Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: The Children's Oncology Group. A second approach is to anticipate which pre-existing subclonal populations will be drug-resistant, identify molecular vulnerabilities for these drug-resistant subclones, and design combination therapies focused on eradicating the maximal percentage of the heterogeneous tumor mass during first-line therapy. 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). In order to sustain chronic proliferation, cancer cells must meet the demanding needs imposed by energy metabolism and cellular division. Preuss E, Hugle M, Reimann R, Schlecht M, Fulda S. Pan-mammalian target of rapamycin (mTOR) inhibitor AZD8055 primes rhabdomyosarcoma cells for ABT-737-induced apoptosis by down-regulating Mcl-1 protein. One group reported that the oncogenic signaling circuit between the Notch and YAP pathways drives stemness and tumorigenesis in ERMS, suggesting a rationale for co-targeting Notch and YAP (131). Pediatr Blood Cancer. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. doi: 10.1016/S1470-2045(18)30337-1, 50. Int J Radiat Oncol Biol Phys. Cell-Cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. Future studies should focus on elucidating potential resistance mechanisms to IGF-1R inhibition and identifying predictive biomarkers for IGF-1R inhibition sensitivity. Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: a rational choice. (2019) 25:2560. doi: 10.1158/1078-0432.CCR-18-0432, 165. Genes Chromosomes Cancer. Dobson CC, Naing T, Beug ST, Faye MD, Chabot J, St-Jean M, et al. doi: 10.1053/j.sempedsurg.2016.09.011, 2. There are considerations as to whether the concept of maintenance therapy or absolute duration of therapy is the more relevant metric for treatment. (2015) 527:32935. Several phosphorylation sites are known to influence protein stability of the fusion product. 9:1458. doi: 10.3389/fonc.2019.01458. Unlike for localized disease, for metastatic RMS multimodal therapy frequently fails due to lack of a proper local therapy to treat metastatic sites such as the bone marrow and lungs. Robinson GW, Kaste SC, Chemaitilly W, Bowers DC, Laughton S, Smith A, et al. In this review, we summarize the current frontline multi-modality therapy for RMS according to pediatric protocols, highlight emerging targeted therapies and immunotherapies identified by preclinical studies, and discuss early clinical trial data and the implications they hold for future clinical development. 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). (1998) 16:36413648. Neoplasia. A comprehensive genomic analysis of 147 RMS tumor samples by Shern et al. (2017) 15:81. doi: 10.1038/nrclinonc.2017.166, 178. (2016) 34:1056. Bushweller JH Targeting transcription factors in cancer from undruggable to reality. The oncogenic capacity of the PAX-FOXO1 fusion proteins has been well characterized by multiple studies and has been shown to act as a dominant-acting oncogene in driving tumorigenesis in fusion-positive RMS (FP RMS) (4, 17). Yamanaka H, Oue T, Uehara S, Fukuzawa M. Hedgehog signal inhibitor forskolin suppresses cell proliferation and tumor growth of human rhabdomyosarcoma xenograft. BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. (1988) 61:20920. Am J Clin Pathol. Episode 13 with Danna Nelson - Death With Dignity Podcast While high dose therapy failed to improve survival, oral maintenance therapy was a promising alternative, since the oral administration can provide long lasting exposure to chemotherapy without increasing toxic side effects. AGE 30s Danna M Nelson Tukwila, WA (Cascade View) View Full Report USED TO LIVE IN Tukwila, WA Maple Valley, WA RELATED TO Ken L Nelson Donna Marie Nelson Kathleen Ellen Nelson Phone | Address | Email AGE 50s Danna L Nelson Elmont, NY (Hempstead) View Full Report MAY GO BY Danna L Sanders Danna L Smith USED TO LIVE IN Tumour heterogeneity and resistance to cancer therapies. Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). Terezakis SA, Wharam MD. (2015) 11:6117. doi: 10.1080/2162402X.2018.1481558, 155. Metastatic rhabdomyosarcoma: still room for improvement. Blood. Rhabdomyosarcoma in children differs from the form of the disease typically seen in adults. The two major subtypes of RMS, originally . N Engl J Med. J Clin Oncol. PLOS Genetics. Because this is a cancer of embryonal cells, it is much more common in children, although it can occur in adults. Upregulation of PAX3-FOXO1 transcripts and its stabilization by PLK1 phosphorylation permit the cell to progress past the G2/M checkpoint (101). Most common variant in the gynecologic tract is embryonal, which typically presents as a polypoid vaginal or cervical mass in children and adolescents. Immune checkpoint blockade in cancer therapy. Cancer Chemother Pharmacol. The majority of ARMS tumors harbor a recurrent chromosomal translocation, t(2;13)(q35;q14) or t(1;13)(p36;q14). Danna Nelson (83 matches): Phone Number, Email, Address - Spokeo (2019) 66:e27935. This treatment combination was based on preclinical evidence which reported that IGF-1R inhibition promotes a bypass resistance pathway through other kinases, such as the SRC family kinase YES (107) and ALK (108), suggesting that targeting multiple RTKs in combination is likely necessary to overcome resistance. doi: 10.1002/cncr.24465, PubMed Abstract | CrossRef Full Text | Google Scholar, 3. Lancet Oncol. Patients with the PAX7-FOXO1 rearrangement have superior overall survival (82%) compared to patients with the PAX3-FOXO1 rearrangement (61%) (12). Moreover, children do not yet have a fully developed immune system, which is required for optimal response to immunotherapy. Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round-cell tumors: a feasibility study at St. Jude Children's Research Hospital. It was a pleasure listening and conversing with Danna, as she is the first individual we've interviewed for the DwD Podcast who is in a similar . J Clin Oncol. Cancer Cell. Loupe JM, Miller PJ, Ruffin DR, Stark MW, Hollenbach AD. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. Nat Rev Cancer. doi: 10.1038/onc.2010.368, 119. Of all ARMS patients, approximately 60% express PAX3-FOXO1, 20% express PAX7-FOXO1, 20% are fusion negative (11, 12), and a small subset express rare variants such as PAX3-FOXO4 or PAX3-NOXA1 (12). For now, most clinical trials opened for RMS exploit known drugs targeting common pathways which are dysregulated in other human cancers (Figure 2). 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). (2005) 23:261828. (2002) 62:470410. Disappointingly, phase II trials for children with relapsed RMS have not demonstrated meaningful, single-agent activity of targeted inhibitors, such as a monoclonal antibody against IGF-1R (R1507) and a multi-kinase inhibitor, sorafenib (78, 79). (2018) 34:41126.e19. Biochem Biophys Res Commun. doi: 10.1002/pbc.24532, 39. N Engl J Med. A recent publication used a zebrafish transgenic model of ERMS to identify intracellular NOTCH1 (ICN1) as an important regulator of balancing self-renewal and differentiation in ERMS (129). Lancet Oncol. (2010) 28:12406. Until recently, TFs were considered to be an undruggable class of proteins due to an absence of deep hydrophobic pockets, large protein-protein interaction interfaces, and nuclear localization (82). Hoshino, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. As reviewed by DeRenzo et al., treatment of solid pediatric tumors presents a unique set of challenges that must be carefully taken into consideration. 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). Molecular pathogenesis of rhabdomyosarcoma. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Another upstream enzyme, acetyltransferase KAT2B (P/CAF) is known to modulate fusion protein stability by acetylating residues K426 and K429 (102). Gallego S, Zanetti I, Orbach D, Ranchere D, Shipley J, Zin A, et al. FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells. (2004) 22:478794. Pediatr Blood Cancer. Clin Transl Radiat Oncol. We were excited to sit down and interview Danna Nelson, a young woman living in Minnesota with a rare cancer called rhabdomyosarcoma; an aggressive cancer which forms in the soft tissues. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Saltzman AF, Cost NG. Because cancer cells are more reliant on the G2/M checkpoint for DNA repair than normal cells due to G1/S DNA repair deficiencies, Wee1 inhibition can halt progression through the G2/M checkpoint and selectively induce apoptosis in cancer cells. Hedrick E, Crose L, Linardic CM, Safe S. Histone deacetylase inhibitors inhibit rhabdomyosarcoma by reactive oxygen speciesdependent targeting of specificity protein transcription factors. Whereas, previous studies focused on fusion status as an important prognostic marker in low- and intermediate-risk RMS (38, 41, 42), a review of high-risk RMS cases found that fusion status does not offer the same level of predictive value for metastatic patients.