Noninvasive molecular imaging of c-Myc activation in living mice

Area of Science:

• Molecular Biology
• Biochemistry
• Oncology

Background:

• Cytoplasmic Myc protein (c-Myc) is a key regulator of gene expression, crucial for normal cell function and tumor growth.
• Dysregulation of c-Myc is implicated in numerous human cancers, making it a significant therapeutic target.
• Current therapeutic strategies primarily target c-Myc at the non-protein level, with limited methods for directly monitoring its activity in vivo.

Purpose of the Study:

• To develop a molecular imaging sensor for noninvasive detection and quantification of c-Myc activity in living organisms.
• To assess the phosphorylation-mediated interaction between glycogen synthase kinase 3beta (GSK3beta) and c-Myc as a readout for c-Myc activity.
• To enable real-time monitoring of c-Myc-targeted drug efficacy in preclinical cancer models.

Main Methods:

• Utilized a split Firefly luciferase (FL) complementation strategy to create a sensor system.
• Engineered two fusion proteins: GSK3beta-CFL and NFL-c-Myc, linking protein fragments to split FL components.
• Validated sensor performance in cell culture and in vivo using mouse xenograft and liver tumor models.

Main Results:

• The sensor system successfully detected and quantified phosphorylation-specific GSK3beta-c-Myc interactions, correlating with c-Myc phosphorylation levels.
• Demonstrated the sensor's ability to monitor inhibition of c-Myc activity through various pathways.
• Observed early detection of drug-induced inhibition of c-Myc activity, preceding changes in tumor size in animal models.

Conclusions:

• The developed reporter system offers an innovative approach to study functional c-Myc in biological processes and cancer.
• Provides a rapid, quantitative method for assessing cancer response to c-Myc-targeted therapies in vivo.
• Facilitates drug development by enabling noninvasive monitoring of therapeutic efficacy in living subjects.