Integrative Biology of Rhabdomysarcoma Using Genetic Murine Models

Davis, Lady; Keller, Cheryl A.

doi:10.1158/aacr.edb-12-8540

Cited by 5 publications

(5 citation statements)

References 9 publications

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“…16 Furthermore, the average number of trials per indication can be as low as 1.5 (in one review, 63% of rare cancer indications were based on a single pivotal trial). 17 Parenthetically, smaller clinical trial sizes may make preclinical animal models even more important for prioritization of compounds to move forward to the clinic, particularly physiologically accurate, immunocompetent murine transgenic models 18 or zebrafish models. 11 On the other hand, the potential downside of smaller clinical trial cohort size is that postmarketing trials or safety findings may not confirm the disease advantage of the orphan drug.…”

Section: The Brief Case For Rare Disease Drug Developmentmentioning

confidence: 99%

“…The value of transgenic models of pediatric cancer has been reviewed more extensively elsewhere. 18 For a detailed description of eRMS models, see Kikuchi et al 127 Nevertheless, many of these models (including genetically engineered conditional models) are readily available from the NCI Mouse Models of Human Cancer Consortium (http:// mouse.ncifcrf.gov/) or other repositories such as The Jackson Laboratory. In some cases, these genetically engineered models have been characterized for immunocompetence on a hairless background strain, thereby facilitating preclinical drug studies using optical imaging in the pharma setting.…”

Section: The Case For Rms In Terms Of Drug-development Resourcesmentioning

confidence: 99%

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Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma

et al. 2013

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Rare diseases typically affect fewer than 200,000 patients annually, yet because thousands of rare diseases exist, the cumulative impact is millions of patients worldwide. Every form of childhood cancer qualifies as a rare disease-including the childhood muscle cancer, rhabdomyosarcoma (RMS). The next few years promise to be an exceptionally good era of opportunity for public-private collaboration for rare and childhood cancers. Not only do certain governmental regulation advantages exist, but these advantages are being made permanent with special incentives for pediatric orphan drug-product development. Coupled with a growing understanding of sarcoma tumor biology, synergy with pharmaceutical muscle disease drug-development programs, and emerging publically available preclinical and clinical tools, the outlook for academic-community-industry partnerships in RMS drug development looks promising.

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Section: The Brief Case For Rare Disease Drug Developmentmentioning

confidence: 99%

Section: The Case For Rms In Terms Of Drug-development Resourcesmentioning

confidence: 99%

Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma

et al. 2013

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“…Soft tissue sarcomas are among the most common and deadliest childhood cancers (1,2). Despite improved survival for other childhood cancers, progress for particularly metastatic sarcoma has been minimal, and therapeutic options remain limited (2,3).…”

Section: Introductionmentioning

confidence: 99%

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

et al. 2018

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemo- and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which in turn de-repressed the microRNA miR-27a. This re-expression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase I clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase I-b cohort expansion or phase II clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

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“…The 5-yr event-free survival (EFS) for fusion-negative ARMS is 29% ( Rudzinski et al 2017 ). Despite advancements in uncovering the clinical and mutational profiles of the myriad RMS subtypes, such as recurrent TP53 tumor suppressor gene loss of function in PAX fusion-negative (PFN) RMS, survival rates have not seen similar significant improvement ( Breneman et al 2003 ; Williams et al 2004 ; Davis and Keller 2012 ; Malempati and Hawkins 2012 ; Rudzinski et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Refractory alveolar rhabdomyosarcoma in an 11-year-old male

Ricker

Woods

Simonson³

et al. 2021

Cold Spring Harb Mol Case Stud

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Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar rhabdomyosarcoma is the most aggressive subtype with an 8% 5-yr disease-free survival rate when a chromosomal fusion is present and a 29% 5-yr disease-free survival rate when negative for a fusion event. The underlying biology of PAX -fusion-negative alveolar rhabdomyosarcoma remains largely unexplored and is exceedingly rare in Li–Fraumeni syndrome patients. Here, we present the case of an 11-yr-old male with fusion-negative alveolar rhabdomyosarcoma studied at end of life with a comprehensive functional genomics characterization, resulting in identification of potential therapeutic targets for broader investigation.

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Integrative Biology of Rhabdomysarcoma Using Genetic Murine Models

Cited by 5 publications

References 9 publications

Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma

Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Refractory alveolar rhabdomyosarcoma in an 11-year-old male

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