Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

Stone, Helen B.; Bernhard, Eric J.; Coleman, C. Norman; Deye, James A.; Capala, Jacek; Mitchell, James B.; Brown, J. Martin

doi:10.1016/j.tranon.2016.01.002

Cited by 51 publications

(41 citation statements)

References 72 publications

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“…While regrowth delay assays may not necessarily correspond to local tumor control, they are useful for evaluating drug-radiation interaction, mechanisms of action and microenvironmental effects. The initial models may be xenografts as are now employed or newer models from patient-derived tumors with the models selected based on their utility for predicting clinical results (16). …”

Section: Toward Improved Pre-clinical Models Of Radiation Modifiersmentioning

confidence: 99%

“…This result may be due in part to the quality and validity of the pre-clinical data. Stone et al (16) after examining the details of 125 reported in vitro and in vivo preclinical studies on radiation-modifiers concluded that future preclinical studies must include: a) use of appropriate preclinical models that best represent the clinical setting of extant “standard-of-care” multi-modality cancer therapy, b) fastidious calibration and dosimetry of radiation sources (17), c) detailed and accurate descriptions of experimental methodology and results, and d) clinically relevant drugs, doses, schedules, and assay conditions. Of critical importance is the recognition that the mechanism of action of a molecular-targeted drug may be different when used by itself to target a specific tumor pathway compared to how it affects combination therapy that includes radiation.…”

Section: Introductionmentioning

confidence: 99%

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Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Coleman

Higgins

Brown

et al. 2016

Clinical Cancer Research

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There is an urgent need to improve reproducibility and translatability of preclinical data in order to fully exploit opportunities for molecular therapeutics involving radiation and radio-chemotherapy. For in vitro the clonogenic assay remains the current state-of-the-art of preclinical assays, while newer moderate- and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action and address immune modulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies, for example, regrowth delay measures bulk tumor killing while local tumor control assesses effects on CSC. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radio-chemotherapy for most tumors. Radiation models are compatible with, but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapy enhancer may be different than its interaction with radiation and/or radio-chemotherapy. This provides an opportunity to expand the use of molecular-targeted agents.

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Section: Toward Improved Pre-clinical Models Of Radiation Modifiersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Coleman

Higgins

Brown

et al. 2016

Clinical Cancer Research

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“…This also raises critical questions for translational brain tumor research in general: What is the optimal tumor burden at the start of preclinical survival or tumor growth-delay studies, and what is the best modality for determining enrollment threshold (BLI, MRI, histopathology, etc.) (discussed below) [75,80,81]? Additionally, evidence of the importance of the tumor microenvironment in governing the response to radiation continues to emerge [82]), highlighting an obvious shortcoming of PDOX models.…”

Section: Outstanding Questions and Future Directionsmentioning

confidence: 99%

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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“…If they perform calibration, most facilities use a variation of the approach described in TG-61, a document describing methods to calculate an absorbed dose to water for 40-300 kVp x-rays [47][48][49]. Far too many publications fail to provide sufficient detail to enable replication of radiation delivery and even fewer provide details regarding the frequency and type of calibration performed [50]. At our institution, monthly quality assurance is performed by a member of the UW Calibration Lab using a custom-built compact 4x4cm phantom and Gafchromic EBT3 film which has known spatial precision and relatively flat energy response [51].…”

Section: Radiation Deliverymentioning

confidence: 99%

“…The ease of studying drug or radiation sensitivity in vitro has allowed for the discovery of chemotherapeutics and molecularly targeted agents that sensitize cells to RT [54,55]. These studies are then translated into murine models with varying rates of success and unfortunately, these studies are rarely translated to clinic with a disappointing number of clinical advances [50,[55][56][57]. Hypotheses explaining this divide include: 1) disparity in tumor microenvironment (TME) between animal models and human tumors; 2) PK/PD challenges limiting drug availability; 3) failure to confirm target inhibition; 4) unanticipated overlapping toxicities; 5) imprecise and inaccurate RT dose delivery impairing interpretation of data; and 6) testing in a limited number of cell lines; and, 7) failure to test with RT.…”

Section: Challenges In Drug and Radiation Deliverymentioning

confidence: 99%

Patient Derived Models to Study Head and Neck Cancer Radiation Response

Cosper¹,

Abel²,

Lee³

et al. 2020

Preprint

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Patient derived model systems are important tools for studying novel anti-cancer therapies. Patient derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient derived models for radiation research including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues.

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Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

Cited by 51 publications

References 72 publications

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Preclinical Models of Craniospinal Irradiation for Medulloblastoma

Patient Derived Models to Study Head and Neck Cancer Radiation Response

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