So far, preclinical evaluation of Smo inhibitors has been difficult to interpret due to the heterogeneity of response in preclinical models, depending on the RMS cell line and Smo inhibitor assessed (125, 126). doi: 10.1002/mpo.1303, 151. van den Broeke LT, Pendleton CD, Mackall C, Helman LJ, Berzofsky JA. PLoS Genet. Conceptually, it is more effective to target one upstream transcription factor than multiple downstream signaling cascades and hundreds of target genes. (2015) 348:137681. (2015) 16:72936. Geyer N, Ridzewski R, Bauer J, Kuzyakova M, Dittmann K, Dullin C, et al. An alternative approach to disrupting PAX-FOXO1 activity is to target essential protein-protein interactions with co-regulators and chromatin-remodeling proteins required for oncogenic transcriptional activity. Fundraiser for Dan Nelson by Cristina Cutts : Support Danna! - GoFundMe Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the undruggable cancer targets. However, narrowly focusing on identifying these targets is inadequate, and a commensurate amount of effort ought to be given to studying mechanisms of resistance to targeted therapy. The link between Hh signaling and RMS was first described by Hahn et al. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 19752005. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Yan C, Brunson DC, Tang Q, Do D, Iftimia NA, Moore JC, et al. 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. (2011) 334:112933. 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). The current frontline treatment for all risk-groups of RMS is a multi-modal approach, comprising chemotherapy, surgical resection, and/or radiation therapy. PLK1 phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma. Weigel BJ, Breitfeld PP, Hawkins D, Crist WM, Baker KS. Bhm M, Wachtel M, Marques JG, Streiff N, Laubscher D, Nanni P, et al. In FN RMS, activating mutations in RTKs caused by molecular lesions can lead to hyperactive RTK signaling. (2013) 153:32034. doi: 10.1002/cncr.27934, 53. Received: 04 October 2019; Accepted: 05 December 2019; Published: 20 December 2019. ), conferring these tumors molecular dependencies which can be targeted by clinically available drugs (19). Med Pediatr Oncol. Ignatius MS, Hayes MN, Lobbardi R, Chen EY, McCarthy KM, Sreenivas P, et al. (2013) 140:8290. Pathology Outlines - Rhabdomyosarcoma Missiaglia E, Williamson D, Chisholm J, Wirapati P, Pierron G, Petel F, et al. (2017) 35:10508. doi: 10.1200/JCO.2017.35.15_suppl.10508, 164. Independently, another group found that CHD4 acts as a crucial coregulator of PAX3-FOXO1 (identified as a top candidate from a siRNA screen of 60 candidate interactors), suggesting the role of CHD4 as a therapeutic target in FP RMS (93). Pediatr Blood Cancer. doi: 10.1056/NEJMoa1414428, 169. (2013) 25:2735. Access to clinical trials for adolescents with soft tissue sarcomas: enrollment in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Moreover, children do not yet have a fully developed immune system, which is required for optimal response to immunotherapy. Toward a drug development path that targets metastatic progression in osteosarcoma. 45. Int J Cancer. Advances in Cancer Research. Arndt CA. doi: 10.1200/JCO.2018.36.18_suppl.LBA2, 58. doi: 10.1016/j.cell.2013.03.036, 92. (2008) 72:88491. J Pediatr Hematol Oncol. The inconsistent results from these retrospective studies can be partly explained by methodological biases of convenience sampling, where samples are not truly representative of the whole population but rather chosen based on archival sample availability (3335). doi: 10.1038/oncsis.2015.2, 104. (1998) 2:7787. doi: 10.1002/gcc.10026, 120. Cancer Res. The relationship between Hh signaling dysregulation and RMS has subsequently been supported by several studies (115118). A recent preclinical study reported that the combination of olaparib and temozolomide (DNA-damaging agent) is a potent therapy for elimination of tumor cells in a human xenografted tumor zebrafish model of RMS. (2018) 5:e1448246. Does aggressive local treatment have an impact on survival in children with metastatic rhabdomyosarcoma? The Wee1 kinase arrests the cell cycle at the G2/M checkpoint for necessary DNA repair before entry into mitosis. McDonald MW, Esiashvili N, George BA, Katzenstein HM, Olson TA, Rapkin LB, et al. (2001) 23:2726. Figure 1. The 2013 World Health Organization (WHO) classification of skeletal muscle tumors modified the histologic classification of RMS to . Below, we summarize the key preclinical and clinical findings on novel targeted therapy and immunotherapy options in RMS (Figure 2). Molecular pathogenesis of rhabdomyosarcoma. RMS is historically classified based on histopathologic features into distinct clinical subtypes embryonal RMS (ERMS), alveolar RMS (ARMS), pleomorphic, and spindle cell and sclerosing RMS (ssRMS) (4, 5). Nat Rev Cancer. doi: 10.1016/j.ccell.2018.07.012, 141. (2015) 372:252132. Cancer Cell. doi: 10.1200/EDBK_200773, 159. Nat Med. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. National Cancer Institute (NIH), United States, Institute of Cancer Research (ICR), United Kingdom. doi: 10.1093/hmg/4.12.2355 Available online at: https://cancerres.aacrjournals.org/content/62/16/4704.long, 11. 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. In general, there are two approaches for targeting the regulatory networks of PAX-FOXO1; (1) targeting the regulatory kinases that influence protein stability, and (2) targeting the regulatory kinases required for activation of the fusion protein. Sasaki T, Rodig SJ, Chirieac LR, Jnne PA. Nucleic Acids Res. doi: 10.1200/JCO.2010.29.7390, 77. 1. (2002) 20:71926. The 2;13 and 1;14 translocations encode for a chimeric transcription factor (TF), consisting of the N-terminal DNA binding domain of PAX3 or PAX7 fused to the C-terminal transactivation domain of FOXO1 (9, 10). Many of these post-translational modification sites (phosphorylation, acetylation, methylation) in the fusion protein have been identified through high throughput mass spectrometry experiments or in vitro enzymatic screens performed in wildtype FOXO1 TF (99). 14 Articles, This article is part of the Research Topic, Future DirectionsPersonalized Therapy and Overcoming Drug Resistance, https://cancerres.aacrjournals.org/content/62/16/4704.long, https://www.abstractsonline.com/pp8/#!/6812/presentation/9413, Creative Commons Attribution License (CC BY). doi: 10.1200/JCO.2010.34.0000, 180. | By Compassion & Choices | Facebook Log In Forgot Account? (2001) 91:61321. (2005) 54:52634. (2016) 235:31927. In North America, the COG does not currently regard maintenance therapy as the standard of care for metastatic RMS; however, COG study protocols include much longer absolute durations of therapy. Current targeted therapies and immunotherapies targets under evaluation in preclinical and/or clinical development in North America and Europe for rhabdomyosarcoma. European studies use overall survival as the study end-point, preferring less aggressive local treatment (omission of RT if possible) to mitigate late toxicities, while tolerating a greater risk of relapsed disease. Nat Commun. (2015) 160:124660. (2010) 28:465863. Ipilimumab is a first-in-class anti-CTLA-4 immune checkpoint inhibitor approved for treatment of metastatic melanoma and was recently evaluated in a phase I clinical trial for the treatment of pediatric advanced solid tumors. doi: 10.1002/gcc.21953, 14. doi: 10.1200/JCO.2001.19.12.3091, 26. Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. European Intergroup Studies (MMT489 and MMT491) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors. Identification of serines 201 and 209 as sites of Pax3 phosphorylation and the altered phosphorylation status of Pax3-FOXO1 during early myogenic differentiation. J Clin Oncol. Children's oncology Group's 2013 blueprint for research: soft tissue sarcomas. (2018) 10:eaan4470. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. Wexler LH. Yet, emerging strategies to directly drug transcription factors are currently being explored in other human cancers. Davicioni E, Anderson JR, Buckley JD, Meyer WH, Triche TJ. Nat Genet. After three decades of controversy regarding the inclusion of doxorubicin in the chemotherapy regimen (43, 4648), an open-label phase 3 trial (EpSSG RMS 2005) conclusively showed that addition of doxorubicin to the standard IVA backbone did not improve patient outcomes in high-risk rhabdomyosarcoma (49). Refine Your Search Results All Filters Danna B Nelson, 73 Resides in West Jordan, UT Lived In Salt Lake City UT, Draper UT Related To Brent Nelson, Jason Nelson, Bruce Nelson, Katherine Nelson doi: 10.1200/JCO.2015.64.3395, 177. Even though ipilimumab is safely tolerated in these patients, its efficacy as a monotherapy is limited. Small molecule inhibitors against oncogenic fusion proteins have achieved remarkable clinical success in some human cancers, such as the targeting of BCR-ABL in leukemia and EML4-ALK1 in lung carcinoma (80, 81). Initial efforts to bring immunotherapies designed for adults into rhabdomyosarcoma pediatric trials has been met with limited success. At MSK Kids, we use precision genetic testing to assess rhabdomyosarcomas. Sci Transl Med. Based on support from preclinical testing, a Phase I study was opened to evaluate enoblituzumab, an Fc-enhanced, humanized IgG1 monoclonal antibody specific for B7-H3 and engineered with an Fc domain with increased affinity for the activating receptor CD16A, thereby enhancing antibody dependent cellular cytotoxicity (ADCC) (157). The results in 13 patients treated by radiation therapy alone and in combination with surgery and chemotherapy indicate that this tumor is moderately radiosensitive and can be locally controlled for significant periods of time with radiation therapy. Danna Collette Nelson on Instagram: "To the dearest and most loving Cancer Chemother Pharmacol. Administration of HER2-CAR T cells after lymphodepletion safely improves T cell expansion and induces clinical responses in patients with advanced sarcomas [abstract no. J Clin Oncol. doi: 10.1016/bs.acr.2018.02.006, 98. Aberrant Hh signaling can be attributed to various germline mutations loss of chromosomal region 9q22 containing PTCH in 33% of ERMS tumors (119, 120), loss of SUFU in 18% ERMS tumors (121), and/or genomic amplification of 12q13-15 containing the GLI1 gene in a small subset of ARMS tumors (116). Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Mathematical modeling can be used to predict the optimal dosing schedules which can sustain drug sensitivity, as demonstrated by a study which used an algorithm to design a tyrosine kinase inhibitor (TKI) dosing schedule for treatment of non-small cell lung cancers (178). Ribas A, Wolchok JD. Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. We present a single institution analysis of CNS involvement of pediatric rhabdomyosarcoma. Upon activation of the mitochondrial apoptotic pathway, Smac is released into the cytosol, where it binds and neutralizes XIAPs, thereby allowing the caspase cascade to proceed. There is a known link between RMS and cancer predisposition syndromes, such as Li-Frameni syndrome, neurofibromatosis, Beckwith-Wiedemann syndrome, and Costello syndrome (19). Both ERMS and ARMS were sensitive to combination treatment, suggesting the broad therapeutic potential of PARP inhibition in RMS (138). Am Soc Clin Oncol Educ Book. Cancer Discov. The different types and grades of rhabdomyosarcoma require different treatment approaches. 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: 10.1074/jbc.M110.104745, 136. 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. (2006) 24:384451. These are muscles that we control to move parts of our body. doi: 10.1053/j.sempedsurg.2016.09.011, 2. The HD CWS-96 trial was a non-randomized trial comparing the efficacy of high dose therapy (HDT) vs. oral maintenance therapy (OMT) in patients with stage IV soft tissue sarcoma (69). J Clin Oncol. (2016) 63:6349. doi: 10.1002/pbc.21494, 70. J Clin Oncol. Decades of clinical and basic research have gradually improved our understanding of the pathophysiology of RMS and helped to optimize clinical care. Mascarenhas L, Lyden ER, Breitfeld PP, Walterhouse DO, Donaldson SS, Paidas CN, et al. J Clin Oncol. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. These are: embryonal rhabdomyosarcoma. The authors show that BRD4 small molecule inhibitor, JQ1 selectively disrupts the interaction between BRD4 and PAX3-FOXO1, leading to rapid degradation of the fusion gene and abrogation of transcriptional output (89). This is more feasible than other inhibitory approaches, since the ligand only needs to bind to a tractable surface, rather than a specific functional site which is much harder to target. However, safety concerns over off-target effects by the RNAi transcripts and the toxicity of delivery systems remain significant obstacles to translation of this approach into the clinic. (2003) 348:694701. J Clin Oncol. (2004) 22:478794. Koscielniak E, Harms D, Henze G, Jrgens H, Gadner H, Herbst M, et al. Because this is a cancer of embryonal cells, it is much more common in children, although it can occur in adults. Other potential cell surface immune targets (FGFR4, SLC19A1, ACVR2A, EPHB4) were identified by Khan et al., in a study which used gene expression datasets to rank potential immune targets by their differential expression between 12 pediatric cancer tissues and normal tissue (165). doi: 10.1056/NEJMoa1302369, 173. At microscopy . P/CAF mediates PAX3FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma. Several factors can affect survival. doi: 10.1200/JCO.1998.16.11.3641, 66. (2015) 21:5030. doi: 10.1158/1078-0432.CCR-15-0365, 148. (2012) 51:66274. doi: 10.1016/j.radonc.2014.08.033, 54. CDK4 and its binding partner Cyclin D are required for progression through the G1/S checkpoint, and its overexpression allows cancer cells to adapt to the high proliferation rates needed to sustain tumorigenesis. Postow MA, Callahan MK, Wolchok JD. doi: 10.1038/s41568-019-0169-x, 184. Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). The Hedgehog (Hh) pathway is a highly conserved developmental pathway, which plays crucial roles in embryonic development, stem cell biology, and tissue homeostasis (113).
