Review Molecular Cancer Therapeutics Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma Anke E.M. van Erp1, Yvonne M.H. Versleijen-Jonkers1, Winette T.A. van der Graaf1,2, and Emmy D.G. Fleuren3 Abstract Targeted therapies have revolutionized cancer treatment; in this regard, as this affects multiple hallmarks of cancer at however, progress lags behind in alveolar (ARMS) and embry- once. To determine the most promising and clinically relevant onal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly targeted therapy–based combination treatments for ARMS and occurring at pediatric and young adult age. Insulin-like growth ERMS, we provide an extensive overview of preclinical and factor 1 receptor (IGF1R)-directed targeted therapy is one of the (early) clinical data concerning a variety of targeted therapy– few single-agent treatments with clinical activity in these dis- based combination treatments. We concentrated on the most eases. However, clinical effects only occur in a small subset of common classes of targeted therapies investigated in rhabdo- patients and are often of short duration due to treatment myosarcoma to date, including those directed against receptor resistance. Rational selection of combination treatments of tyrosine kinases and associated downstream signaling path- either multiple targeted therapies or targeted therapies with ways, the Hedgehog signaling pathway, apoptosis pathway, chemotherapy could hypothetically circumvent treatment resis- DNA damage response, cell-cycle regulators, oncogenic fusion tance mechanisms and enhance clinical efficacy. Simultaneous proteins, and epigenetic modifiers. Mol Cancer Ther; 17(7); 1365–80. targeting of distinct mechanisms might be of particular interest Ó2018 AACR. Introduction treatment including surgery, chemotherapy, and radiotherapy has increased the 5-year overall survival (OS) to approximately Rhabdomyosarcoma is the most common type of soft-tissue 70%–90% for intermediate- and low-risk rhabdomyosarcoma, sarcoma (STS) observed in young patients with the most respectively. However, patients with high-risk rhabdomyosar- frequent subtypes being embryonal (ERMS) and alveolar rhab- coma still have a 5-year OS of <40%. In addition, treatment- domyosarcoma (ARMS). ERMS represents approximately 70% related toxicities severely decrease quality of life (1, 2). In an of childhood rhabdomyosarcoma and is most often observed attempt to increase survival and improve quality of life, the in the head and neck region and genitourinary track. ARMS is field of targeted therapy has gained substantial interest in seen in approximately 30% of rhabdomyosarcoma cases and rhabdomyosarcoma, and its potential is supported by various usually occurs in the deep tissue of the extremities. The majority lines of (pre)clinical research, which are mainly centered on of ARMS tumors are characterized by a fusion between PAX3 or targeted therapies originally developed for other tumor types. PAX7 on chromosome 2 and FOXO1 on chromosome 13 In the clinic, however, intrinsic and acquired resistance (80%). The remaining 20% are fusion negative. Although mechanisms have emerged as common pitfalls in rhabdomyo- generally ARMS have a poorer outcome compared with ERMS, sarcoma treatment. As such, increasing evidence exists that fusion-negative ARMS show a genetic profile similar to ERMS single-agent targeted therapy will not be sufficient to reach and an equally favorable clinical outcome. Multimodality clinical efficacy in patients with rhabdomyosarcoma. The cur- rent hypothesis is that combination therapy could enhance clinical efficacy and/or decrease treatment-associated toxicities. In this regard, simultaneous targeting of different mechanisms 1Department of Medical Oncology, Radboud University Medical Center, Nijme- gen, the Netherlands. 2The Institute of Cancer Research, Division of Clinical of action could be more effective as opposed to combining Studies, Clinical and Translational Sarcoma Research and The Royal Marsden inhibitors of similar classes, as the characteristic hallmarks of NHS Foundation Trust, Sutton, United Kingdom. 3The Institute of Cancer cancer illustrate that tumor progression is regulated by a wide Research, Division of Clinical Studies, Clinical and Translational Sarcoma variety of different processes. Research, Sutton, United Kingdom. To determine the most promising and clinically relevant Note: Supplementary data for this article are available at Molecular Cancer combination treatments for rhabdomyosarcoma, we reviewed Therapeutics Online (http://mct.aacrjournals.org/). the preclinical and (early) clinical trial data addressing combi- Corresponding Authors: Winette T.A. van der Graaf, Division of Clinical Studies, nations of targeted therapies or targeted therapy combined with The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, chemotherapy. We focused on the most common classes of 15 Cotswold Road, SM2 5NG, Sutton, United Kingdom. Phone: 4402-0872- targeted therapies investigated in rhabdomyosarcoma to date, 24448; Fax: þ31-24-36-15025; E-mail: [email protected]; and including those directed against receptor tyrosine kinases (RTK) Emmy D.G. Fleuren, emmy.fl[email protected] andassociateddownstreamsignaling pathways, the Hedgehog doi: 10.1158/1535-7163.MCT-17-1131 signaling pathway, apoptosis pathway, DNA damage response, Ó2018 American Association for Cancer Research. cell-cycle regulators, fusion proteins, and epigenetic modifiers. www.aacrjournals.org 1365 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. van Erp et al. RTKs and a limited decrease of downstream AKT activity upon RTKs are membrane-bound proteins involved in signal trans- IGF1R antibody treatment. IGF1R antibodies combined with duction to the tumor cell. Activation by extracellular ligand recombinant IGFBP2, the PI3K inhibitor BKM130, or the binding or genetic mutations can lead to constitutive activity. mTOR inhibitor Ku-0063784 resensitized the resistant cell Intracellular signaling pathways, including the PI3K/AKT/mTOR, lines to IGF1R targeting (12). The possible low bioavailability RAS/MEK/ERK, and JAK/STAT3 pathway, are subsequently acti- of recombinant IGFBP2 could affect the clinical potential of vated. Several RTKs have been identified as possible targets for this particular combination treatment. Clinical trials did therapy in rhabdomyosarcoma, including the insulin-like growth show a partial response (PR) in a patient with IGF1R-positive factor 1 receptor (IGF1R), anaplastic lymphoma kinase (ALK), soft-tissue sarcoma and stable disease (SD) in 2 of 11 pediatric, platelet-derived growth factor receptors a and b (PDFGRa/b), adolescent, and young adult (AYA) patients with rhabdomyo- VEGFR, EGFR, and the fibroblast growth factor receptor 4 sarcoma for the combination of IGF1R inhibitors and mTOR (FGFR4; Fig. 1A; ref. 3). Despite the promising preclinical effects, inhibitors (Table 2; refs. 13–16). This shows that only a small clinical efficacy is limited and observed in small subsets of pati- group responded to treatment and one study showed that the ents (4, 5). Combination treatment might enhance the clinical addition of temsirolimus led to increased toxicity without a efficacy of RTK-targeted therapies (Table 1). clear increase in efficacy in most patients (15). Nevertheless, these data do show that combined targeted therapy can over- IGF1R/ALK. One way of optimizing IGF1R treatment might be come primary treatment resistance and suggest that, when its combination with other (R)TK inhibitors. As coexpression of given simultaneously, might delay or prevent treatment resis- the RTKs IGF1R and ALK has been described in rhabdomyo- tance altogether. sarcoma, this may present a rational combination. In vitro, Because chemotherapy remains fundamental in rhabdomyo- combined anti-IGF1R antibody R1507 and ALK inhibitor sarcoma treatment, combinations with chemotherapy have TAE684 treatment showed synergism in ARMS cell lines. In been investigated. In young patients with ARMS and ERMS, ERMS, however, no enhanced effect was observed (6). In ARMS, the combination of the IGF1R antibody cixutumumab with the characteristic PAX3-FOXO1 protein can enhance IGF1R conventional chemotherapy was compared with the combina- and ALK transcription, possibly explaining this difference in tion of temozolomide with conventional chemotherapy. The sensitivity. However, we, among others, could not find intrinsic combination with cixutumumab led to a higher percentage ALK activity in rhabdomyosarcoma cells (7–9). In addition, the of patients reaching an 18-month event-free survival (EFS; antitumor effects observed with the ALK inhibitor ceritinib cixutumumab 68% vs. temozolomide 39%; NCT01055314; were mostly explained by its capacity to inhibit IGF1R signaling Table 2). Of note, the combination with cixutumumab had (9). Combined treatment of ceritinib with the multikinase more reports of high-grade toxicity compared with the combi- inhibitor sorafenib showed synergistic effect in vitro (8). In nation with temozolomide. High-grade toxicities were, how- addition, we observed high activity of the signaling protein Src ever, only observed in a very small group (3/97, 3%), leaving post ceritinib treatment in both subtypes, and combined treat- the combination with cixutumumab preferential to the combi- ment of ceritinib and the Src inhibitor dasatinib was synergistic nation with temozolomide (17). Although preclinical research in vitro (9).