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

Weigel, Brenda; Lyden, Elizabeth; Anderson, James R.; Meyer, William H.; Parham, David M.; Rodeberg, David A.; Michalski, Jeff M.; Hawkins, Douglas S.; Arndt, Carola A.S.

doi:10.1200/jco.2015.63.4048

Cited by 167 publications

(217 citation statements)

References 20 publications

Supporting

Mentioning

210

Contrasting

Order By: Relevance

“…Breast malignancies commonly diagnosed in children and adolescents have been reported to be metastases originating from neuroblastoma, RMS, or hematologic malignancies [23]. RMS presents mostly at around 5 years of age and in adolescence [5]. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Primary Rhabdomyosarcoma of the Breast: Imaging Findings and Literature Review

et al. 2018

View full text Add to dashboard Cite

Background: Primary breast rhabdomyosarcoma (RMS) can occur in children. There is a lack of knowledge regarding radiologic findings and added diffusion-weighted magnetic resonance imaging (MRI) features of RMS in the literature. Case Report: A 12-year-old girl was diagnosed with primary alveolar RMS of the breast. Gray scale ultrasound revealed posterior acoustic enhancement behind a well-circumscribed, multilobulated hypoechoic mass. Doppler ultrasound revealed increased peripheral and central vascularity. Hypointense septations on T2-weighted image exhibiting more enhancement than the stroma on late gadolinium-enhanced images were striking within a hyperintense mass. A hyperintense hemorrhagic focus on T1-weighted image was present in the absence of any necrosis. Avid enhancement on early postcontrast images proceeding from the periphery to the center was depicted. Conclusion: A rapidly enlarging mass with an echogenic peripheral rim together with posterior acoustic enhancement on gray scale ultrasound, intense vascularity on Doppler ultrasound, axillary lymphadenopathy, and satellite nodules on MRI should raise suspicion. Enhancing central and peripheral septations are suggestive of RMS. Dynamic contrast-enhanced MRI in suspected cases can provide valuable data in the differential diagnosis.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The most common primary sites of RMS are the head and neck region (40%) [3], the genitourinary system (22%), the extremities (18%), the trunk, chest wall, perineum, and retroperitoneum [4,5], and the biliary tract [6]. Breast involvement is very rare, both as a primary or as a metastatic site [7].…”

Section: Introductionmentioning

confidence: 99%

Primary Rhabdomyosarcoma of the Breast: Imaging Findings and Literature Review

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Although overall survival for children with RMS approaches 70%, the presence of the paired box 3-forkhead box O1 (PAX3-FOXO1) fusion strongly associates with adverse outcome predictors such as an extremity primary site and metastatic disease at diagnosis (16). Despite 30 y of clinical trials, PAX3-FOXO1 fusion-positive RMS patients with metastatic disease are considered incurable with current therapies (17). Difficulties in directly inhibiting the PAX3-FOXO1 transcription factor chimera and a largely unaltered genomic landscape in RMS have, to date, precluded precision medicine in this disease (18,19).…”

Section: Significancementioning

confidence: 99%

Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma

Sabnis

Guerriero

Olivas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cytosolic and organelle-based heat-shock protein (HSP) chaperones ensure proper folding and function of nascent and injured polypeptides to support cell growth. Under conditions of cellular stress, including oncogenic transformation, proteostasis components maintain homeostasis and prevent apoptosis. Although this cancerrelevant function has provided a rationale for therapeutically targeting proteostasis regulators (e.g., HSP90), cancer-subtype dependencies upon particular proteostasis components are relatively undefined. Here, we show that human rhabdomyosarcoma (RMS) cells, but not several other cancer cell types, depend upon heatshock protein 70 kDA (HSP70) for survival. HSP70-targeted therapy (but not chemotherapeutic agents) promoted apoptosis in RMS cells by triggering an unfolded protein response (UPR) that induced PRKR-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor α (eIF2α)-CEBP homologous protein (CHOP) signaling and CHOP-mediated cell death. Intriguingly, inhibition of only cytosolic HSP70 induced the UPR, suggesting that the essential activity of HSP70 in RMS cells lies at the endoplasmic reticulumcytosol interface. We also found that increased CHOP mRNA in clinical specimens was a biomarker for poor outcomes in chemotherapy-treated RMS patients. The data suggest that, like human epidermal growth factor receptor 2 (HER2) amplification in breast cancer, increased CHOP in RMS is a biomarker of decreased response to chemotherapy but enhanced response to targeted therapy. Our findings identify the cytosolic HSP70-UPR axis as an unexpected regulator of RMS pathogenesis, revealing HSP70-targeted therapy as a promising strategy to engage CHOP-mediated apoptosis and improve RMS treatment. Our study highlights the utility of dissecting cancer subtype-specific dependencies on proteostasis networks to uncover unanticipated cancer vulnerabilities.T he synthesis and folding of proteins is a highly regulated process in both normal and malignant cells (1). The protein homeostasis ("proteostasis") network that operates in cancer cells offers targets for therapeutic development, such as the proteasome and specific protein chaperones (2, 3). For example, the heat-shock protein 90 kDa (HSP90) chaperone maintains the stability of some mutant oncoproteins and permits the outgrowth of drug-resistant cells, fueling the development of small molecule HSP90 inhibitors as anticancer agents (4). Despite promising early results, these HSP90 inhibitors do not show large-scale clinical success across the majority of cancers tested (4). Proteasome inhibitor treatment has made a substantial impact on cancer patient outcomes but to date has been highly effective in only a small number of malignancies (5). Although the proteostasis network provides an increasingly rich landscape beyond these two targets, the dependence of particular cancer subtypes on specific proteostasis components is not well defined. Filling this knowledge gap is essential to elaborate the role of proteostasis in the pathogenesis...

show abstract

“…The most recent Children's Oncology Group (COG) trial for low-risk RMS showed that patients have an excellent outcome [2-year event-free survival (EFS), 88%; overall survival (OS), 98%] with short therapy duration (9). Whereas the most recent COG high-risk RMS study showed poor outcome in 3-year EFS 38% (10).…”

Section: Introductionmentioning

confidence: 99%

Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

Ueno

Uehara

Nakahata

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.

show abstract

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

Cited by 167 publications

References 20 publications

Primary Rhabdomyosarcoma of the Breast: Imaging Findings and Literature Review

Primary Rhabdomyosarcoma of the Breast: Imaging Findings and Literature Review

Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma

Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

Contact Info

Product

Resources

About