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PubMed | University of Texas Health Science Center at San Antonio, University of Oregon, Cleveland Clinic, Childrens Cancer Therapy Development Institute and Duke University
Type: | Journal: Scientific reports | Year: 2016

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.


Noujaim J.,Royal Marsden Hospital | Thway K.,Royal Marsden Hospital | Sheri A.,Royal Marsden Hospital | Keller C.,Childrens Cancer Therapy Development Institute | Jones R.L.,Royal Marsden Hospital
International Journal of Surgical Pathology | Year: 2016

Soft tissue tumors (STTs) are rare mesenchymal neoplasms accounting for less than 1% of adult cancers. More than 50 different subtypes of STTs have been identified, with this number expected to grow as our understanding of the complex genetic landscape of these diseases improves. As the classification of soft tissue neoplasms continues to diversify, so does the approach to therapy. Accurate histopathologic diagnosis, utilizing the appropriate ancillary immunohistochemical and molecular diagnostic platforms, underpins the oncologic management of soft tissue sarcomas. As increasing numbers of reproducible genetic abnormalities in soft tissue neoplasms are defined, molecular genetic and molecular cytogenetic investigations have become a standard part of the ancillary diagnostic repertoire. However, other soft tissue neoplasms lack reproducible genetic abnormalities, and for these, traditional histology and immunohistochemistry remain the cornerstones for diagnosis. Here, we give an overview of histology-driven therapy in STTs, highlighting the critical role of accurate surgical pathology in guiding the systemic treatment of patients with these neoplasms, and the importance of close collaboration between the surgical pathologist and the oncologist. We also summarize what is considered standard practice in nonhistology- and histology-driven therapy. © The Author(s) 2015.


Wilhelm K.,Max Planck Institute for Heart and Lung Research | Happel K.,Max Planck Institute for Heart and Lung Research | Eelen G.,Catholic University of Leuven | Eelen G.,Vesalius Research Center | And 23 more authors.
Nature | Year: 2016

Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. We find that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c-MYC), a powerful driver of anabolic metabolism and growth. MYC ablation impairs glycolysis, mitochondrial function and proliferation of ECs while its EC-specific overexpression fuels these processes. Moreover, restoration of MYC signalling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behaviour. Our findings identify FOXO1 as a critical rheostat of vascular expansion and define the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation. © 2016 Macmillan Publishers Limited. All rights reserved.


Geltzeiler M.,Oregon Health And Science University | Li G.,Oregon Health And Science University | Abraham J.,Oregon Health And Science University | Keller C.,Oregon Health And Science University | Keller C.,Childrens Cancer Therapy Development Institute
Frontiers in Oncology | Year: 2015

Rhabdomyosarcomas of the parotid and submandibular glands have the histological appearance of a skeletal muscle tumor yet can be found in tissue with no striated muscular elements. We examine the potential cell-of-origin for rhabdomyosarcoma and whether salivary tumors represent primary malignancy or metastasis. We have previously established genetically engineered mouse models of rhabdomyosarcoma. In these mice, rhabdomyosarcoma is only induced when a Pax3:Foxo1 fusion oncogene is activated with concurrent loss of p53 function (for alveolar rhabdomyosarcoma) or loss of p53 function alone (for embryonal rhabdomyosarcoma) using Cre-lox technology. These mutations are only activated under the control of promoters specific for selected cell lineages, previously thought to be myogenesis-restricted. RT-PCR and immunohistochemistry for lineage-specific promoter gene products reveal these promoters are active in wild-type mouse salivary gland. Given that mouse rhabdomyosarcoma frequently originates in the salivary glands and these myogenic-related promoters are normally expressed in salivary tissue, a high likelihood exists that the salivary gland contains a cell-of-origin of this muscle-related cancer. © 2015 Geltzeiler, Li, Abraham and Keller.


PubMed | Childrens Cancer Therapy Development Institute and Royal Marsden Hospital
Type: Journal Article | Journal: International journal of surgical pathology | Year: 2016

Soft tissue tumors (STTs) are rare mesenchymal neoplasms accounting for less than 1% of adult cancers. More than 50 different subtypes of STTs have been identified, with this number expected to grow as our understanding of the complex genetic landscape of these diseases improves. As the classification of soft tissue neoplasms continues to diversify, so does the approach to therapy. Accurate histopathologic diagnosis, utilizing the appropriate ancillary immunohistochemical and molecular diagnostic platforms, underpins the oncologic management of soft tissue sarcomas. As increasing numbers of reproducible genetic abnormalities in soft tissue neoplasms are defined, molecular genetic and molecular cytogenetic investigations have become a standard part of the ancillary diagnostic repertoire. However, other soft tissue neoplasms lack reproducible genetic abnormalities, and for these, traditional histology and immunohistochemistry remain the cornerstones for diagnosis. Here, we give an overview of histology-driven therapy in STTs, highlighting the critical role of accurate surgical pathology in guiding the systemic treatment of patients with these neoplasms, and the importance of close collaboration between the surgical pathologist and the oncologist. We also summarize what is considered standard practice in nonhistology- and histology-driven therapy.


PubMed | Oregon Health And Science University, Childrens Cancer Therapy Development Institute and Southern Illinois University Carbondale
Type: Journal Article | Journal: Oncogene | Year: 2016

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children that shares many features of developing skeletal muscle. TBX2, a T-box family member, is highly upregulated in tumor cells of both major RMS subtypes where it functions as an oncogene. TBX2 is a repressor that is often overexpressed in cancer cells and functions in bypassing cell growth control, including the repression of the cell cycle regulators p14 and p21. We have found that TBX2 directly represses the tumor-suppressor phosphatase and tensin homolog (PTEN) in both RMS and normal muscle. Exogenous expression of TBX2 in normal muscle cells downregulates PTEN, and depletion or interference with TBX2 in RMS cells upregulates PTEN. Human RMS tumors show high levels of TBX2 and correspondingly low levels of PTEN. The expression of PTEN in clinical RMS samples is relatively uncharacterized, and we establish that suppression of PTEN is a frequent event in both subtypes of RMS. TBX2 represses PTEN by directly binding to the promoter and recruiting the histone deacetylase, HDAC1. RMS cells have high levels of activated AKT owing to the deregulation of phosphoinositide-3 kinase (PI3K) signaling, and depletion or interference with TBX2, which upregulates PTEN, results in a reduction of phospho-AKT. We have also found that the highly related T-box family member TBX3 does not repress PTEN in the muscle lineage. This work suggests that TBX2 is a central component of the PTEN/PI3K/AKT signaling pathway deregulation in RMS cells and that targeting TBX2 in RMS tumors may offer a novel therapeutic approach for RMS.


PubMed | Regeneron Pharmaceuticals Inc., VU University Amsterdam, Harvard University, Childrens Cancer Therapy Development Institute and 2 more.
Type: Journal Article | Journal: Science translational medicine | Year: 2016

Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1


Randolph M.E.,Emory University | Randolph M.E.,Childrens Cancer Therapy Development Institute | Pavlath G.K.,Emory University
Frontiers in Aging Neuroscience | Year: 2015

The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease. © 2015 Randolph and Pavlath.


PubMed | University of Washington and Childrens Cancer Therapy Development Institute
Type: | Journal: Frontiers in oncology | Year: 2017

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from germline mutations of the


PubMed | Childrens Cancer Therapy Development Institute
Type: | Journal: Frontiers in pediatrics | Year: 2016

Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain but also challenging to characterize histologically. A community-driven approach to educating parents and families, regarding the need for donated tissue, is necessary for scientists to have access to resources for murine models and drug discovery. Herein, we describe the currently available resources, existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

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