Optical imaging platform to unravel metabolic reprogramming of cancer: a path for improved treatments

Projektinformationen

METABOLIGHT

ID Finanzhilfevereinbarung: 866338

DOI

10.3030/866338

Das Projekt endete am 31 Januar 2024

EK-Unterschriftsdatum 12 Februar 2020

Startdatum 1 Juni 2020

Enddatum 31 Mai 2025

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 997 375,00

EU-Beitrag

€ 1 997 375,00

Koordiniert durch

SWISSLUMIX SARL
Switzerland

Periodic Reporting for period 3 - METABOLIGHT (Optical imaging platform to unravel metabolic reprogramming of cancer: a path for improved treatments)

Berichtszeitraum: 2023-06-01 bis 2024-11-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Cancer remains one of the leading causes of death globally and no efficient treatments currently exist for many cancer types. Recent investigations revealed that cancer possesses several important metabolic features, such as differential utilization of many essential metabolites. These phenomena are collectively referred to as "metabolic reprogramming", which is now recognized as one of the important hallmarks of cancer. These metabolic alterations often promote tumorigenesis but also provide opportunities for potential anti-cancer therapies based on potent metabolic inhibitors recently developed. However, no efficient methodologies currently exist that allow noninvasive imaging and quantification of the uptake of essential metabolites in animal models of disease. Thus, our knowledge of which cancers depend on which specific nutrient remains very limited. This significantly hampers the development of efficient drug combinations for the treatment of cancer. Therefore, better understanding of cancer-specific exogenous metabolite dependencies in various types of tumors may lead to identification of improved cancer treatments.

To address the unmet need for nutrient uptake imaging tools, we propose to develop a novel METABOLIGHT imaging platform based on ultrasensitive bioluminescent imaging. The applications of the novel platform will focus on the development of probes for various metabolites previously reported to play important roles in cancer metabolism. We will then use this platform to investigate the metabolic reprogramming of two different liver cancers, which may lead to the generation of novel, effective treatments of this deadly disease.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We successfully expanded the use of our METABOLIGHT imaging platform to novel classes of metabolites such as amino acids, fatty acids, and nucleosides. We also performed thorough validation of these novel reagents to assure that the reagents fulfill the requirements for physiological behavior, stability, safety, and robust signal generation. In addition, we optimized delivery vehicles, and concentrations to achieve high signal/background ratios.
We also developed the novel assay that allows application of the platform in clinical samples such as T-cells. This assay obviates the use of cells and tissues that express luciferase and significantly expands the application of the platform. Using one of our newly developed probes, we also investigated the role of nicotinamide riboside uptake in T cells and several human cancer types. Our results emphasize the need for better understanding of the uptake process of powerful nutraceuticals and metabolites in cancer progressing and the necessity to personalize their use in certain patient populations.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our new results significantly expanded the state of art of the existing tools for optical imaging of metabolite absorption. Our paper on novel bioluminescent probe for nicotinamide riboside uptake was published in high-impact journal and our findings emphasized the important role of metabolite uptake in cancer metabolism. In addition, we made significant progress in validation of other essential metabolites that play essential role in cancer progression and metastasis.
Liver cancer is the fifth most prevalent type of cancer globally, representing the second most common cause of death by cancer due to the associated rate of mortality, which is higher than that for any other tumor type with very limited treatment options. We plan to apply the novel imaging platform we developed to unravel cancer metabolism of liver tumors during tumor progression with the goal of identification of potent metabolic inhibitors. In addition, we also plan to test novel drug combinations for improved therapy of liver cancers based on combination of current treatments and existing cancer metabolic inhibitors. In conclusion, we believe that the studies outlined in the remaining part of the work will result in improved therapeutic options for the two most common types of liver cancer.