Author ORCID Identifier
0000-0001-6169-7372
Date of Graduation
8-2021
Document Type
Dissertation (PhD)
Program Affiliation
Experimental Therapeutics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Don L. Gibbons
Committee Member
Andrew Gladden
Committee Member
Jichao Chen
Committee Member
Lauren Byers
Committee Member
Walter Hittelman
Committee Member
Varsha Gandhi
Abstract
Lung cancer is a heterogeneous disease composed of genetically and phenotypically distinct tumor cells as well as a heterogeneous microenvironment consisting of non-cancer cells and extracellular matrix. Constant interactions among these components ultimately leads to a complex tumor tissue that is ever evolving and poses a therapeutic challenge for sustained benefit. Strategies for targeting lung cancers are largely guided by the genetic alterations identified in the tumor specimens. However, in order to gain a better understanding of lung cancer progression and develop effective treatment modalities, studying tumor in context of its microenvironment is crucial. The first aim of this project was to establish an experimental model to capture tumor heterogeneity. We developed an Ex Vivo Tumor system that preserved tumor composition and allowed the introduction of specific modifications in the tumor microenvironment to investigate their role in tumor progression. We utilized this system to demonstrate the role of extrinsic as well as intrinsic alterations that modify tumor cell behavior. Next, we explored the biological phenomenon epithelial-to-mesenchymal transition as a source of tumor cell heterogeneity and therapeutic resistance. Genetically identical KRAS mutant lung cancer cells displayed different phenotypic states that were associated with distinct survival pathways that allowed cancer cells to escape therapeutic targeting. With the use of extensive in vitro, ex vivo and in vivo models, we identified that a combinatorial approach of utilizing CDK4 and MEK inhibitors to effectively control tumor growth by targeting distinct tumor subpopulations within lung cancer and prevented emergent resistance to either single agent.
Keywords
Lung cancer, heterogeneity, ex vivo tumors, CDK4 inhibitors, MEK inhibitors, EMT