@erosolaraijs/cure 2.2.0 → 2.3.1

package/dist/capabilities/emergingTherapeutics.js

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+/**
+ * 新兴治疗技术框架 (Emerging Therapeutics Framework)
+ *
+ * ███████╗███╗   ███╗███████╗██████╗  ██████╗ ██╗███╗   ██╗ ██████╗
+ * ██╔════╝████╗ ████║██╔════╝██╔══██╗██╔════╝ ██║████╗  ██║██╔════╝
+ * █████╗  ██╔████╔██║█████╗  ██████╔╝██║  ███╗██║██╔██╗ ██║██║  ███╗
+ * ██╔══╝  ██║╚██╔╝██║██╔══╝  ██╔══██╗██║   ██║██║██║╚██╗██║██║   ██║
+ * ███████╗██║ ╚═╝ ██║███████╗██║  ██║╚██████╔╝██║██║ ╚████║╚██████╔╝
+ * ╚══════╝╚═╝     ╚═╝╚══════╝╚═╝  ╚═╝ ╚═════╝ ╚═╝╚═╝  ╚═══╝ ╚═════╝
+ *
+ * Cutting-edge cancer treatment technologies and novel targets:
+ * - 细胞治疗 (Cellular Therapies)
+ * - 靶向蛋白降解 (Targeted Protein Degradation)
+ * - 基因编辑 (Gene Editing)
+ * - 新型抗体技术 (Novel Antibody Technologies)
+ * - 纳米医学 (Nanomedicine)
+ * - 人工智能药物发现 (AI-Driven Drug Discovery)
+ */
+// ═══════════════════════════════════════════════════════════════════════════════
+// EMERGING THERAPEUTICS MODULE
+// ═══════════════════════════════════════════════════════════════════════════════
+export class EmergingTherapeuticsModule {
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // NEXT-GENERATION CELLULAR THERAPIES
+    // ═══════════════════════════════════════════════════════════════════════════════
+    nextGenCellular = [
+        // NEXT-GEN CAR-T
+        { id: 'cell-cart-armored', name: 'Armored CAR-T Cells',
+            type: 'car_t', target: 'Various', generation: '4th Generation',
+            modifications: ['Constitutive IL-15 secretion', 'IL-21 secretion', 'PD-1 dominant negative', '4-1BBL co-stimulation', 'Checkpoint knockout'],
+            cancerTypes: ['Solid Tumors', 'Hematologic Malignancies'],
+            advantages: ['Enhanced persistence', 'TME modulation', 'Reduced exhaustion', 'Better solid tumor activity'],
+            clinicalStatus: 'Phase I/II trials',
+            keyTrials: ['Multiple ongoing trials'],
+            manufacturers: ['Lyell Immunopharma', 'Poseida', 'Caribou'] },
+        { id: 'cell-cart-allogeneic', name: 'Allogeneic Off-the-Shelf CAR-T',
+            type: 'car_t', target: 'CD19, BCMA, CD70', generation: 'Allogeneic',
+            modifications: ['TCR knockout (TRAC)', 'HLA knockout', 'CD52 knockout for lymphodepletion resistance', 'NK cell evasion'],
+            cancerTypes: ['B-cell malignancies', 'Multiple Myeloma', 'T-cell malignancies'],
+            advantages: ['Immediate availability', 'Lower cost potential', 'Standardized product', 'No apheresis needed'],
+            clinicalStatus: 'Phase I/II - Mixed results, improving',
+            keyTrials: ['ALPHA2', 'COBALT-LYM', 'UNIVERSAL'],
+            manufacturers: ['Allogene', 'CRISPR Therapeutics', 'Precision BioSciences', 'Caribou Biosciences'] },
+        { id: 'cell-cart-logic-gated', name: 'Logic-Gated CAR-T',
+            type: 'car_t', target: 'Multiple antigens', generation: 'Synthetic Biology',
+            modifications: ['AND gate (require 2 antigens)', 'NOT gate (avoid normal tissues)', 'OR gate (target either)', 'SynNotch receptors'],
+            cancerTypes: ['Solid tumors with heterogeneous expression'],
+            advantages: ['Improved specificity', 'Reduced on-target off-tumor toxicity', 'Adaptable'],
+            clinicalStatus: 'Phase I trials',
+            keyTrials: ['Emerging'],
+            manufacturers: ['A2 Biotherapeutics', 'Poseida', 'Tmunity'] },
+        { id: 'cell-cart-in-vivo', name: 'In Vivo CAR-T Generation',
+            type: 'car_t', target: 'CD19', generation: 'In Vivo Programming',
+            modifications: ['LNP-delivered mRNA', 'No ex vivo manufacturing', 'Repeated dosing possible'],
+            cancerTypes: ['B-cell malignancies'],
+            advantages: ['No manufacturing delay', 'Lower cost', 'Outpatient potential', 'Repeat dosing'],
+            clinicalStatus: 'Phase I',
+            keyTrials: ['LUMNI-T'],
+            manufacturers: ['Capstan Therapeutics', 'Ensoma', 'Umoja Biopharma'] },
+        // CAR-NK
+        { id: 'cell-car-nk', name: 'CAR-NK Cells',
+            type: 'car_nk', target: 'CD19, CD70, HER2, NKG2D ligands', generation: 'Various',
+            modifications: ['Cord blood derived', 'iPSC-derived', 'IL-15 armored', 'CD16 enhanced (ADCC)'],
+            cancerTypes: ['Hematologic malignancies', 'Solid tumors'],
+            advantages: ['No GvHD', 'Off-the-shelf potential', 'No CRS', 'Native anti-tumor activity'],
+            clinicalStatus: 'Phase I/II',
+            keyTrials: ['NCT03056339 (MD Anderson)', 'THINK trial'],
+            manufacturers: ['Fate Therapeutics', 'Nkarta', 'Century Therapeutics', 'Takeda'] },
+        // TIL THERAPY
+        { id: 'cell-til', name: 'Tumor-Infiltrating Lymphocyte (TIL) Therapy',
+            type: 'til', target: 'Tumor neoantigens', generation: 'Autologous',
+            modifications: ['Lifileucel (FDA approved)', 'Selected TIL', 'Gene-edited TIL', 'Neoantigen-enriched'],
+            cancerTypes: ['Melanoma (approved)', 'NSCLC', 'Cervical', 'Head and Neck', 'Other solid tumors'],
+            advantages: ['Polyclonal response', 'Target multiple neoantigens', 'Proven efficacy in melanoma'],
+            clinicalStatus: 'FDA Approved (Melanoma), Phase II/III (other)',
+            keyTrials: ['C-144-01', 'IOV-COM-202'],
+            manufacturers: ['Iovance Biotherapeutics', 'Instil Bio', 'BioNTech'] },
+        // TCR-T
+        { id: 'cell-tcr-t', name: 'TCR-T Cell Therapy',
+            type: 'tcr_t', target: 'Intracellular antigens (MAGE-A4, NY-ESO-1, WT1, KRAS)', generation: 'Engineered TCR',
+            modifications: ['Affinity-enhanced TCR', 'HLA-independent TCR mimic', 'Soluble TCR bispecifics'],
+            cancerTypes: ['Synovial sarcoma', 'Myxoid liposarcoma', 'Melanoma', 'NSCLC', 'Ovarian'],
+            advantages: ['Target intracellular antigens', 'Broader target space', 'Shared tumor antigens'],
+            clinicalStatus: 'Phase I/II - Afami-cel approved',
+            keyTrials: ['SPEARHEAD-1', 'IGNYTE-ESO'],
+            manufacturers: ['Adaptimmune', 'TCR2', 'Immatics'] },
+        // IPSC-DERIVED
+        { id: 'cell-ipsc', name: 'iPSC-Derived Cellular Therapies',
+            type: 'ipsc_derived', target: 'Various', generation: 'iPSC Platform',
+            modifications: ['Unlimited expansion', 'Genetic engineering', 'NK cells, T cells, macrophages'],
+            cancerTypes: ['Hematologic and solid tumors'],
+            advantages: ['Unlimited supply', 'Consistent quality', 'Multi-edit capability', 'Off-the-shelf'],
+            clinicalStatus: 'Phase I',
+            keyTrials: ['FT500 series', 'FT819 (CD19 CAR)'],
+            manufacturers: ['Fate Therapeutics', 'Century Therapeutics', 'Shoreline Biosciences'] },
+        // GAMMA-DELTA T CELLS
+        { id: 'cell-gamma-delta', name: 'Gamma-Delta T Cell Therapy',
+            type: 'gamma_delta', target: 'Stress ligands, BTN3A1', generation: 'Vγ9Vδ2',
+            modifications: ['Ex vivo expanded', 'CAR-modified', 'Allogeneic'],
+            cancerTypes: ['Hematologic malignancies', 'Solid tumors'],
+            advantages: ['MHC-unrestricted', 'Recognize stressed cells', 'Allogeneic safe', 'Tissue resident'],
+            clinicalStatus: 'Phase I/II',
+            keyTrials: ['Multiple ongoing'],
+            manufacturers: ['IN8bio', 'Adicet Bio', 'Lava Therapeutics'] },
+        // CAR-MACROPHAGES
+        { id: 'cell-car-m', name: 'CAR-Macrophage Therapy',
+            type: 'car_m', target: 'HER2, Mesothelin', generation: '1st Generation',
+            modifications: ['Chimeric antigen receptor on macrophages', 'Phagocytosis and antigen presentation'],
+            cancerTypes: ['Solid tumors (HER2+, Mesothelin+)'],
+            advantages: ['Solid tumor trafficking', 'TME remodeling', 'Antigen presentation', 'No CRS expected'],
+            clinicalStatus: 'Phase I',
+            keyTrials: ['CT-0508'],
+            manufacturers: ['Carisma Therapeutics', 'Myeloid Therapeutics'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // TARGETED PROTEIN DEGRADERS (PROTACS, MOLECULAR GLUES)
+    // ═══════════════════════════════════════════════════════════════════════════════
+    proteinDegraders = [
+        { id: 'protac-ar', name: 'AR-PROTAC (Bavdegalutamide/ARV-110)',
+            type: 'protac', target: 'Androgen Receptor', e3Ligase: 'Cereblon', linker: 'PEG-based',
+            cancerTypes: ['Metastatic Castration-Resistant Prostate Cancer'],
+            status: 'Phase II', advantages: ['Degrades full-length and variants', 'Overcomes AR mutations', 'Oral bioavailable'],
+            company: 'Arvinas', references: ['ASCO 2023'] },
+        { id: 'protac-er', name: 'ER-PROTAC (Vepdegestrant/ARV-471)',
+            type: 'protac', target: 'Estrogen Receptor', e3Ligase: 'Cereblon', linker: 'Optimized',
+            cancerTypes: ['ER+ Breast Cancer', 'ESR1 mutant'],
+            status: 'Phase III (VERITAC)', advantages: ['Degrades ER including ESR1 mutants', 'Oral SERD replacement', 'Combination with CDK4/6i'],
+            company: 'Arvinas/Pfizer', references: ['SABCS 2023', 'VERITAC-2'] },
+        { id: 'protac-bcl-xl', name: 'BCL-XL PROTAC (DT2216)',
+            type: 'protac', target: 'BCL-XL', e3Ligase: 'VHL', linker: 'Optimized',
+            cancerTypes: ['T-cell lymphoma', 'AML', 'Solid tumors'],
+            status: 'Phase I', advantages: ['Platelet-sparing degradation', 'Selective toxicity'],
+            company: 'Dialectic Therapeutics', references: ['Preclinical publications'] },
+        { id: 'protac-brd4', name: 'BRD4-PROTAC (FHD-609)',
+            type: 'protac', target: 'BRD4', e3Ligase: 'Cereblon', linker: 'Click chemistry',
+            cancerTypes: ['Synovial sarcoma', 'AML'],
+            status: 'Phase I', advantages: ['Deep BRD4 degradation', 'Overcomes BET inhibitor resistance'],
+            company: 'Foghorn Therapeutics', references: ['Ongoing trials'] },
+        { id: 'protac-stat3', name: 'STAT3-PROTAC (KT-333)',
+            type: 'protac', target: 'STAT3', e3Ligase: 'Cereblon', linker: 'Optimized',
+            cancerTypes: ['Liquid and solid tumors with STAT3 activation'],
+            status: 'Phase I', advantages: ['Degrades "undruggable" STAT3', 'Pan-tumor potential'],
+            company: 'Kymera Therapeutics', references: ['ASCO 2023'] },
+        { id: 'protac-irak4', name: 'IRAK4-PROTAC (KT-474)',
+            type: 'protac', target: 'IRAK4', e3Ligase: 'Cereblon', linker: 'Optimized',
+            cancerTypes: ['MYD88-mutant DLBCL', 'Inflammatory conditions'],
+            status: 'Phase II', advantages: ['Blocks TLR/IL-1R signaling', 'MYD88 mutation specific'],
+            company: 'Kymera/Sanofi', references: ['Phase I data 2023'] },
+        { id: 'glue-gspt1', name: 'GSPT1 Molecular Glue (MRT-2359)',
+            type: 'molecular_glue', target: 'GSPT1 (Translation termination)', e3Ligase: 'Cereblon', linker: 'N/A (direct)',
+            cancerTypes: ['MYC-driven cancers', 'SCLC', 'Multiple myeloma'],
+            status: 'Phase I', advantages: ['Novel MOA - translation termination', 'MYC vulnerability'],
+            company: 'Monte Rosa Therapeutics', references: ['Cell 2022'] },
+        { id: 'glue-ikzf2', name: 'IKZF2 (Helios) Degrader (Mezigdomide)',
+            type: 'molecular_glue', target: 'IKZF2/Aiolos/Ikaros', e3Ligase: 'Cereblon', linker: 'N/A',
+            cancerTypes: ['Multiple Myeloma', 'DLBCL'],
+            status: 'Phase III (SUCCESSOR-1)', advantages: ['More potent than lenalidomide', 'Overcomes IMiD resistance'],
+            company: 'BMS', references: ['ASH 2023'] },
+        { id: 'glue-cdk-cyclin', name: 'CDK/Cyclin Molecular Glue',
+            type: 'molecular_glue', target: 'CDK2/Cyclin E', e3Ligase: 'DDB1-CUL4', linker: 'N/A',
+            cancerTypes: ['CDK4/6i resistant breast cancer', 'RB-deficient tumors'],
+            status: 'Preclinical/Phase I', advantages: ['Overcomes CDK4/6i resistance', 'Cyclin E amplification'],
+            company: 'Multiple', references: ['Nature 2023'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // RADIOPHARMACEUTICALS (ALPHA, BETA, AUGER EMITTERS)
+    // ═══════════════════════════════════════════════════════════════════════════════
+    radiopharmaceuticals = [
+        { id: 'rp-psma-617', name: 'Lu-177 PSMA-617 (Pluvicto)',
+            radioisotope: 'Lutetium-177', halfLife: '6.7 days', emissionType: 'beta',
+            targetingMoiety: 'Small molecule PSMA ligand', target: 'PSMA',
+            cancerTypes: ['Metastatic Castration-Resistant Prostate Cancer'],
+            approvalStatus: 'FDA Approved',
+            keyTrials: ['VISION', 'PSMAfore'],
+            advantages: ['Targeted internal radiation', 'Imaging-therapy theranostic', 'Good tolerability'],
+            sideEffects: ['Dry mouth', 'Fatigue', 'Cytopenias', 'Renal (rare)'] },
+        { id: 'rp-dotatate', name: 'Lu-177 DOTATATE (Lutathera)',
+            radioisotope: 'Lutetium-177', halfLife: '6.7 days', emissionType: 'beta',
+            targetingMoiety: 'Somatostatin analogue', target: 'SSTR2',
+            cancerTypes: ['GI NETs', 'Pancreatic NETs', 'Paraganglioma/Pheochromocytoma'],
+            approvalStatus: 'FDA Approved',
+            keyTrials: ['NETTER-1', 'NETTER-2'],
+            advantages: ['PRRT standard of care', 'Good response rates', 'Theranostic with Ga-68'],
+            sideEffects: ['Nausea', 'Fatigue', 'Cytopenias', 'Carcinoid crisis (prevention needed)'] },
+        { id: 'rp-actinium-psma', name: 'Actinium-225 PSMA (Ac-225 PSMA)',
+            radioisotope: 'Actinium-225', halfLife: '10 days', emissionType: 'alpha',
+            targetingMoiety: 'PSMA ligand', target: 'PSMA',
+            cancerTypes: ['mCRPC (Lu-177 refractory)'],
+            approvalStatus: 'Investigational',
+            keyTrials: ['AcTION', 'Various institutional'],
+            advantages: ['Alpha particles - high LET', 'Overcomes Lu-177 resistance', 'DNA double-strand breaks'],
+            sideEffects: ['Xerostomia (significant)', 'Renal toxicity concerns', 'Daughter isotope redistribution'] },
+        { id: 'rp-fapi', name: 'Lu-177/Ac-225 FAPI',
+            radioisotope: 'Lutetium-177 or Actinium-225', halfLife: 'Variable', emissionType: 'beta',
+            targetingMoiety: 'Fibroblast Activation Protein Inhibitor', target: 'FAP (tumor stroma)',
+            cancerTypes: ['Pan-solid tumors', 'Pancreatic', 'Colorectal', 'Sarcoma'],
+            approvalStatus: 'Investigational',
+            keyTrials: ['Multiple Phase I/II'],
+            advantages: ['Broad tumor targeting', 'Stromal targeting', 'Theranostic'],
+            sideEffects: ['Under investigation'] },
+        { id: 'rp-pb212', name: 'Pb-212 DOTAMTATE',
+            radioisotope: 'Lead-212', halfLife: '10.6 hours', emissionType: 'alpha',
+            targetingMoiety: 'Somatostatin analogue', target: 'SSTR2',
+            cancerTypes: ['Neuroendocrine tumors'],
+            approvalStatus: 'Phase II/III (TREASURE)',
+            keyTrials: ['TREASURE'],
+            advantages: ['Alpha particle therapy', 'Shorter half-life (less lodging)', 'AlphaMedix platform'],
+            sideEffects: ['Under investigation'] },
+        { id: 'rp-her2-adc-rad', name: 'Radiolabeled HER2 ADC',
+            radioisotope: 'Various', halfLife: 'Variable', emissionType: 'beta',
+            targetingMoiety: 'Antibody-drug conjugate', target: 'HER2',
+            cancerTypes: ['HER2+ Breast', 'HER2+ Gastric'],
+            approvalStatus: 'Investigational',
+            keyTrials: ['Emerging'],
+            advantages: ['Combines ADC with radioimmunotherapy', 'Bystander effect'],
+            sideEffects: ['Under investigation'] },
+        { id: 'rp-i131-mibg', name: 'I-131 MIBG (Azedra)',
+            radioisotope: 'Iodine-131', halfLife: '8 days', emissionType: 'beta',
+            targetingMoiety: 'Norepinephrine analogue', target: 'Norepinephrine transporter',
+            cancerTypes: ['Pheochromocytoma', 'Paraganglioma', 'Neuroblastoma'],
+            approvalStatus: 'FDA Approved',
+            keyTrials: ['Pivotal trials completed'],
+            advantages: ['Theranostic with imaging', 'Established efficacy'],
+            sideEffects: ['Myelosuppression', 'Thyroid protection needed'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // NOVEL ANTIBODY TECHNOLOGIES
+    // ═══════════════════════════════════════════════════════════════════════════════
+    novelAntibodyTech = [
+        { id: 'ab-trispecific', name: 'Trispecific Antibodies',
+            category: 'antibody', mechanism: 'Engage T-cells + NK-cells + tumor antigen simultaneously',
+            targets: ['HER2xCD3xCD16', 'BCMAxCD3xCD28', 'Other combinations'],
+            cancerTypes: ['Solid tumors', 'Hematologic malignancies'],
+            developmentStage: 'phase_1', keyTrials: ['Multiple early phase'],
+            advantages: ['Multi-mechanism killing', 'Enhanced ADCC + T-cell engagement', 'Costimulation built-in'],
+            challenges: ['Manufacturing complexity', 'Potential for enhanced toxicity'],
+            estimatedTimeline: '3-5 years to approval', companies: ['Sanofi', 'Genentech', 'Xencor'],
+            references: ['Early clinical data 2023'] },
+        { id: 'ab-probody', name: 'Probody (Masked Antibodies)',
+            category: 'antibody', mechanism: 'Masked in normal tissue, activated in TME by proteases',
+            targets: ['CD166', 'CD71', 'PD-L1', 'CD47'],
+            cancerTypes: ['Solid tumors with on-target toxicity concerns'],
+            developmentStage: 'phase_2', keyTrials: ['Praluzatamab ravtansine'],
+            advantages: ['Reduced systemic toxicity', 'Improved therapeutic window', 'Better tolerated'],
+            challenges: ['Protease specificity', 'Heterogeneous activation'],
+            estimatedTimeline: '2-4 years', companies: ['CytomX', 'Amgen'],
+            references: ['ASCO/AACR presentations'] },
+        { id: 'ab-bicycle', name: 'Bicycle Peptides (Constrained Peptides)',
+            category: 'antibody', mechanism: 'Small bicyclic peptides with antibody-like binding',
+            targets: ['Nectin-4', 'EphA2', 'MT1-MMP', 'CD137'],
+            cancerTypes: ['Solid tumors', 'Enhanced tissue penetration needed'],
+            developmentStage: 'phase_2', keyTrials: ['BT5528', 'BT8009'],
+            advantages: ['Small size - rapid tumor penetration', 'Short half-life (less toxicity)', 'Multi-specific potential'],
+            challenges: ['Short half-life (frequent dosing)', 'Manufacturing scale'],
+            estimatedTimeline: '3-5 years', companies: ['Bicycle Therapeutics'],
+            references: ['ASCO 2023 data'] },
+        { id: 'ab-nanobody', name: 'Nanobodies/VHH Antibodies',
+            category: 'antibody', mechanism: 'Single-domain camelid antibodies with enhanced properties',
+            targets: ['Various - modular platform'],
+            cancerTypes: ['Solid tumors', 'CNS tumors', 'Theranostics'],
+            developmentStage: 'phase_2', keyTrials: ['Ciltacabtagene (BCMA nanobody CAR)'],
+            advantages: ['Small size', 'Stability', 'Tissue penetration', 'Multispecific easy'],
+            challenges: ['Immunogenicity potential', 'Short half-life'],
+            estimatedTimeline: '2-4 years', companies: ['Ablynx/Sanofi', 'Multiple'],
+            references: ['Carvykti approval'] },
+        { id: 'ab-conditionally-active', name: 'Conditionally Active Biologics',
+            category: 'antibody', mechanism: 'pH-sensitive or TME-activated antibodies',
+            targets: ['Various - platform technology'],
+            cancerTypes: ['Solid tumors'],
+            developmentStage: 'phase_1', keyTrials: ['Emerging'],
+            advantages: ['Reduced systemic toxicity', 'TME-specific activation'],
+            challenges: ['Conditional activation reliability'],
+            estimatedTimeline: '4-6 years', companies: ['Bioatla', 'Others'],
+            references: ['Platform publications'] },
+        { id: 'ab-multispecific-io', name: 'Multispecific IO Antibodies',
+            category: 'antibody', mechanism: 'Target multiple immune checkpoints simultaneously',
+            targets: ['PD-1xLAG3', 'PD-1xTIM3', 'PD-1xTIGIT', 'CTLA-4xPD-L1'],
+            cancerTypes: ['ICI-resistant tumors', 'Cold tumors'],
+            developmentStage: 'phase_2', keyTrials: ['Multiple'],
+            advantages: ['Single molecule dual checkpoint', 'Enhanced efficacy potential'],
+            challenges: ['Toxicity management', 'Optimal combinations unclear'],
+            estimatedTimeline: '2-4 years', companies: ['Regeneron', 'Roche', 'Multiple'],
+            references: ['Clinical trial data'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // NUCLEIC ACID THERAPEUTICS (mRNA, siRNA, ASO, CRISPR)
+    // ═══════════════════════════════════════════════════════════════════════════════
+    nucleicAcidTherapies = [
+        { id: 'na-mrna-vaccine', name: 'Personalized mRNA Neoantigen Vaccines',
+            category: 'nucleic_acid', mechanism: 'Patient-specific neoantigen mRNA cancer vaccine',
+            targets: ['Personalized neoantigens (up to 34 per patient)'],
+            cancerTypes: ['Melanoma', 'Pancreatic', 'Colorectal', 'NSCLC', 'Head and Neck'],
+            developmentStage: 'phase_2', keyTrials: ['KEYNOTE-942 (mRNA-4157)', 'Autogene cevumeran'],
+            advantages: ['Personalized', 'Rapid manufacturing', 'Strong T-cell responses'],
+            challenges: ['Manufacturing turnaround time', 'Cost', 'Prediction accuracy'],
+            estimatedTimeline: '2-3 years (melanoma adjuvant)', companies: ['Moderna', 'BioNTech', 'Genentech'],
+            references: ['KEYNOTE-942 Nature Medicine 2023'] },
+        { id: 'na-mrna-car', name: 'mRNA-Encoded CAR-T',
+            category: 'nucleic_acid', mechanism: 'LNP-delivered mRNA for in vivo CAR expression',
+            targets: ['CD19', 'Others'],
+            cancerTypes: ['B-cell malignancies'],
+            developmentStage: 'phase_1', keyTrials: ['Emerging'],
+            advantages: ['No viral vectors', 'Transient expression (safety)', 'Repeat dosing'],
+            challenges: ['Transient expression (efficacy)', 'LNP delivery optimization'],
+            estimatedTimeline: '4-6 years', companies: ['Capstan', 'Carisma'],
+            references: ['Preclinical data'] },
+        { id: 'na-sirna-oncology', name: 'siRNA Therapeutics for Cancer',
+            category: 'nucleic_acid', mechanism: 'RNA interference to silence oncogenes',
+            targets: ['KRAS', 'MYC', 'PD-L1', 'STAT3'],
+            cancerTypes: ['Various solid tumors'],
+            developmentStage: 'phase_1', keyTrials: ['DCR-MYC', 'siG12D-LODER'],
+            advantages: ['Target "undruggable" proteins', 'Potent knockdown'],
+            challenges: ['Delivery to tumors', 'Endosomal escape', 'Durability'],
+            estimatedTimeline: '5-7 years', companies: ['Arrowhead', 'Alnylam', 'Dicerna'],
+            references: ['Ongoing development'] },
+        { id: 'na-aso-splice', name: 'Splice-Switching ASOs for Cancer',
+            category: 'nucleic_acid', mechanism: 'Alter splicing of oncogenic or therapeutic targets',
+            targets: ['BCL-X (shift to pro-apoptotic)', 'MDM4', 'STAT3'],
+            cancerTypes: ['Solid tumors', 'Hematologic malignancies'],
+            developmentStage: 'phase_1', keyTrials: ['Limited oncology ASOs'],
+            advantages: ['Precise splice modulation', 'Target non-coding regions'],
+            challenges: ['Tumor delivery', 'Off-target splicing'],
+            estimatedTimeline: '5-8 years', companies: ['Ionis', 'Stoke Therapeutics'],
+            references: ['Preclinical publications'] },
+        { id: 'na-crispr-knockout', name: 'CRISPR-Edited Cell Therapies',
+            category: 'gene_therapy', mechanism: 'CRISPR knockout of checkpoints/TCR in T-cells',
+            targets: ['TRAC', 'PD-1', 'TIM-3', 'LAG-3', 'Beta-2-microglobulin'],
+            cancerTypes: ['Various - platform for cell therapy'],
+            developmentStage: 'phase_1', keyTrials: ['CRISPR-edited CAR-T trials'],
+            advantages: ['Multi-edit capability', 'Precise editing', 'Enhanced CAR-T function'],
+            challenges: ['Off-target editing', 'Regulatory scrutiny'],
+            estimatedTimeline: '3-5 years', companies: ['CRISPR Therapeutics', 'Intellia', 'Caribou'],
+            references: ['CTX110 data'] },
+        { id: 'na-crispr-screen', name: 'CRISPR Screening-Derived Targets',
+            category: 'gene_therapy', mechanism: 'Identify new targets through CRISPR screens',
+            targets: ['Novel synthetic lethalities', 'Immune evasion mechanisms'],
+            cancerTypes: ['Target discovery platform'],
+            developmentStage: 'preclinical', keyTrials: ['Drug development stage'],
+            advantages: ['Unbiased discovery', 'Novel target identification'],
+            challenges: ['Translation to therapeutics', 'Validation'],
+            estimatedTimeline: '5-10 years to drugs', companies: ['KSQ', 'Maze', 'Multiple academic'],
+            references: ['Nature publications'] },
+        { id: 'na-base-editing', name: 'Base Editing Therapeutics',
+            category: 'gene_therapy', mechanism: 'Precise single nucleotide changes without DSBs',
+            targets: ['Oncogenic mutations', 'Regulatory sequences'],
+            cancerTypes: ['Potentially any with targetable mutations'],
+            developmentStage: 'preclinical', keyTrials: ['Emerging'],
+            advantages: ['Precise editing', 'No double-strand breaks', 'Lower off-target'],
+            challenges: ['Delivery', 'Bystander editing'],
+            estimatedTimeline: '5-8 years', companies: ['Beam Therapeutics', 'Verve'],
+            references: ['Technology papers'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // NOVEL DRUG TARGETS (PREVIOUSLY UNDRUGGABLE)
+    // ═══════════════════════════════════════════════════════════════════════════════
+    novelTargets = [
+        { gene: 'MYC', protein: 'c-MYC Transcription Factor',
+            pathway: 'Transcription', targetType: 'oncogene', druggability: 'undruggable_becoming_druggable',
+            cancerTypes: ['Burkitt lymphoma', 'SCLC', 'Neuroblastoma', 'Many solid tumors'],
+            approachesInDevelopment: ['MYC-MAX disruption', 'PROTAC degradation', 'siRNA', 'Aurora A inhibition (destabilize)', 'GSPT1 degraders'],
+            leadCompounds: [
+                { name: 'MRT-2359', stage: 'Phase I', company: 'Monte Rosa' },
+                { name: 'EN-4', stage: 'Preclinical', company: 'Encode Biosciences' }
+            ],
+            rationale: 'MYC drives 70%+ of cancers but lacks druggable pockets - indirect approaches emerging',
+            references: ['Nature Reviews Cancer 2023'] },
+        { gene: 'TP53', protein: 'p53 Tumor Suppressor',
+            pathway: 'Cell cycle/Apoptosis', targetType: 'tumor_suppressor', druggability: 'undruggable_becoming_druggable',
+            cancerTypes: ['>50% of all cancers have p53 alterations'],
+            approachesInDevelopment: ['MDM2 inhibitors (restore WT)', 'p53 reactivators (mutant)', 'Gene therapy', 'Synthetic lethality'],
+            leadCompounds: [
+                { name: 'Milademetan', stage: 'Phase II', company: 'RainOncology' },
+                { name: 'PC14586 (rezatapopt)', stage: 'Phase II', company: 'PMV Pharma' },
+                { name: 'APR-246', stage: 'Phase III', company: 'Aprea' }
+            ],
+            rationale: 'Mutant p53 reactivation and synthetic lethality approaches gaining traction',
+            references: ['Cancer Discovery 2023'] },
+        { gene: 'RAS (pan)', protein: 'All RAS Isoforms',
+            pathway: 'RAS/MAPK', targetType: 'oncogene', druggability: 'undruggable_becoming_druggable',
+            cancerTypes: ['Pancreatic', 'Colorectal', 'NSCLC', 'Melanoma'],
+            approachesInDevelopment: ['Mutation-specific (G12C done, G12D, G12V emerging)', 'Pan-RAS', 'RAS degraders', 'SOS1', 'SHP2'],
+            leadCompounds: [
+                { name: 'MRTX1133 (G12D)', stage: 'Phase I/II', company: 'Mirati' },
+                { name: 'RMC-6236 (pan-RAS)', stage: 'Phase I', company: 'Revolution Medicines' },
+                { name: 'RMC-6291 (G12C degrader)', stage: 'Phase I', company: 'Revolution Medicines' }
+            ],
+            rationale: 'KRAS G12C breakthrough opened the door - now expanding to all RAS',
+            references: ['NEJM 2023 RAS inhibitors'] },
+        { gene: 'ARID1A', protein: 'AT-Rich Interaction Domain 1A',
+            pathway: 'SWI/SNF Chromatin Remodeling', targetType: 'synthetic_lethality', druggability: 'medium',
+            cancerTypes: ['Ovarian clear cell', 'Endometrial', 'Gastric', 'Cholangiocarcinoma'],
+            approachesInDevelopment: ['EZH2 inhibition (synthetic lethal)', 'HDAC inhibition', 'ATR inhibition', 'ARID1B targeting'],
+            leadCompounds: [
+                { name: 'Tazemetostat', stage: 'Approved (EZH2)', company: 'Epizyme' },
+                { name: 'Novel ARID1B inhibitors', stage: 'Preclinical', company: 'Multiple' }
+            ],
+            rationale: 'ARID1A loss creates dependencies that can be therapeutically exploited',
+            references: ['Nature Medicine synthetic lethality'] },
+        { gene: 'SMARCA4', protein: 'BRG1 (SWI/SNF ATPase)',
+            pathway: 'SWI/SNF Chromatin Remodeling', targetType: 'synthetic_lethality', druggability: 'medium',
+            cancerTypes: ['NSCLC', 'Ovarian (SCCOHT)', 'Thoracic SMARCA4-deficient tumors'],
+            approachesInDevelopment: ['CDK4/6 inhibition', 'SMARCA2 inhibition', 'Aurora A inhibition', 'EZH2 inhibition'],
+            leadCompounds: [
+                { name: 'SMARCA2 degraders', stage: 'Phase I', company: 'Foghorn' },
+                { name: 'FHD-286', stage: 'Phase I', company: 'Foghorn Therapeutics' }
+            ],
+            rationale: 'SMARCA4 loss creates dependency on SMARCA2 paralog',
+            references: ['Nature 2023 SMARCA4'] },
+        { gene: 'MTAP', protein: 'Methylthioadenosine Phosphorylase',
+            pathway: 'Methionine Salvage', targetType: 'synthetic_lethality', druggability: 'high',
+            cancerTypes: ['Pancreatic', 'GBM', 'Mesothelioma', 'NSCLC (15% deleted)'],
+            approachesInDevelopment: ['MAT2A inhibition', 'PRMT5 inhibition', 'Dual MAT2A/PRMT5'],
+            leadCompounds: [
+                { name: 'IDE397 (MAT2A)', stage: 'Phase II', company: 'IDEAYA' },
+                { name: 'AMG 193 (PRMT5)', stage: 'Phase I', company: 'Amgen' },
+                { name: 'TNG908 (PRMT5)', stage: 'Phase I', company: 'Tango' }
+            ],
+            rationale: 'MTAP co-deletion with CDKN2A creates metabolic vulnerability',
+            references: ['AACR 2023 MTAP'] },
+        { gene: 'WRN', protein: 'Werner Syndrome RecQ Like Helicase',
+            pathway: 'DNA Repair', targetType: 'synthetic_lethality', druggability: 'high',
+            cancerTypes: ['MSI-H/dMMR cancers (colorectal, endometrial, gastric)'],
+            approachesInDevelopment: ['WRN helicase inhibitors', 'WRN degraders'],
+            leadCompounds: [
+                { name: 'HRO761', stage: 'Phase I', company: 'Novartis' },
+                { name: 'VVD-133214', stage: 'Phase I', company: 'Vividion' }
+            ],
+            rationale: 'MSI-H tumors depend on WRN - synthetic lethal opportunity',
+            references: ['Nature Cancer 2022'] },
+        { gene: 'USP1', protein: 'Ubiquitin-Specific Protease 1',
+            pathway: 'DNA Repair/Fanconi Anemia', targetType: 'synthetic_lethality', druggability: 'high',
+            cancerTypes: ['BRCA1/2 mutant cancers', 'PARP inhibitor resistant'],
+            approachesInDevelopment: ['USP1 inhibitors'],
+            leadCompounds: [
+                { name: 'KSQ-4279', stage: 'Phase I', company: 'KSQ Therapeutics' },
+                { name: 'TNG348', stage: 'Phase I', company: 'Tango Therapeutics' }
+            ],
+            rationale: 'USP1 inhibition synthetic lethal with BRCA deficiency, overcomes PARPi resistance',
+            references: ['Cell 2022'] },
+        { gene: 'POLQ', protein: 'DNA Polymerase Theta',
+            pathway: 'DNA Repair (TMEJ)', targetType: 'synthetic_lethality', druggability: 'high',
+            cancerTypes: ['HRD tumors', 'BRCA-mutant', 'PARP-resistant'],
+            approachesInDevelopment: ['POLQ inhibitors', 'Combination with PARP inhibitors'],
+            leadCompounds: [
+                { name: 'ART4215', stage: 'Phase I', company: 'Artios' },
+                { name: 'Novobiocin (repurposed)', stage: 'Phase I', company: 'Academic' }
+            ],
+            rationale: 'Alternative to PARP inhibition for HRD tumors',
+            references: ['Nature Cancer 2023'] },
+        { gene: 'CD47', protein: 'CD47 "Don\'t Eat Me" Signal',
+            pathway: 'Innate Immunity', targetType: 'immune', druggability: 'high',
+            cancerTypes: ['AML', 'MDS', 'NHL', 'Solid tumors'],
+            approachesInDevelopment: ['Anti-CD47 antibodies', 'SIRPα decoys', 'Bispecifics'],
+            leadCompounds: [
+                { name: 'Magrolimab', stage: 'Phase III', company: 'Gilead' },
+                { name: 'Evorpacept', stage: 'Phase III', company: 'ALX Oncology' }
+            ],
+            rationale: 'Block macrophage checkpoint to enable phagocytosis',
+            references: ['Blood 2023'] },
+        { gene: 'HPK1', protein: 'Hematopoietic Progenitor Kinase 1',
+            pathway: 'T-cell Signaling', targetType: 'immune', druggability: 'high',
+            cancerTypes: ['Solid tumors (IO combinations)'],
+            approachesInDevelopment: ['Small molecule HPK1 inhibitors'],
+            leadCompounds: [
+                { name: 'CFI-402411', stage: 'Phase I', company: 'Treadwell/Pfizer' }
+            ],
+            rationale: 'HPK1 inhibition enhances T-cell activation and anti-tumor immunity',
+            references: ['Science Translational Medicine'] },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // AI-DISCOVERED DRUGS
+    // ═══════════════════════════════════════════════════════════════════════════════
+    aiDiscoveredDrugs = [
+        { id: 'ai-dsp-1181', name: 'DSP-1181',
+            aiPlatform: 'Exscientia', discoveryMethod: 'AI-driven design + active learning',
+            target: 'Serotonin receptor', indication: 'OCD (first; oncology follow)',
+            developmentStage: 'Phase I completed', company: 'Sumitomo Dainippon/Exscientia',
+            timeFromDiscoveryToClinic: '12 months (vs typical 4-5 years)',
+            novelty: 'First AI-designed drug to enter clinical trials' },
+        { id: 'ai-insilico-isk', name: 'INS018_055',
+            aiPlatform: 'Insilico Medicine', discoveryMethod: 'Generative AI + chemistry optimization',
+            target: 'TNIK (Traf2 and Nck-Interacting Kinase)', indication: 'Idiopathic Pulmonary Fibrosis (oncology applications potential)',
+            developmentStage: 'Phase II', company: 'Insilico Medicine',
+            timeFromDiscoveryToClinic: '18 months',
+            novelty: 'Novel target + novel molecule both AI-discovered' },
+        { id: 'ai-recursion-rxc', name: 'REC-994',
+            aiPlatform: 'Recursion', discoveryMethod: 'Phenotypic screening + ML',
+            target: 'GM-CSF signaling', indication: 'CCM (Cerebral Cavernous Malformations)',
+            developmentStage: 'Phase II/III', company: 'Recursion Pharmaceuticals',
+            timeFromDiscoveryToClinic: 'Repurposed - accelerated',
+            novelty: 'AI-enabled drug repurposing' },
+        { id: 'ai-isomorphic', name: 'Isomorphic Labs Compounds',
+            aiPlatform: 'AlphaFold/DeepMind', discoveryMethod: 'Structure prediction + drug design',
+            target: 'Multiple', indication: 'Eli Lilly and Novartis partnerships',
+            developmentStage: 'Preclinical/Early Phase', company: 'Isomorphic Labs/Lilly/Novartis',
+            timeFromDiscoveryToClinic: 'In progress',
+            novelty: 'DeepMind-powered structure-based drug design' },
+        { id: 'ai-absci', name: 'Absci Biologic Designs',
+            aiPlatform: 'Absci Integrated Drug Creation', discoveryMethod: 'Generative AI for antibody design',
+            target: 'Multiple biologic targets', indication: 'Various',
+            developmentStage: 'Preclinical', company: 'Absci/Partners',
+            timeFromDiscoveryToClinic: 'De novo antibody in 6 weeks',
+            novelty: 'Zero-shot generative antibody design' },
+        { id: 'ai-xaira', name: 'Xaira Therapeutics Pipeline',
+            aiPlatform: 'Multiple AI platforms', discoveryMethod: 'Lab-in-the-loop AI drug discovery',
+            target: 'Undisclosed', indication: 'Oncology and beyond',
+            developmentStage: 'Discovery/Preclinical', company: 'Xaira Therapeutics',
+            timeFromDiscoveryToClinic: 'Building pipeline',
+            novelty: '$1B+ AI drug discovery company (2024)' },
+        { id: 'ai-tempus', name: 'Tempus AI-Matched Trials',
+            aiPlatform: 'Tempus', discoveryMethod: 'AI matching patients to trials and treatments',
+            target: 'N/A - Platform', indication: 'Precision matching across cancers',
+            developmentStage: 'Clinical implementation', company: 'Tempus',
+            timeFromDiscoveryToClinic: 'Real-time matching',
+            novelty: 'AI-driven clinical decision support and trial matching' },
+    ];
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // PUBLIC API METHODS
+    // ═══════════════════════════════════════════════════════════════════════════════
+    async getNextGenCellularTherapies(type) {
+        let therapies = this.nextGenCellular;
+        if (type) {
+            therapies = therapies.filter(t => t.type === type);
+        }
+        return therapies;
+    }
+    async getProteinDegraders(targetType) {
+        let degraders = this.proteinDegraders;
+        if (targetType) {
+            degraders = degraders.filter(d => d.type === targetType);
+        }
+        return degraders;
+    }
+    async getRadiopharmaceuticals(emissionType) {
+        let therapies = this.radiopharmaceuticals;
+        if (emissionType) {
+            therapies = therapies.filter(t => t.emissionType === emissionType);
+        }
+        return therapies;
+    }
+    async getNovelAntibodyTech() {
+        return this.novelAntibodyTech;
+    }
+    async getNucleicAcidTherapies() {
+        return this.nucleicAcidTherapies;
+    }
+    async getNovelTargets(druggability) {
+        let targets = this.novelTargets;
+        if (druggability) {
+            targets = targets.filter(t => t.druggability === druggability);
+        }
+        return targets;
+    }
+    async getAIDiscoveredDrugs() {
+        return this.aiDiscoveredDrugs;
+    }
+    async getAllEmergingTherapies() {
+        return {
+            cellularTherapies: this.nextGenCellular,
+            proteinDegraders: this.proteinDegraders,
+            radiopharmaceuticals: this.radiopharmaceuticals,
+            novelAntibodies: this.novelAntibodyTech,
+            nucleicAcidTherapies: this.nucleicAcidTherapies,
+            novelTargets: this.novelTargets,
+            aiDiscoveredDrugs: this.aiDiscoveredDrugs
+        };
+    }
+    async searchEmergingTherapiesForCancer(cancerType) {
+        const lowerCancer = cancerType.toLowerCase();
+        return {
+            cellular: this.nextGenCellular.filter(t => t.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer))),
+            degraders: this.proteinDegraders.filter(d => d.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer))),
+            radiopharmaceuticals: this.radiopharmaceuticals.filter(r => r.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer))),
+            antibodies: this.novelAntibodyTech.filter(a => a.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer))),
+            nucleicAcid: this.nucleicAcidTherapies.filter(n => n.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer))),
+            targets: this.novelTargets.filter(t => t.cancerTypes.some(c => c.toLowerCase().includes(lowerCancer)))
+        };
+    }
+    getStatistics() {
+        const allTherapies = [
+            ...this.novelAntibodyTech,
+            ...this.nucleicAcidTherapies
+        ];
+        const stageBreakdown = {};
+        allTherapies.forEach(t => {
+            stageBreakdown[t.developmentStage] = (stageBreakdown[t.developmentStage] || 0) + 1;
+        });
+        return {
+            totalCellularTherapies: this.nextGenCellular.length,
+            totalProteinDegraders: this.proteinDegraders.length,
+            totalRadiopharmaceuticals: this.radiopharmaceuticals.length,
+            totalNovelAntibodies: this.novelAntibodyTech.length,
+            totalNucleicAcid: this.nucleicAcidTherapies.length,
+            totalNovelTargets: this.novelTargets.length,
+            totalAIDrugs: this.aiDiscoveredDrugs.length,
+            breakdownByStage: stageBreakdown
+        };
+    }
+}
+//# sourceMappingURL=emergingTherapeutics.js.map