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Novel strategies to investigate and therapeutically modulate cancer metabolism

Abstract

In response to increased anabolic demands to support their survival and growth, cancer cells rewire cellular signaling and metabolic networks. While analysis of this rewiring can reveal vulnerabilities within cancers, it is becoming clear that more profound understandings of fundamental cancer biology are required for the successful therapeutic exploitation of cancer signaling and metabolism, two very complex and highly-regulated systems with multiple pathways contributing to their plasticity and robustness.

This thesis is the product of translational research efforts focused upon gaining a better understanding of fundamental aspects of cancer biology. The goals of the thesis are to 1) acquire novel insights of cancer biology to more precisely design therapeutic interventions to target cancers, more specifically pancreatic ductal adenocarcinoma (PDAC), one of most deadly cancers, and to 2) develop diagnostic tools that enable better characterization of metabolic characteristics of cancers.

Chapter 1 concerns the development of a clinically-applicable positron emission tomography (PET) probe for monitoring nucleotide metabolism at the whole-body level in a non-invasive way. This study makes us think about biology across different scales, from molecular to whole-body levels.

In Chapter 2, the synthetic lethality screening tethered to chloroquine, an inhibitor of lysosome-dependent recycling pathways, which PDAC cells rely on to generate metabolic substrates is performed. The findings reveal that the inhibition of lysosomal recycling makes PDAC cells rely on replication stress response pathway for the survival due to impaired de novo nucleotide biosynthesis.

In chapter 3, I use multiple models of KRAS G12C mutant PDAC to profile the adaptive resistance mechanisms within cellular signaling and metabolic networks which arise from direct inhibition of mutant KRAS, the oncogenic driver of PDAC. This was followed by mapping the impacts of co-inhibition of oncogenic KRAS and the identified adaptive resistance mechanisms. Metabolomic analyses reveal metabolic vulnerabilities induced by co-inhibition of oncogenic KRAS and the adaptive resistance.

In the final chapter, I summarize ongoing projects and future directions that concern fundamental biology of PDAC metabolism.

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