Meanwhile, patients who demonstrate relapse after low-risk disease may benefit from salvage chemotherapy, such as irinotecan/vincristine or alternating vincristine/doxorubicin/cyclophosphamide, and etoposide/ofosfamide (76, 77). Notably, several GSK3 inhibitors significantly suppressed transcriptional activity of PAX3-FOXO1, leading to inhibition of cellular proliferation and induction of apoptosis in ARMS cell lines (106). 44. Cells of the tumor are identified as rhabdomyoblasts. PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Even though ipilimumab is safely tolerated in these patients, its efficacy as a monotherapy is limited. Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. Nat Med. Such gene expression approaches can be a useful strategy to generate a list of possible immune targets, but validation that these targets are actually expressed at the protein level on tumor cells (and not expressed on normal cells) is required before they are considered for CAR T therapy. doi: 10.1002/pbc.21093, 78. Ignatius MS, Hayes MN, Lobbardi R, Chen EY, McCarthy KM, Sreenivas P, et al. Does aggressive local treatment have an impact on survival in children with metastatic rhabdomyosarcoma? As such, there is a need to identify reliable and objective biomarkers to determine the most effective therapy for each patient. doi: 10.1002/pbc.22958, 33. Rhabdomyosarcoma treatment usually involves a combination of treatments, including chemotherapy, surgery and radiation therapy. Constitutive activation of RTK signaling can reprogram numerous intracellular signaling pathways (metabolism, differentiation, apoptosis, growth) to promote tumor progression (Figure 2). A recent study designed a screen for epigenetic chemical probes to differentiate between super-enhancer driven transcription and constitutive transcription, revealing that the acetylation-axis is more important for the core regulatory TF circuit than the methylation-axis (90). These improvements follow collaborative group clinical trial efforts, which have enabled improvements in chemotherapeutic dosing regimens, local control, and management of treatment-related toxicities. doi: 10.1038/onc.2015.267, 118. Pediatr Blood Cancer. Novel approaches to drug transcription factors are currently being investigated in other disease contexts, with the possibility of adapting these strategies for targeting PAX-FOXO1. N Engl J Med. Ridzewski R, Rettberg D, Dittmann K, Cuvelier N, Fulda S, Hahn H. Hedgehog Inhibitors in Rhabdomyosarcoma: a comparison of four compounds and responsiveness of four cell lines. This raises the possibility that the PAX-FOXO1 chimeric proteins can be leveraged as novel tumor-associated antigens in immunotherapy. [1] Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis. As many of you know, Danna recently found out she has a tumor in her lung, meaning that her Rhabdomyosarcoma has metastasized and she has had to make the impossible decision to leave Finland and return to her childhood home in Minnesota. Receptor tyrosine kinases are a family of membrane-bound cell surface receptors which are aberrantly activated in many human malignancies. Efficacy of ifosfamide and doxorubicin given as a phase II window in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group*. doi: 10.1200/JCO.2007.14.7207, 30. Yet, emerging strategies to directly drug transcription factors are currently being explored in other human cancers. Survival outcomes for patients with metastatic disease remain dismal (event free survival <20%, excluding patients <10 years old diagnosed with ERMS), and the frontline treatment has not advanced significantly over the last 30 years (22, 29, 60). (2014) 120:244856. doi: 10.1016/j.cell.2012.08.038, 143. doi: 10.1007/s00262-004-0625-6, 153. (2014) 32:10003. doi: 10.1200/jco.2014.32.15_suppl.10003, 40. Barr FG. Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Drno B, Mortier L, et al. Lovn J, Heather Hoke A, Charles Lin Y, Lau A, David Orlando A, Christopher Vakoc R, et al. Trends Pharmacol Sci. PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines. Taken together, these data point to the effective approach of combining PARP inhibitors with radiotherapy, sensitizing cancer cells to the ionizing radiation and tolerating lower doses of radiation. doi: 10.1038/s41588-018-0044-9, 89. Nat Rev Clin Oncol. doi: 10.1016/j.ijrobp.2008.01.058, 55. The selective disruption of super-enhancers by small molecule inhibitors can specifically suppress transcription at key oncogenic drivers (91). One pediatric RMS patient treated achieved a complete response for 12 months, but relapsed later (163). Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Int J Cancer. Khan et al. Due to the extensive cross-talk across RTK signaling axes, combination therapies are likely needed to derive therapeutic benefit from this approach. Since the VAC/IVA regimen was first established four decades ago, the chemotherapy backbone has remained the same besides changes in duration, dosage, and route of administration. Pak E, Segal RA. Pediatr Blood Cancer. For patients diagnosed with metastatic rhabdomyosarcoma, insufficient local therapy options and incomplete eradication of occult microscopic residual disease are the most common causes of treatment failure (176). Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. Fredericks WJ, Ayyanathan K, Herlyn M, Friedman JR, Rauscher FJ III An engineered PAX3-KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3-FKHR oncogene. Direct modulation of apoptotic machinery has been exploited therapeutically in many human cancers, as most cancer cells are more sensitive to apoptotic induction than normal cells (142, 143). doi: 10.1038/mt.2009.133. Identification of serines 201 and 209 as sites of Pax3 phosphorylation and the altered phosphorylation status of Pax3-FOXO1 during early myogenic differentiation. Another recent preclinical study of CAR T cells targeting B7-H3 (an immune checkpoint antigen) in xenograft models of various pediatric solid tumors, including RMS demonstrated that they could induce tumor regression in xenograft models (164). doi: 10.1002/pbc.25548, 79. Pipeline of preclinical and clinical development for targeted therapies and immunotherapies of rhabdomyosarcoma. (2006) 24:384451. This trial (NCT03041701) is open to patients with relapsed or refractory RMS and its aim is to study the combination of the IFG-1R monoclonal antibody, ganitumab in combination with the SRC family kinase inhibitor, dasatinib. PAX3FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. (2019) 25:2560. doi: 10.1158/1078-0432.CCR-18-0432, 165. The advantage of the PROTAC approach over traditional pharmacological inhibition is that a single molecule could be used for multiple rounds of proteasome-targeted degradation. Geyer N, Ridzewski R, Bauer J, Kuzyakova M, Dittmann K, Dullin C, et al. This article aims to provide nurses with a clinical overview of rhabdomyosarcoma, a rare type of soft tissue sarcoma. Other studies have implicated that inhibition of another epigenetic regulator, histone deacetylase (HDAC) has antitumor effects in preclinical RMS models. AH was a participant in the BIH-Charit Clinical Scientist Program funded by the CharitUniversittsmedizin Berlin and the Berlin Institute of Health. Insights into pediatric rhabdomyosarcoma research: challenges and goals. doi: 10.1016/j.cell.2019.04.004, 139. In cases of metastatic RMS, clinical risk factors remain the major predictors of outcome. Pediatric Blood Cancer. (2002) 38:15864. An ongoing clinical trial (NCT02780804) of the HDAC1/2/3 inhibitor entinostat in pediatric patients with advanced solid tumors is expected to shed new insight on HDAC inhibitors in RMS. doi: 10.1097/00003086-200004000-00005, 150. Arndt CAS, Hawkins DS, Meyer WH, Sencer SF, Neglia JP, Anderson JR. Oncogene. Terezakis SA, Wharam MD. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. As recently reviewed here (183), patients with hot tumor microenvironments (immune infiltrated) respond better to immune checkpoint blockade, whereas patients with cold tumor microenvironments (immune non-infiltrated) are better suited for adoptive T cell therapy. Briscoe J, Thrond PP. J Clin Oncol. Rhabdomyosarcoma in children differs from the form of the disease typically seen in adults. Results from the COG ARST0431 trial for patients with high-risk RMS found that high-dose chemotherapy (dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation) did not produce meaningful benefit for most patients, except for a minority of patients with embryonal histology and limited metastatic disease (restricted to lungs) (63). Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study. (2015) 11:e1005075. Therapeutically actionable targets (at least one existing small molecule inhibitor or antibody) are indicated with an asterisk (*). (2009) 17:177987. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Only a small subset of TFs form the core regulatory circuit of TFs, which cancer cells are uniquely dependent on (88, 89). A recent publication demonstrated that liposome-protamine-siRNA (LRP) particles targeting PAX3-FOXO1 were efficiently delivered to ARMS cell lines and downregulated PAX3-FOXO1 and its target genes in vitro, leading to delayed tumor growth and inhibition of tumor initiation in ARMS xenograft models (84). reported there to be no correlation between fusion status and clinical outcome (31, 32). doi: 10.1126/scitranslmed.aan4470, 113. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. The development of BH3 mimetics, small molecule inhibitors which mimic the function BH3-only proteins by antagonizing the pro-survival function of anti-apoptotic Bcl-2 family, has recently gained traction as a therapeutic intervention in a number of human cancers. Med Pediatr Oncol. doi: 10.1200/JCO.2009.26.3814, 17. Stegmaier S, Poremba C, Schaefer KL, Leuschner I, Kazanowska B, Bekassy AN, et al. A pilot trial of consolidative immunotherapy (integration of immunotherapy into a multi-modal chemotherapeutic regimen), which administered vaccines of dendritic cells pulsed with breakpoint peptides reported positive outcomes in patients with high-risk pediatric ARMS, highlighting that vaccine-based approaches targeting the fusion protein could still be a valuable strategy. Among the five structurally diverse BET bromodomain inhibitors tested in this study, OTX015 was reported to be most potent across a range of FP RMS cell lines, but its clinical efficacy has not been evaluated. Another study highlighted that downregulation of Notch3 is sufficient to induce RMS cells into a terminal myogenic differentiation program, suggesting Notch3 as another potential therapeutic target (130). (2001) 19:3091102. (2005) 54:52634. Blood. Cancer Discov. Nat Rev Cancer. Effective clinical translation of these agents remains an ongoing challenge, underscoring the need to elucidate why tumors eventually acquire resistance to targeted therapy. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, and can be subcategorized histologically and/or based on PAX-FOXO1 fusion gene status. Over the last four decades, there have been no significant improvements in clinical outcomes for advanced and metastatic RMS patients, underscoring a need for new treatment options for these groups. However, extended local therapy (RT or chemotherapy) is not always feasible in patients. (2013) 17:60723. (2015) 15:686. doi: 10.1038/nrc4018, 99. Most common variant in the gynecologic tract is embryonal, which typically presents as a polypoid vaginal or cervical mass in children and adolescents. (2015) 160:124660. (2010) 1:94151. Challenges of designing CAR T cell therapy for solid tumor malignancies include: heterogeneous antigen expression, limited migration of T cells to tumor sites, and an immunosuppressive, hostile microenvironment (158). Conversely, North American studies tend to focus on event-free survival as the study end-point, so treatment strategies favor more aggressive local treatment with radiation therapy (1). Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma. Jones DTW, Banito A, Grnewald TGP, Haber M, Jger N, Kool M, et al. It was a pleasure listening and conversing with Danna, as she is the first individual weve interviewed for the DwD Podcast who is in a similar position as Andrew; a young adult living with a terminal disease, simply looking to have a choice during their end of life experience. A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. doi: 10.1200/JCO.2015.64.3395, 177. doi: 10.1007/s00280-016-3077-8, 140. CHD4 is required for the recruitment of the transcriptional machinery, and its role in nucleosome eviction is required for transcription to proceed. Pediatr Blood Cancer. J Biol Chem. Several studies have shown the that RTK inhibitors can induce tumor regression in preclinical models (summarized in Table 1). Knowing the type of rhabdomyosarcoma helps your specialist decide on the . Conceptually, it is more effective to target one upstream transcription factor than multiple downstream signaling cascades and hundreds of target genes. (2000) 20:501931. As whole-genome and transcriptome sequencing of rhabdomyosarcoma tumors has revealed, the genomic diversity of this disease requires a personalized (genotype-guided) approach to therapy. doi: 10.1080/2162402X.2018.1481558, 155. Pembrolizumab versus ipilimumab in advanced melanoma. Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, et al. doi: 10.1200/JCO.2010.32.1984, 76. doi: 10.1002/cncr.31553, 41. Monocolonal antibodies can directly target cancer cells through a number of mechanisms, including inhibition of oncogenic signaling pathways, delivery of cytotoxic moieties to malignant cells, or induction of antibody-dependent cellular toxicity (155). Skapek SX, Anderson J, Barr FG, Bridge JA, Gastier-Foster JM, Parham DM, et al. IGF-1R inhibition activates a YES/SFK bypass resistance pathway: rational basis for co-targeting IGF-1R and Yes/SFK kinase in rhabdomyosarcoma. Intermittent dosing relies on the principle that periods of interspersed drug-withdrawal between drug-treatments can restore drug sensitivity by allowing drug-sensitive subpopulations to repopulate the tumor mass. We were excited to sit down and interview Danna Nelson, a young woman living in Minnesota with a rare cancer called rhabdomyosarcoma; an aggressive . Desantes K, Maris JM, McDowell K, Mackall C, Shankar S, Vasselli J, et al. (2017) 35:TPS2596. Maintenance chemotherapy in rhabdomyosarcoma: the new standard of care. (2008) 72:88491. Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's Sarcoma and primitive neuroectodermal tumor of bone. doi: 10.1038/onc.2010.368, 119. While the identification of novel therapeutic vulnerabilities for RMS is gaining significant traction, it is equally important for clinicians to remain one step ahead by being able to anticipate resistance mechanisms and to identify strategies to overcome resistance accordingly. Decades of clinical and basic research have gradually improved our understanding of the pathophysiology of RMS and helped to optimise clinical care.
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