Evaluation of potential therapeutics for non-small cell lung cancer using 3D tumor spheroid models

Summary

The development of novel and improved therapies for cancers requires robust means of investigation that both effectively recapitulate tumor biology while also utilizing resources efficiently. 3D tissue culture methods, namely spheroids and organoids, have emerged as an effective bridge between conventional in vitro methods and in vivo animal models in cancer research. This thesis provides background into lung cancer and the current landscape of 3D in vitro models of cancer, as well as... Show moreThe development of novel and improved therapies for cancers requires robust means of investigation that both effectively recapitulate tumor biology while also utilizing resources efficiently. 3D tissue culture methods, namely spheroids and organoids, have emerged as an effective bridge between conventional in vitro methods and in vivo animal models in cancer research. This thesis provides background into lung cancer and the current landscape of 3D in vitro models of cancer, as well as detailing two studies in which multicellular tumor spheroids were used to investigate the therapeutic potential of candidate compounds. The first study uses an NCI-H358 multicellular tumor spheroid to investigate three compounds: Apigenin, a plant derived flavonoid; MSU42011, a novel retinoid x receptor (RXR) agonist; and CEP-1347, a mixed lineage kinase (MLK) inhibitor. It was found that Apigenin alone decreased the viability of spheroids, and that the combination of Apigenin and CEP-1347 synergistically decreased viability and increased cell death within the spheroids.The second study uses a murine lung adenocarcinoma tumor spheroid model to investigate the effects of MSU-71, a novel inhibitor of the nuclear factor erythroid 2-related factor (NRF2) pathway, on macrophage-induced invasion and migration. This compound blocked both migration in conventional experiments along with spheroid invasion, indicating its potential efficacy in preventing LUAD progression. This study also adapted the spheroid invasion model for use in multiple human LUAD cell lines and THP-1 conditioned medium. The findings presented herein demonstrate the versatility and value of 3D tumor spheroid models in the cancer drug development field. Show less