Recent Results in Cancer Research

1985

DOI: 10.1007/978-3-642-82372-5_8

|View full text |Cite

|

Sign up to set email alerts

|

Development of Three Human Small Cell Lung Cancer Models in Nude Mice

Heinz‐Herbert Fiebig

¹

,

²

,

³

et al.

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Discussion2

Csc In Vitro Modeling Techniques1

Recent Advances In Model Development1

Introduction1

Citation Types

Supporting

1

Mentioning

21

Contrasting

0

Year Published

1988

1988

2024

2024

Publication Types

Select...

Article5

Book5

Relationship

Self Cite0

Independent10

Authors

Journals

Cited by 52 publications

(22 citation statements)

References 1 publication

Supporting

1

Mentioning

21

Contrasting

0

Order By: Relevance

“…Prior investigations have focused on specific cancers, e.g. Secondary liver cancer [15] lung [24], pancreatic cancer [16], pediatric osteosarcomas [14], or pediatric rhabdomyosarcoma [25], rather than a spectrum of malignancies. To examine the suitability of the panel of tumorgraft models generated in our lab as molecularly-relevant preclinical models, we directly compared a number of phenotypic and genotypic features of the tumorgrafts to the originating patient tumors from which they were derived.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue

¹

,

²

,

³

et al. 2012

View full text Add to dashboard Cite

BackgroundThere is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status.MethodsFresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection.ResultsFresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity.ConclusionsThe preservation of the patient’s tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.

“…Prior investigations have focused on specific cancers, e.g. Secondary liver cancer [15] lung [24], pancreatic cancer [16], pediatric osteosarcomas [14], or pediatric rhabdomyosarcoma [25], rather than a spectrum of malignancies. To examine the suitability of the panel of tumorgraft models generated in our lab as molecularly-relevant preclinical models, we directly compared a number of phenotypic and genotypic features of the tumorgrafts to the originating patient tumors from which they were derived.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue

¹

,

²

,

³

et al. 2012

View full text Add to dashboard Cite

BackgroundThere is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status.MethodsFresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection.ResultsFresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity.ConclusionsThe preservation of the patient’s tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.

“…Combined clinical and PDX studies have shown a high degree of correlation between clinical response to cytotoxic agents in adult patients with lung cancer and response to the same agents in PDX models generated from these patients (40). PDX models have been shown to be predictive of clinical outcomes and are being used for preclinical and clinical drug evaluation (41, 42).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Bax and mTOR for Cancer Therapeutics

¹

,

²

,

³

et al. 2017

Cancer Research

View full text Add to dashboard Cite

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues which inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.

“…2a). To improve the concordance between laboratory experiments and clinical data, patient-derived xenografts (PDX) were developed with hopes of maintaining an in vivo tumor model with a closer relationship to the original tissue [103–105]. PDX models are now considered the gold standard for pre-clinical trials for testing of new therapies in vivo (Fig.…”

Section: Csc In Vitro Modeling Techniquesmentioning

confidence: 99%

Modeling head and neck cancer stem cell-mediated tumorigenesis

¹

,

²

2016

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

A large body of literature has emerged supporting the importance of cancer stem cells (CSCs) in the pathogenesis of head and neck cancers. CSCs are a sub-population of cells within a tumor that share the properties of self-renewal and multipotency with stem cells from normal tissue. Their functional relevance to the pathobiology of cancer arises from the unique properties of tumorigenicity, chemotherapy resistance, and their ability to metastasize and invade distant tissues. Several molecular profiles have been used to discriminate a stem cell from a non-stem cell. CSCs can be grown for study and further enriched using a number of in vitro techniques. An evolving option for translational research is the use of mathematical and computational models to describe the role of CSCs in complex tumor environments. This review is focused discussing the evidence emerging from modeling approaches that have clarified the impact of CSCs to the biology of cancer.

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Product

Browser Extension Assistant by scite Citation Statement Search Reference Check Visualizations Dashboards Explore Journals Explore Organizations Explore Funders Embedding Badge Embedding Citation Search Pricing

Resources

Blog Help & FAQ Accessibility Statement API Terms For Universities & Governments For Researchers For Publishers For Corporate, Pharma & Enterprise Author Marketing Become an Affiliate Get an organization trial or quote scite Data & Services

About

News & Press Careers Read our Paper Coverage

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Copyright © 2024 scite LLC. All rights reserved.

Made with 💙 for researchers

Part of the Research Solutions Family.