All ETDs from UAB

Advisory Committee Chair

Herbert Chen

Advisory Committee Members

John Shacka

Renata Jaskula-Sztul

James Bibb

Document Type

Thesis

Date of Award

2019

Degree Name by School

Master of Science in Biomedical Science (MSBMS) School of Engineering

Abstract

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that originate in a diverse array of anatomical locations and have widely variable clinical presentations and responses to treatment. Patient-derived xenografts and cell lines are valuable models of tumor biology and for testing personalized therapeutics on tumors prior to their administration to patients. However, as PDX models and cell lines for neuroendocrine tumors are lacking in both number and validity, we have developed a 3D flow perfusion polydimethylsiloxane (PDMS) bioreactor model for the purpose of culturing patient derived NETs. The goal of this thesis is to determine the ability to use the bioreactor to culture human NETs taken directly from patients, evaluate the retention of various cell populations comprising NETs and their stroma within the bioreactor, and to determine if it is possible to conduct a drug trial on a human NET within the bioreactor. We cultured 28 human NETs, including GEP-NETs, MTCs, paragangliomas, and a pulmonary NET, demonstrating an average survival duration of 34 days and a range of 6-83 days. Using 6 human tumors, we demonstrated histologically that, in addition to NET cells, endothelia, lymphocytes, and macrophages persist within the bioreactor for up to 30 days. Lastly, we used human NETs within the bioreactor to conduct a therapeutic trial as a proof of principle. Herein, we describe the ability to culture human NETs ex vivo in a 3D model system. We also describe the maintenance of a heterogeneous population of NET and stromal cells among tumors cultured in the bioreactor over time, retaining key features of the original tumor that have important implications when attempting to translate observations made in preclinical research to patients. We also demonstrate that the bioreactor can be used to conduct drug trials on NETs, and therefore may be useful in the future as a model for evaluating the therapeutic sensitivity of patients’ NETs ex vivo, potentially informing the clinical decision-making process.

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