Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer

Abstract

Purpose: Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapy-probe pair using dynamic nuclear polarization (DNP) enhanced magnetic resonance spectroscopic imaging (MRSI). Experimental Design: CRISPR negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma (HCC) with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-¹³C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous HCC. MRSI evaluated intratumoral pyruvate metabolism while T₂-weighted segmentations quantified tumor growth. Results: Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, HCC required LDH for growth more than the 29 cancer types in this database. LDHi led to a decrease in lactate generation (p13C]-pyruvate is a theranostic strategy for HCC, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening integrates imaging probe selection in order to quantify therapeutic efficacy on a cancer-by-cancer basis.