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

Sokolowski, Elizabeth; Turina, Claire B; Kikuchi, Ken; Langenau, David M.; Keller, Charles

doi:10.1038/onc.2013.129

Cited by 33 publications

(36 citation statements)

References 200 publications

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“…The human MB1208-1 human skeletal myoblast cell line was kindly provided by Dr. Louis Kunkel (Boston Children’s Hospital, Massachusetts). Characteristics of these human RMS (Hinson et al, 2013; Sokolowski et al, 2014) and skeletal myoblast (Alexander et al, 2011) cell lines have been reported previously.…”

Section: Methodsmentioning

confidence: 83%

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Tenente

Hayes

Ignatius

et al. 2017

eLife

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Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.DOI: http://dx.doi.org/10.7554/eLife.19214.001

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Section: Methodsmentioning

confidence: 83%

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Tenente

Hayes

Ignatius

et al. 2017

eLife

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“…A battery of human RMS cell lines are available for probing — a collection that has been expertly reviewed 20,26 . Here, we focus instead on genetically modified RMS model cells.…”

Section: Genetically Modified Rms Cellsmentioning

confidence: 99%

“…Despite these advances, therapies targeting molecular RMS oncogenic drivers are lacking. (For excellent reviews in these areas, we refer readers to Sokolowski et al 20 , Hettmer et al 21 ; and Keller and Guttridge 22 .) Consequently, investigators have made substantial efforts over the past decade to generate new genetic tools with which to dissect RMS (fig.…”

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confidence: 99%

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

2015

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Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.

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“…Families affected by this cancer, patient advocates, clinicians, and scientists need to coalesce their efforts to garner sufficient support from funding sources and the pharmaceutical industry to support the development of curative therapies. Existing preliminary data, strategic considerations by relevant pediatric collaborative groups, and a deep clinical need may provide a fertile ground for partnerships between academic groups and industry (Sokolowski et al 2014). …”

Section: Strategic Considerationsmentioning

confidence: 99%

“…Insufficient access to fresh RMS tissue has hindered progress in RMS research. Moreover, there are few existing human RMS cell lines, and these lines are not widely distributed (Sokolowski et al 2014). Tumor biology initiatives are needed to collect sufficient amounts of fresh tumor material from patients with RMS (both children and adults) to support tumor profiling efforts and the generation, long-term storage, and distribution of new cell lines and xenografts for experimentation.…”

Section: Strategic Considerationsmentioning

confidence: 99%

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

Hettmer¹,

Li²,

Billin³

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNAbinding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 ( previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in ,30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusionpositive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.

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

Cited by 33 publications

References 200 publications

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

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