The pediatric preclinical testing program: Description of models and early testing results

Houghton, Peter J.; Morton, Christopher L.; Tucker, Chandra L.; Payne, Debbie; Favours, Edward; Cole, Claire; Görlick, Richard; Kolb, E. Anders; Zhang, Wendong; Lock, Richard B.; Carol, Hernán; Tajbakhsh, Mimi; Reynolds, C. Patrick; Maris, John M.; Courtright, Joshua; Keir, Stephen T.; Friedman, Henry S.; Stopford, Charles M.; Zeidner, Joseph; Wu, Jianrong; Liu, Tiebin; Billups, Catherine A.; Khan, Javed; Ansher, Sherry S.; Zhang, Jian; Smith, Malcolm A.

doi:10.1002/pbc.21078

Cited by 435 publications

(557 citation statements)

References 29 publications

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“…No differences in p4EBP1 expression levels were found in OS-33 tumors, but a slight decrease was observed in cisplatintreated OS-1 tumors (p 5 0.04). 4 In vivo responses were defined as described by Houghton et al 51 In short, the mean relative tumor volume (RTV) of the treatment group (T) was divided by the mean RTV of the control group (C): T/C. Criteria: T/C 15% high response; T/C 45% but >15% intermediate response; T/C > 45% low response.…”

Section: Treatment Effects On the Mtor-pathwaymentioning

confidence: 99%

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

et al. 2014

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Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. Osteosarcoma is the most commonly diagnosed primary malignant tumor of the bone mainly affecting children and adolescents. 1 Current standard treatment regimens consist of surgery and polychemotherapy. Unfortunately, despite multimodal treatment the final outcome has not improved significantly during the last decade and severe side effects of intensive chemotherapy treatment schedules are observed frequently. On top of that, research on targeted treatments in osteosarcomas lags behind. This underscores the absolute need for novel, targeted therapies to treat these often young patients.Blocking of mammalian target of rapamycin (mTOR) signaling emerged as a promising approach to target osteosarcomas. mTOR, also known as sirolimus effector protein, is an intracellular serine/threonine kinase involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade and signals downstream of several receptor tyrosine kinases (RTKs), including but not limited to the insulin-like growth factor 1

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Section: Treatment Effects On the Mtor-pathwaymentioning

confidence: 99%

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

et al. 2014

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“…With a consortium of laboratories in the United States and abroad, the program is able to quickly screen a large number of agents using in vitro and in vivo models. (65,(69)(70)(71) The in vitro models are cell lines, with the in vivo models typically human patient-derived tumors grown as heterotopic xenografts in severe combined immunodeficiency mice. Although osteosarcoma can be grown in orthotopic as well as heterotopic sites, the heterotopic site permits frequent tumor size measurements using a caliper, which is feasible and cost-effective.…”

Section: Preclinical Screeningmentioning

confidence: 99%

“…This program has generated a large amount of data, including characterizations of the model systems, that has rapidly been published or made available through Web-based applications (http://home.ccr.cancer.gov/oncology/oncogenomics/). (65,(69)(70)(71) Canine Models…”

Section: Preclinical Screeningmentioning

confidence: 99%

Osteosarcoma

Görlick

Khanna

2010

Journal of Bone and Mineral Research

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It has been difficult to identify the molecular features central to the pathogenesis of osteosarcoma owing to a lack of understanding of the cell or origin, the absence of identifiable precursor lesions, and its marked genetic complexity at the time of presentation. Interestingly, several human genetic disorders and familial cancer syndromes, such as Li-Fraumeni syndrome, are linked to an increased risk of osteosarcoma. Association of these same genetic alterations and osteosarcoma risk have been confirmed in murine models. Osteosarcoma is associated with a variety of genetic abnormalities that are among the most commonly observed in human cancer; it remains unclear, however, what events initiate and are necessary to form osteosarcoma. The availability of new resources for studying osteosarcoma and newer research methodologies offer an opportunity and promise to answer these currently unanswered questions. Even in the absence of a more fundamental understanding of osteosarcoma, association studies and preclinical drug testing may yield clinically relevant information. ß

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“…A complete response (CR) was defined as the disappearance of measurable tumor mass or if measured tumor volume was less than 100 mm 3 after initiating therapy. 42 Data are expressed as the mean § SEM. One-way analysis of variance with Dunnett's test (GraphPad PRISM 4) was used for analysis.…”

Section: Drug Treatmentsmentioning

confidence: 99%

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun

Liu

Ahluwalia

et al. 2015

Cancer Biology & Therapy

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The pediatric preclinical testing program: Description of models and early testing results

Cited by 435 publications

References 29 publications

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

Osteosarcoma

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

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