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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
An in vivo platform for translational drug development in pancreatic cancer
Belen Rubio-Viqueira1, Antonio Jimeno, George Cusatis
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center and the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Abstract:
Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.
Insights
This study developed a new preclinical model for pancreatic cancer drug development using patient-derived xenografts in mice. This platform aids in identifying optimal drug doses and biomarkers for targeted anticancer therapies.
Area of Science:
- Oncology
- Translational Medicine
- Cancer Research
Background:
- Developing targeted anticancer agents requires precise biological dosing and activity biomarkers.
- Existing preclinical models are insufficient for optimal translational drug development.
Purpose of the Study:
- To create a novel preclinical model for translational drug development, using pancreatic cancer as a prototype.
- To establish a platform for integrating drug screening and biomarker discovery.
Main Methods:
- Xenografting of resected pancreatic tumors from 14 patients into nude mice.
- Serial passages of tumors in successive mouse cohorts to create drug-testing cohorts.
- Genotypic analysis to confirm tumor feature maintenance across passages.
Main Results:
- Xenografted tumors retained fundamental genotypic features and recapitulated pancreatic cancer's genetic heterogeneity.
- The model proved effective for integrating drug screening with biomarker discovery.
- Tumor susceptibility to anticancer agents remained consistent across passages, creating a perpetual live bank.
Conclusions:
- The developed in vivo platform supports translational drug development for pancreatic cancer.
- This model facilitates the creation of a stable database for tumor-drug responses and biomarkers.
- It enables the application of new technologies for enhanced anticancer agent development.
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