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Dissertation_Shahi Thakuri.pdf (4.71 MB)
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MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS
Author Info
Shahi Thakuri, Pradip
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168
Abstract Details
Year and Degree
2019, Doctor of Philosophy, University of Akron, Biomedical Engineering.
Abstract
Cancer treatments have shifted toward using therapies that target specific oncogenic molecules in cells. However, cancer cells develop adaptive responses to such targeted therapies and render them ineffective. Understanding mechanisms of resistance to targeted therapies is critical to improve the treatments outcome. We addressed this unresolved problem using three-dimensional (3D) tumor spheroid cultures under long-term cyclic treatment and recovery cycles. This regimen mimicked how cancer patients receive chemotherapy and allowed cancer cells to develop adaptive resistance to inhibitors of oncogenic protein kinases. Our phenotypic compound testing paralleled with comprehensive molecular analysis of tumor spheroids identified activation of specific signaling pathways that promoted adaptive drug resistance of colorectal cancer cells. Using a design-driven approach, we developed drug combinations that effectively suppressed both initially active and treatment-induced oncogenic signaling in cancer cells. To address potential toxicity of drug combinations to normal tissues, we identified low-dose synergistic drug pairs and demonstrated their use in a sequential combination treatment regimen to effectively inhibit growth of tumor spheroids and minimize toxicity to normal cells. Incorporating patient-derived cells in our 3D tumor model will help identify drivers of drug resistance toward realizing personalized cancer medicine with effective and safe combinations of targeted drugs.
Committee
Hossein Tavana, PhD (Advisor)
Marnie Saunders, PhD (Committee Member)
Ge Zhang, PhD (Committee Member)
Sailaja Paruchuri, PhD (Committee Member)
Nic Leipzig, PhD (Committee Member)
Pages
201 p.
Subject Headings
Biology
;
Biomedical Engineering
;
Engineering
Keywords
Adaptive response, Resistance, Spheroid, Cyclic treatment, Regimen, Drug Combination, Synergism, Personalized medicine
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Citations
Shahi Thakuri, P. (2019).
MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS
[Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168
APA Style (7th edition)
Shahi Thakuri, Pradip.
MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS.
2019. University of Akron, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168.
MLA Style (8th edition)
Shahi Thakuri, Pradip. "MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS." Doctoral dissertation, University of Akron, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168
Chicago Manual of Style (17th edition)
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Document number:
akron1574725861735168
Download Count:
286
Copyright Info
© 2019, some rights reserved.
MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS by Pradip Shahi Thakuri is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Akron and OhioLINK.