Abstract 2235: Intercepting metastasis: 8-step CRISPR design via multi-modal foundation models.

Abstract Background: Metastasis accounts for >90% of cancer deaths, yet CRISPR design tools prioritize on-target efficiency alone (CRISPOR, Benchling), ignoring stage-specific biology (EMT, extravasation, colonization). No existing tool integrates essentiality (DepMap), chromatin accessibility (ENCODE), and metastatic cascade relevance into guide selection. We present Interception, a stage-aware CRISPR framework targeting vulnerabilities across the metastatic cascade. Methods: We compute three orthogonal signals: (i) Functionality (Evo2): predict variant impact on protein function; (ii) Essentiality (DepMap): prioritize genes critical for metastatic survival; (iii) Regulatory (GTEx eQTLs): predict expression changes. Target-Lock score quantifies gene relevance to specific metastatic stages (e.g., EMT vs. extravasation) using literature-derived weights. Guide candidates are generated with PAM constraints, scored for efficacy (Evo2-predicted expression change via sigmoid transformation) and safety (minimap2 genome-wide alignment with exponential mismatch decay), then ranked by Assassin score (0.40×efficacy + 0.30×safety + 0.30×mission fit). Weights were optimized via ablation study on 304 gene-stage pairs. All outputs include full provenance and are reproducible via frozen scripts/environment. Results: Target-Lock significantly outperformed single-metric baselines: AUROC 0.976 (ours) vs. 0.61 (DepMap alone), 0.58 (Evo2 alone), 0.52 (random); AUPRC 0.948 vs. 0.42 (DepMap), 0.39 (Evo2); Precision@3 = 1.000 (perfect top-3 enrichment) vs. 0.33 (random). All 8 metastatic steps showed significant enrichment (Fisher's exact p < 0.001 for 6/8 steps) with large effect sizes (Cohen's d > 2.0). Guide validation on 20 designs showed mean efficacy 0.548 ± 0.119, safety 0.771 ± 0.210. Structural validation of 15 guide:DNA complexes via AlphaFold 3 Server achieved 100% pass rate (pLDDT 65.6 ± 1.8, iPTM 0.36 ± 0.01)—the first metastasis-targeted CRISPR framework with structural validation. Conclusions: Interception delivers reproducible, mission-aware CRISPR design for metastasis, integrating multi-modal signals, genome-wide safety, and structural validation. Future work will (i) integrate Enformer for chromatin predictions, (ii) expand structural validation to 40 guides (complete 8-step coverage), and (iii) validate in metastatic mouse models (PDX/CDX) to assess in vivo efficacy. Citation Format: Fahad Kiani. Intercepting metastasis: 8-step CRISPR design via multi-modal foundation models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2235.