Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma

Smith, Sally J.; Bianski, Brandon; Orr, Brent A.; Harknett, Gretchen; Onar‐Thomas, Arzu; Gilbertson, Richard J.; Merchant, Thomas E.; Roussel, Martine F.; Tinkle, Christopher L.

doi:10.1016/j.ijrobp.2018.10.015

Cited by 10 publications

(15 citation statements)

References 17 publications

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“…Over a period of 6 years from September 2012 until March 2018, we established, characterized, and maintained 37 PDOX models representing a range of pediatric brain tumors. Several of these models have already been utilized to identify novel targeted therapies including those that have been translated into clinical trials for children with primary or recurrent/progressive malignant brain tumors [28,40].…”

Section: Introductionmentioning

confidence: 99%

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Smith

Mercer

et al. 2020

Acta Neuropathol

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Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

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Section: Introductionmentioning

confidence: 99%

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Smith

Mercer

et al. 2020

Acta Neuropathol

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“…Subsequent work from our group focused on the preclinical incorporation of CSI in the context of PDOX models of medulloblastoma, with the ultimate goal of evaluating adjuvant therapies [78]. PDOX models of very-high-risk SHH medulloblastoma (MYCN amplified, TP53 mutation) and G3 medulloblastoma (MYC amplified) [18] labeled with firefly luciferase were generated in mice, which were monitored for tumor burden by bioluminescence imaging (BLI).…”

Section: Existing Models Of Craniospinal Irradiationmentioning

confidence: 99%

“…Similarly, the incorporation and timing of surgical resection in the preclinical pipeline has yet to be optimized. Whereas Taylor and colleagues were able to model resection and CSI in vivo to molecularly characterize disease recurrence [74], Smith and collaborators focused on developing a protocol that would enable the incorporation of combination therapies [78].…”

Section: Outstanding Questions and Future Directionsmentioning

confidence: 99%

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Preclinical Models of Craniospinal Irradiation for Medulloblastoma

Stripay

Merchant

Roussel

et al. 2020

Cancers

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Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]) with distinct clinical characteristics and prognoses has refocused efforts to better define the optimal role of CSI within and across disease subgroups. The ability to deliver clinically relevant CSI to preclinical models of medulloblastoma offers the potential to study radiation dose and volume effects on tumor control and toxicity in these subgroups and to identify subgroup-specific combination adjuvant therapies. Recent efforts have employed commercial image-guided small animal irradiation systems as well as custom approaches to deliver accurate and reproducible fractionated CSI in various preclinical models of medulloblastoma. Here, we provide an overview of the current clinical indications for, and technical aspects of, irradiation of pediatric medulloblastoma. We then review the current literature on preclinical modeling of and treatment interventions for medulloblastoma and conclude with a summary of challenges in the field of preclinical modeling of CSI for the treatment of leptomeningeal seeding tumors.Cancers 2020, 12, 133 2 of 16 for, medulloblastoma. The review concludes with a summary of outstanding questions in the field of preclinical modeling of RT for pediatric brain tumors and a consideration of future directions for treating leptomeningeal seeding tumors with these approaches. Clinical Management of Medulloblastoma: The Evolving Role of Radiation Therapy BackgroundLike many embryonal tumors, medulloblastoma shows a predilection for distant metastatic spread and leptomeningeal seeding, with subarachnoid dissemination present in approximately 20% to 35% of cases at diagnosis and in most cases at relapse [7,8]. CSI targeting the entire neuraxis has been a standard-of-care therapy for most patients. As cure became a reality, however, long-term survivors were noted to suffer from significant radiation-associated late effects, including neurocognitive and neuroendocrine deficits, bone and soft tissue hypoplasia, vascular insults, and subsequent malignant neoplasms. Thus, efforts have been directed toward maintaining or improving overall survival rates while minimizing treatment-related toxicity. These efforts have primarily focused on modifications to RT approaches that can be broadly grouped as follows: investigations of the effects of adding concurrent and/or adjuvant chemotherapy regimens [9,10]; investigations of the effects of delaying or omitting RT for very young children [11][12][13][14]; investigations of the effects of reductions in the RT dose and field size [15,16]; and, over the past...

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“…ance in a rodent model. [29][30][31] The availability of novel in vivo diagnostic imaging techniques such as micro-PET/CT and MRI imaging for assessing tumor response will further enhance the predictive value and clinical application of these novel RT platforms. 32,33 Another novel RT technique with the potential to improve the therapeutic ratio by decreasing the incidence of normal tissue toxicity is FLASH RT.…”

Section: Advances In Technology and Novel Rt Applicationsmentioning

confidence: 99%

Radiation therapy and molecular‐targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges

Vatner

James²,

Sathiaseelan

et al. 2020

Pediatric Blood & Cancer

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Despite radiation therapy (RT) being an integral part of the treatment of most pediatric cancers and the recent discovery of novel molecular‐targeted agents (MTAs) in this era of precision medicine with the potential to improve the therapeutic ratio of modern chemoradiotherapy regimens, there are only a few preclinical trials being conducted to discover novel radiosensitizers and radioprotectors. This has resulted in a paucity of translational clinical trials combining RT and novel MTAs. This report describes the opportunities and challenges of investigating RT together with MTAs in preclinical testing for immunotherapy, brain tumors, and sarcomas in pediatric oncology. We discuss the need for improving the collaboration between radiation oncologists, biologists, and physicists to improve the reliability, reproducibility, and translational potential of RT‐based preclinical research. Current translational clinical trials using RT and MTAs for immunotherapy, brain tumors, and sarcomas are described. The technologic advances in experimental RT, availability of novel experimental tumor models, advances in immunology and tumor biology, and the discovery of novel MTAs together hold considerable promise for good quality preclinical and clinical multimodality research to improve the current rates of survival and toxicity in children afflicted with cancer.

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Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma

Cited by 10 publications

References 17 publications

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Preclinical Models of Craniospinal Irradiation for Medulloblastoma

Radiation therapy and molecular‐targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges

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