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Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer
Nicholas R Perkons1,2, Omar Johnson1,3, Gabrielle Pilla1,2
1Penn Image Guided Interventions Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania.
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 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 hepatocellular carcinoma. 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, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001).
Conclusions:
These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-by-cancer basis.
Insights
Functional genetic screening identified lactate dehydrogenase as a target for hepatocellular carcinoma. Dynamic nuclear polarization-enhanced magnetic resonance spectroscopic imaging (DNP-MRSI) can predict treatment response to lactate dehydrogenase inhibitors.
Area of Science:
- Oncology
- Medical Imaging
- Genetics
Background:
- Targeted cancer therapies require functional imaging to assess treatment effectiveness.
- Dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI) offers potential for such assessments.
Purpose of the Study:
- To evaluate functional genetic screening for identifying therapeutic targets and selecting imaging probes.
- To characterize a therapy-probe pair using DNP-enhanced MRSI for hepatocellular carcinoma.
Main Methods:
- CRISPR-negative selection screens analyzed gene dependencies in 625 cancer cell lines.
- Follow-up screening in hepatocellular carcinoma used a CRISPR library targeting imaging genes.
- Hyperpolarized [1-13C]-pyruvate MRSI assessed intratumoral pyruvate metabolism before and after lactate dehydrogenase inhibitor (LDHi) administration in rats.
Main Results:
- Genetic screening revealed metabolic vulnerabilities in 17 cancer types suitable for imaging.
- Hepatocellular carcinoma showed high dependence on lactate dehydrogenase (LDH).
- LDH inhibition decreased lactate, inhibited growth dose-dependently, and intratumoral alanine production predicted efficacy.
Conclusions:
- DNP-MRSI of LDH activity with hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma.
- This method quantifies LDHi pharmacodynamics and predicts therapeutic efficacy.
- This establishes a platform for functional genetic screening to guide imaging probe selection for cancer-specific theranostics.
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