoto N, Hayashi K, Takeuchi A, Igarashi K, Tsuchiya H. Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma. Cancers. 2020; 12(7):1758. https://doi.org/10.3390/cancers12071758

Chicago/Turabian Style

Miwa, Shinji, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Kentaro Igarashi, and Hiroyuki Tsuchiya. 2020. "Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma" Cancers 12, no. 7: 1758. https://doi.org/10.3390/cancers12071758

APA Style

Miwa, S., Yamamoto, N., Hayashi, K., Takeuchi, A., Igarashi, K., & Tsuchiya, H. (2020). Recent Advances and Challenges in the Treatment of Rhabdomyosarcoma. Cancers, 12(7), 1758. https://doi.org/10.3390/cancers12071758

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop