Conclusion and Translational Relevance: PARP1 Activity GroundTruth™

Application of the CCR CDx™ step-down methodology to PARP1 establishes GroundTruth™ measurement of active DNA damage sensing and repair initiation, rather than proxy assessment based on PARP expression or inhibitor exposure alone. PARP1 functions dynamically at sites of single-strand breaks and stalled replication forks, with biological relevance encoded in rapid recruitment, chromatin interaction, and spatial clustering.

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GroundTruth™ resolves whether PARP1 is properly localized and functionally engaged at DNA lesions, and whether its spatial organization supports effective repair or reflects dysregulated, compensatory, or hyperactivated states. Step-down validation across imaging modalities confirms that observed PARP1 assemblies represent true biological response rather than transient or nonspecific accumulation.

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At higher resolution, GroundTruth™ reveals repair-domain architecture and persistence, enabling differentiation between productive repair engagement and aberrant PARP1 trapping or exhaustion—states with direct implications for PARP inhibitor sensitivity and toxicity.

By measuring PARP1 behavior directly at the site of DNA damage prior to therapy, GroundTruth™ provides actionable insight into tumor repair dynamics and therapeutic vulnerability, supports rational patient selection, and minimizes ineffective treatment exposure.