Assessing therapy response in patient-derived xenografts

Ortmann, Janosch; Rampášek, Ladislav; Tai, Elijah; Mer, Arvind Singh; Shi, Ruoshi; Stewart, Erin; Mascaux, Céline; Fares, Aline Fusco; Pham, Nhu-An; Beri, Gangesh; Eeles, Christopher; Tkachuk, Denis; Ho, Chantal; Sakashita, Shingo; Weiss, Jessica; Jiang, Xiaoqian; Liu, Geoffrey; Cescon, David W.; O’Brien, Catherine A.; Guo, Sheng; Tsao, Ming‐Sound; Haibe‐Kains, Benjamin; Goldenberg, Anna

doi:10.1126/scitranslmed.abf4969

Cited by 11 publications

(8 citation statements)

References 26 publications

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“…(E) Classification of responder versus non-responder for both wildtype and LTR10.XRCC4 knockout cells, based on xenograft growth curves of untreated or irradiated mice. Three measures were calculated using Ortmann et al (2021) 69 : tumor growth inhibition (TGI), mRECIST, and area under the curve (AUC). (F-G) Average growth curves across replicates (n=9-10) for wildtype (F) versus LTR10.XRCC4 knockout (G) HCT116 xenograft tumors, with and without irradiation, for 28 days.…”

Section: Resultsmentioning

confidence: 99%

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Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic

Simpson

Chuong

2021

Preprint

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Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the processes that configure these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are an abundant source of enhancers that show cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic MAPK/AP1 signaling drives activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements are involved in regulating multiple genes associated with tumorigenesis, including ATG12. Within the human population, individual LTR10 elements show frequent structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers mediate transcriptional dysregulation in response to oncogenic signaling, and shape the evolution of cancer-specific regulatory networks.

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Section: Resultsmentioning

confidence: 99%

“…Tumor measurements were taken twice weekly using digital calipers, and toxicity was monitored by measuring body weight twice weekly and the study ended at 28 days. Tumor growth inhibition was measured using KuLGaP 69 .…”

Section: Methodsmentioning

confidence: 99%

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic

Simpson

Chuong

2021

Preprint

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“…The number of different types of animal models and their relative value for translation research in oncology have grown enormously in recent years [78,79]. Using animal models to assess therapeutic response is widespread, and the elements of experimental design needed to increase translational success have been extensively considered [80,81]. In addition, sophisticated technologies are being applied for the detection, characterization, and monitoring of cancer in animal models, generating comprehensive information about the structure, metabolism, and function of cancer cells and their microenvironment [82].…”

Section: Discussionmentioning

confidence: 99%

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials

et al. 2023

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The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients’ tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

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“…Humanized patient-derived xenografts mouse models are preferred for identifying and validating radiotherapy-specific biological or radiological biomarkers 181 - 183 . The accurate tumor-specific anatomic information and dynamic multi-modality/multi-parametric functional images from biomarker-driven probe-mediated molecular imaging could provide a large and reliable training source for the development of advanced imaging processing tools, such as machine learning and artificial intelligence 184 .…”

Section: Reflection and Future Perspectivementioning

confidence: 99%

Biomarker-driven molecular imaging probes in radiotherapy

Li,

Gong,

Luo

2024

Theranostics

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Background: Biomarker-driven molecular imaging has emerged as an integral part of cancer precision radiotherapy. The use of molecular imaging probes, including nanoprobes, have been explored in radiotherapy imaging to precisely and noninvasively monitor spatiotemporal distribution of biomarkers, potentially revealing tumor-killing mechanisms and therapy-induced adverse effects during radiation treatment. Methods: We summarized literature reports from preclinical studies and clinical trials, which cover two main parts: 1) Clinically-investigated and emerging imaging biomarkers associated with radiotherapy, and 2) instrumental roles, functions, and activatable mechanisms of molecular imaging probes in the radiotherapy workflow. In addition, reflection and future perspectives are proposed. Results: Numerous imaging biomarkers have been continuously explored in decades, while few of them have been successfully validated for their correlation with radiotherapeutic outcomes and/or radiation-induced toxicities. Meanwhile, activatable molecular imaging probes towards the emerging biomarkers have exhibited to be promising in animal or small-scale human studies for precision radiotherapy. Conclusion: Biomarker-driven molecular imaging probes are essential for precision radiotherapy. Despite very inspiring preliminary results, validation of imaging biomarkers and rational design strategies of probes await robust and extensive investigations. Especially, the correlation between imaging biomarkers and radiotherapeutic outcomes/toxicities should be established through multi-center collaboration involving a large cohort of patients.

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Assessing therapy response in patient-derived xenografts

Abstract: We propose a measure for robust quantification of in vivo drug response that accounts for variation across both treatment and control replicates.

Cited by 11 publications

References 26 publications

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials

Biomarker-driven molecular imaging probes in radiotherapy

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