Development of Novel Therapeutic Strategies to Target Therapy Resistance and Cancer Stem Cells

Abstract

This thesis focuses on the core issues of multidrug resistance (MDR) in cancer, a process that hinders the success of chemotherapeutic treatments. MDR involves various mechanisms, including the upregulation of ABC transporter pumps, like MRP1, and increased cancer stemness, which contributes to malignancy and recurrence.

The thesis comprises seven chapters: a literature review (Chapter 1), methodology (Chapter 2), results (Chapters 3-5), and discussions on findings and future studies (Chapters 6) and final discussion and overall summary (Chapter 7).

Chapter 3 delves into the novel roles of MRP1 in cellular iron metabolism and proliferation, its interaction with c-Myc, and the effects on cellular proliferation. Silencing and inhibition studies reveal MRP1's role in regulating iron regulatory proteins through c-Myc.

Chapter 4 investigates the role of ABC transporters in cancer stemness, revealing their connection with stemness states in different tumor types.

Chapter 5 explores strategies for targeting drug-resistant cancer cells, demonstrating how doxycycline reduces the stemness marker SOX2 across multiple tumor types through a unique pathway.

Chapter 6 examines the alteration of metabolism and stemness in drug-resistant cancer cells and strategies for targeting the cysteine metabolism pathway. The findings provide insights into cancer stemness regulation and potential therapeutic strategies, improving the efficacy of chemotherapeutics.

The work reported in this thesis reveals an underlying and unique mechanism in regulation of SOX2-mediated cancer stemness. Moreover, the use of DXC to remove stemness was demonstrated to be a promising therapeutic strategy in combination with other common chemotherapeutics agents. These findings presented in this thesis enables us to understand cancer stemness better and improve the efficacy of current chemotherapeutics, which ultimately improve overall quality of life.