Graduation Year

2018

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Subhra Mohapatra, Ph.D.

Co-Major Professor

Srinivas Bharadwaj, Ph.D.

Committee Member

Andreas Seyfang, Ph.D.

Committee Member

Bala Chandran, Ph.D.

Committee Member

Vrushank Davé, Ph.D.

Keywords

Chemotherapy, 3D culture, Drug Synergy

Abstract

The failure of lung cancer treatments has been attributed partly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. It has been suggested that a very small group of specific cells within the heterogeneous tumors, cancer initiating stem cells (CSC), develop resistance to treatment, survive and later initiate the growth of new tumors. Due to their pivotal role in maintenance and relapse of tumors following the acquisition of drug resistance, we reasoned that novel drugs targeting cancer cells and CSC might provide the most effective treatments, if not a cure. To this end, we reported a polymeric nanofiber scaffold on which tumor cells develop into tumor organoids termed “tumoroids” that resemble in vivo tumors. Herein we report that lung cancer cells grown on the scaffold acquire CSC properties (aldehyde dehydrogenase (ALDH) activity, sphere formation, and tumor initiation). We have identified two key pathways that regulate this expansion namely Natriuretic Peptide Receptor A signaling (NPRA) and Wnt/β-catenin signaling. Screening of an NCI Diversity set identified a lead candidate drug targeting CSC, namely Actinomycin D (AD). AD is a well-studied anti-cancer drug, however it is known to have several drawbacks including high clinical toxicity and the development of resistance. In order to overcome these drawbacks, we tested AD treatment in combination with the angiotensin receptor antagonist, Telmisartan (TS) because it has been reported to reduce fibrosis in tumors allowing them to be more permeable to drugs. We have found that this novel combination treatment is effective in blocking CSC enrichment in the polymeric nanofiber scaffold model. Furthermore, we demonstrate the effectiveness and synergistic action of the combination treatment in both an in vivo syngeneic mouse model and xenograft model revealing its ability to reduce tumor burden. We also provide evidence that β-catenin activation is at least partially responsible for the increase in CSC seen in scaffold culture and that the combination treatment reduces tumor burden in part by inhbiting Wnt/β-catenin pathway. This work establishes the utility of the scaffold-inspired tumoroids as a model system capable of enriching CSC in vitro or ex vivo for targeted drug screening and personalized medicine. It also identifies a promising novel treatment targeting CSC that, with further study, may be useful to improve therapeutic outcomes for lung cancer.

Download

Share

COinS