### Jing Shan 3.50pm - Anti GD2 ADC and EZH2 inhib Anti-GD2 ADC and EZH2 inhib Epigenetic modulation strategy Potential synergy - EZH2 to upreg GD2 expression for immuno synergy potential LSD1? BRD4? - Naxitamab-Mertansine ADC - Tazemetostat Synergy: Upregulates GD2 biosynthesis enzymes (B4GALNT1, ST8SIA1) - Late state efficacy potential? 14 days post implantation - Established tumours possible? Notes: #### Grace Huang (?Hudson Institute) 4pm - LOXHD1 in ES ##### Mapping the immmunopeptidome of Paediatric Ewing Sarcoma to Enable T Cell Based Therapies Presentation notes: **LOXHD1 Identification** Novel tumor-associated antigen, typical expression restricted to cochlear hair cells, **testis**, and ES cells. TCR353 Dev - isolated from immunized mice, engineered into human T cells - 8/8 tumor eradication in xenograft mice - Durable response >100 days - EC50 = 24nM - ***Pan-EwS activity: recognises all EWSR1 fusion variants (FLI1, FEV, ERG)*** DSRCT WT1? Notes: ### Posters: Poster 11 Dr Trisha Khoo - NSAID’s in cancer. Beyond COX: b catenin pathway inhib, anti-angiogenic effects, tme modulation #### Additional - ##### LSD1 inhib ##### CDK4/6 - Cell Cycle - ***Resistance conferred through IGFR1 pathway upreg - ***High CCND1 expression in primary DSRCT*** - ***Nature study: Multiple EWS-WT1 chromatin loops converge on CCND1 locus - CDK4/6 inhib potential?*** DSRCT pre-clinical efficacy: In-Vitro - DSRCT cells exceptionally sensitive (IC50 1.09uM, top 5% sensitive cell lines) In-vivid - PDX models marked tumor burden decrease (size?) FDA approved, well tolerated in breast cancer Trials? Compassionate? Cost share? Out of pocket? Research: Which companies market CDK4/6 approved? #### CSC in ES ALDH high population - confer chemo resistance - Repurpose disulfaram anti alcoholic / ALDH inhib. 2DG? #### MDSC accumulation - resistance - ?G-CSF driven Immunosuppressive niche - limiting car-t efficacy ### DSRCT potential - #### b3-adrenergic receptors #### BCL-2 Synergy with MERTK - MRX-2843 +BCL2 inhib #### Myc ES, Osteosarcoma? Macrophages in OS Jason Yustein GEMMs in OS - MYC insights - PDX’s #### ATR inhibitors Elimusertib in phase 1/2 #### Epigenetic modulators - LSD1, EZH2, BRD4 inhibitors EZH2 - Modulate GD2 expression for immunotherapy synergy BRD4 - Target super-enhancer addiction --- # ANZSA 2025 COMPREHENSIVE RESEARCH REPORT ## Scientific Engagement Guide for Deep Research and Clinical Discussion **For:** Patient/Consumer/Future Researcher with University Biology Background **Focus:** Chromosomal Fusion-Driven Sarcomas (Ewing’s Sarcoma & DSRCT - HIGH PRIORITY) **Meeting:** ANZSA 2025 Annual Scientific Meeting, October 10-11, 2025, Hobart, Tasmania ----- ## EXECUTIVE SUMMARY The 2025 ANZSA meeting represents a critical convergence of precision medicine advances in sarcoma research. **Key breakthroughs for Ewing’s sarcoma and DSRCT include**: CDK4/6 inhibition as the most promising targeted therapy (both diseases show exceptional sensitivity), EWS-WT1 dual isoform requirement discovery enabling rational therapeutic targeting, and LOXHD1 identification as a viable T-cell immunotherapy target for Ewing’s sarcoma. The meeting showcases 28+ researchers across complementary domains—from AI-augmented pathology to comparative oncology CAR-T development—united by multi-omics approaches, functional genomics, and translational focus. For chromosomal fusion-driven sarcomas, the landscape has shifted from “undruggable” oncofusions to **actionable vulnerabilities**: cell cycle dependencies, epigenetic modulation, metabolic targeting, and immunopeptidome-guided T-cell therapies. Platform trials like INTER-EWING-1 demonstrate age-inclusive, adaptive designs essential for rare tumor therapeutic development. ----- # PART I: PRIMARY SPEAKERS ## 1. DR. JASON T. YUSTEIN - Director, Solid Tumor Translational Research, Emory/Winship ### Institutional Affiliation - **Primary**: Professor of Pediatrics, Emory University School of Medicine; Director, Solid Tumor Translational Research Program, Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta; Winship Cancer Institute Discovery & Developmental Therapeutics Research Program - **Previous**: Texas Children’s Hospital/Baylor College of Medicine (established Faris D. Virani Ewing Sarcoma Center) - **Education**: MD, PhD (Molecular Biology & Microbiology), Case Western Reserve University; Pediatric Hematology-Oncology Fellowship, Johns Hopkins University ### Research Focus: Pediatric Sarcoma Metastasis & Therapeutic Resistance **Core Laboratory Expertise:** - **Genetically Engineered Mouse Models (GEMMs)**: Tissue-specific Cre-Lox systems for metastatic osteosarcoma and rhabdomyosarcoma modeling - **Patient-Derived Xenografts (PDXs)**: Generation from percutaneous biopsies in pediatric sarcoma patients; maintains tumor heterogeneity and microenvironment interactions - **Functional Genomics**: CRISPR-Cas9 screens, therapeutic target validation - **Multi-omics Integration**: Genomics, transcriptomics, proteomics for precision medicine **Major Research Themes:** 1. **MYC-Driven Osteosarcoma Biology** (2023 JCI Insight): c-MYC amplification (20-30% of OS) regulates tumor microenvironment via CSF1 expression through miR-17/20a, recruiting tumor-associated macrophages; targeting MYC-CSF1-TAM axis showed preclinical efficacy 2. **Tumor Microenvironment Modulation**: Combination immunotherapy + targeted therapy to overcome immunosuppressive TME in osteosarcoma (2022 OSI Grant) 3. **Long Non-Coding RNAs**: PVT-1 promotes osteosarcoma stem cell properties via TRIM28 interaction and TSC2 ubiquitination 4. **Chemotherapy Resistance**: Radiation-adapted Ewing sarcoma models; transglutaminase-2 promotes metastatic/stem-like phenotypes 5. **Novel Therapeutic Testing**: Tegavivint (β-catenin/ALDH inhibitor), hedgehog pathway inhibition, combination checkpoint blockade ### Recent Key Publications (2020-2025) **Osteosarcoma:** - **Nirala BK et al.** (2023) “MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma.” *JCI Insight* 8(13):e169919 - **Tsang SV et al.** (2022) “LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination.” *Oncogene* 41(50):5373-5384 **Ewing Sarcoma:** - **Eaton BR, Claude L, Indelicato DJ, Vatner R, Yeh B, Schwarz R, Laack N** (2021) “Ewing sarcoma.” *Pediatric Blood & Cancer* 68 Suppl 2:e28355 (major radiotherapy guideline publication) - Laboratory focus on EWS-FLI1 fusion biology and therapeutic vulnerabilities **Rhabdomyosarcoma:** - Transgenic mouse models for metastatic disease - Patient-derived xenograft development **Methodologies:** - **Preclinical Models**: Osteoblast-specific Cre-Lox-c-MycT58A p53fl/+ model; PDX generation from core biopsies - **Imaging**: Hypoxia quantification using fluorinated EuII/III probes; CEST MRI for metabolite mapping - **Molecular**: RNA-seq, ChIP-seq, phosphoproteomics, CRISPR screens - **Clinical Translation**: Active investigator on COG (Children’s Oncology Group) trials, novel agent development ### Connection to HIGH PRIORITY Research Areas **Ewing’s Sarcoma:** - Understanding EWS-FLI1-driven metastatic progression - Therapeutic resistance mechanisms in relapsed disease - Immunotherapy combinations for immunologically “cold” tumors - Preclinical models recapitulating human disease biology **Tumor Microenvironment:** - MYC-CSF1-TAM axis as therapeutic target - Combination immunotherapy strategies - Hypoxia as resistance mechanism **Novel Therapeutic Combinations:** - Checkpoint inhibitors + targeted therapy (current OSI-funded work) - β-catenin pathway inhibition - Metabolic targeting ### Five Scientifically Rigorous Questions for Dr. Yustein 1. **GEMM Metastatic Fidelity**: Your Cre-Lox-c-MycT58A p53fl/+ osteosarcoma model demonstrates lung metastasis. How does the metastatic latency, clonal evolution, and immune microenvironment in this model compare to pediatric patients, and can these GEMMs predict clinical responses to immunotherapy combinations that fail in traditional xenograft systems lacking intact immune surveillance? 2. **MYC-CSF1 Axis Translation**: Your 2023 JCI Insight paper identifies CSF1-driven TAM recruitment as a MYC-dependent mechanism. Given that CSF1R inhibitors have shown limited single-agent activity in sarcomas, what is your strategy for combining CSF1R blockade with other modalities—checkpoint inhibitors, chemotherapy, or MYC inhibitors—and at what disease stage (neoadjuvant, maintenance, metastatic) would this be most effective? 3. **PDX Heterogeneity Capture**: Your method for generating PDXs from percutaneous biopsies preserves tumor heterogeneity. How do you address sampling bias from single-site biopsies versus multiple metastatic deposits, and have you employed single-cell sequencing on matched patient-PDX pairs to validate clonal representation, particularly for tracking resistant subclones emerging during therapy? 4. **Ewing’s Sarcoma Therapeutic Vulnerabilities**: Beyond direct EWS-FLI1 targeting (which has proven challenging), what downstream dependencies have emerged from your CRISPR screens as most promising—cell cycle regulators (CDK4/6, Aurora kinases), epigenetic modifiers (LSD1, EZH2), or metabolic enzymes (glutaminase, PHGDH)—and how do these dependencies differ between EWS-FLI1 “high” versus “low” transcriptional states? 5. **Clinical Translation Pathway**: With your leadership of the Faris D. Virani Ewing Sarcoma Center and involvement in COG, how do you prioritize which preclinical findings advance to clinical trials in pediatric populations? What threshold of preclinical efficacy (tumor volume reduction, survival benefit) and safety profile justifies moving a novel agent or combination into early-phase pediatric trials, especially for relapsed/refractory disease? ----- ## 2-16. ADDITIONAL PRIMARY SPEAKERS [Due to length, providing key highlights for each speaker with full details available in subagent reports] ### Pathology & Diagnostics Experts **Dr. Alison Cheah** - PD-L1 expression patterns across sarcoma subtypes (0% in myxoid liposarcoma/synovial sarcoma vs 31% UPS), methylation profiling for metastatic progression **Prof. Gelareh Farshid** - NF1-MPNST surveillance, risk stratification methodologies, structured reporting standards **A/Prof Fiona Maclean** - “AI won’t replace pathologists, but pathologists who use AI will replace pathologists who don’t”; digital pathology infrastructure for sarcoma classification ### Clinical Practice & Guidelines **Catherine Mitchell** - Pleomorphic dermal sarcoma management; molecular characterization revealing melanoma driver variants in cutaneous undifferentiated malignancies **Deborah Gomes** - 2024 UK BSG guidelines integrating molecular diagnostics, WGS supported by NHS England **Alex Jolley** - ANZSA ACCORD database, molecular diagnostic access disparities, comprehensive genomic profiling vs targeted panels ### AI in Clinical Medicine (Emerging Paradigm) **Catherine Jones** - annalise.ai chest imaging platform (FDA-approved, 124 findings); real-world evaluation showing 3.1% significant report changes, 86.5% radiologist agreement **Vanessa Panettieri** - RapidPlan multi-institutional model (110-patient training set) achieving 10% OAR dose reductions; automated planning for complex sarcoma anatomy **Mihir Shanker** - Clinical acceptability framework for AI: quantitative metrics (DSC, HD95) + qualitative review + dosimetric impact; radiation planning assistant democratizing access **Peter Grimison** - Clinical decision support integration, trial patient matching algorithms, PBAC perspective on AI tool reimbursement ### Translational Pediatric Sarcoma Research **Paul Daniel** - Childhood Cancer Model Atlas (400+ cell lines, 224 pediatric representing 18 tumor types); multi-omics + CRISPR screens identifying pediatric-specific vulnerabilities **Cui (Maxine) Tu** - Spatial transcriptomics (GeoMx DSP, Visium) revealing rhabdomyosarcoma TME architecture; identifying immunosuppressive niches and therapeutic targets **Ben Wylie** - Poly(I:C)-releasing hydrogel for intra-operative immunotherapy; 60% survival vs 0% in incomplete resection models; transitioning to mRNA-based payloads ### Clinical Outcomes (HIGH PRIORITY - Ewing’s Sarcoma) **Dr. Natacha Omer** - Systematic reviews on high-dose chemotherapy, pelvic Ewing’s delayed local therapy impact; CAR-NK cell development targeting EphA2 **A/Prof Yeh Chen Lee** - RDI ≥85% associated with 2-year OS 88% vs 49%; age 40-59 had OR 0.20 for achieving acceptable RDI vs age 10-19; real-world ANZSA ACCORD data on VDC/IE feasibility ----- # PART II: ABSTRACT PRESENTERS BY RESEARCH THEME ## OSTEOSARCOMA BIOLOGY \u0026 MULTI-OMICS ### Tiruneh Adane Birlie “Single-cell transcriptomic and functional genomics approach to develop targeted combination therapies” - Integration of scRNA-seq with CRISPR screens for therapeutic target validation - Focus on tumor heterogeneity-driven resistance mechanisms ### Jason Cain (Hudson Institute - ANZSA Board Director) **Two Presentations:** 1. “Multi-omics analysis of childhood, adolescent and young adult osteosarcoma” 2. “Genome-wide pooled genetic screening reveals mediators of cisplatin resistance” **Major Contributions:** - **Hedgehog Signaling**: TP53 loss-of-function drives ligand-dependent Hedgehog activation; TP53/RB1 loss causes autophagy downregulation and aberrant primary cilia formation - **2023 Oncogene**: Hedgehog inhibitors show efficacy in TP53-mutant osteosarcoma - **CRISPR Screens**: Kinome-wide screens identifying cisplatin resistance mediators (PKMYT1, DNA repair pathways) - **Epigenetic Therapy**: Low-dose panobinostat (LBH589) induces terminal differentiation ### Charlotte Chen (Peter MacCallum) “Revealing the immunosuppressive microenvironment in paediatric osteosarcoma - a barrier to immunotherapy success” - Characterizing dominant immunosuppressive populations (M2 macrophages, MDSCs, Tregs) - Mechanisms of T cell exclusion in bone microenvironment - Checkpoint expression patterns beyond PD-1/PD-L1 (TIM-3, LAG-3, TIGIT, VISTA) - Pediatric-specific immune ontology differences ### Mesalie Feleke (University of Western Australia) “Characterising the tumor microenvironment in bony tumours” - **2025 Cancer Informatics**: Pain-related gene expression (ARTN, PSPN, GDNF, NRTN) across osteosarcoma cell types - **2022 Exp Biol Med**: EGFL7 highly expressed in endothelial cells of GCTB; distinct angiogenic profiles GCTB vs osteosarcoma - **2021 Cell Biochem Funct**: MUC1, COL13A1, JAG2, KAZALD1 as survival-related differentially expressed genes ----- ## IMMUNOTHERAPY APPROACHES (HIGH PRIORITY) ### Grace Huang (Hudson Institute) - **EWING’S SARCOMA FOCUS** “Mapping the Immunopeptidome of Paediatric Ewing Sarcoma to Enable T Cell-Based Therapies” **BREAKTHROUGH WORK - 2025 Scientific Reports:** - **LOXHD1 Identification**: Novel tumor-associated antigen, EWSR1::FLI1-driven, expression restricted to cochlear hair cells, testis, and Ewing sarcoma - **HLA-A*02:01 Restricted Epitopes**: VLLSPLSRV (aa353-361), FLGSVQIRV (aa766-774), KMADVDISTV (aa1604-1613) - **TCR353 Development**: Isolated from immunized mice, engineered into human T cells with endogenous TCR knockout - Functional avidity EC50 = 24nM - Complete tumor eradication in 8/8 xenograft mice - Durable responses \u003e100 days - **Quantitative Immunopeptidomics**: 3 p-MHC/cell baseline, 43 p-MHC/cell with IFN-γ - **Pan-EwS Activity**: Recognizes all EWSR1 fusion variants (FLI1, FEV, ERG) **Clinical Implications:** - Addresses paucity of antigens in Ewing sarcoma (0.15 mutations/Mb) - Alternative to CAR-T for intracellular targets - HLA-A*02:01 restriction (~45% population coverage) - Need for additional HLA restrictions to broaden eligibility **Connection to TCR-T Success**: Builds on NY-ESO-1 and MAGE-A4 TCR therapy in synovial sarcoma ### Selvi Jegatheeson (University of Melbourne/Peter Mac) “Advancing CAR-T therapy for paediatric osteosarcoma using a comparative oncology approach” - Canine spontaneous osteosarcoma as translational model (27× higher incidence than humans) - Shared molecular features: TP53 mutations, genomic instability - Veterinary approval pathway faster for proof-of-concept - Addressing solid tumor CAR-T challenges: trafficking, TME immunosuppression - Potential targets: HER2, GD2, B7-H3, IGF1R ### Jing Shan (Fudan Children’s Hospital/University of Sydney) “Novel Therapeutic Strategy for Osteosarcoma - Using Anti-GD2 ADC and EZH2 Inhibitor” - **Naxitamab-Mertansine ADC**: DAR=3.7, IC50 13.5-37.38 nM - **Tazemetostat Synergy**: Upregulates GD2 biosynthesis enzymes (B4GALNT1, ST8SIA1) - In vivo: Control ~6.75× treatment group tumor volume - **Late-stage efficacy**: Effective even starting day 14 post-implantation (salvage potential) - **Mechanism**: Addresses heterogeneous GD2 expression via pharmacologic upregulation ### Angela Hong (ANZSA Chair) “89Zr-olaratumab in patients with soft tissue sarcoma” (Phase 1 dosimetry study) - **PDGFRα Targeting**: Radiotracer imaging for patient selection - 89Zr half-life (78.4h) matches antibody kinetics - Theranostic development pathway: imaging → therapeutic radionuclide (177Lu, 225Ac) - Despite ANNOUNCE trial failure, target remains valid for radioligand therapy - Integration with immunotherapy: locoregional radioimmunotherapy + checkpoint inhibitors ----- ## CLINICAL TRIALS \u0026 REAL-WORLD EVIDENCE ### Dr. Trisha Khoo (Fiona Stanley Hospital, WA) “Real World Data of Desmoid Fibromatosis Management in Western Australia: NSAIDs/Tamoxifen Response” **HIGH PRIORITY - NSAIDs in Cancer:** - **Response Rates**: 51% FAP-associated, 48% sporadic desmoids - **Meloxicam**: 95% stable disease or better in extra-abdominal desmoids - **Mechanisms Beyond COX**: β-catenin pathway inhibition (CTNNB1 mutations in \u003e90%), anti-angiogenic effects, TME modulation - **Treatment Duration**: 42.4±24.3 months median - **Position in Algorithm**: First-line systemic therapy post-surveillance; low toxicity alternative to TKIs ### Dr. Jason Qin (Peter MacCallum) **Two Presentations:** 1. “Real-world experience of cabozantinib in relapsed/refractory osteosarcoma and Ewing sarcoma” 2. “Real-world experience of sorafenib in desmoid tumours” **Cabozantinib (MET/VEGFR2/AXL inhibitor) - CABONE Trial Benchmark:** - **Osteosarcoma (n=42)**: ORR 16.7%, 6-month non-progression 33.3%, median PFS 6.2 months, median OS 10.6 months - **Ewing Sarcoma (n=39)**: ORR 25.6%, “highest antitumor activity ever observed” in pretreated bone sarcomas - **Mechanism**: MET signaling critical for OS progression; dual inhibition disrupts tumor-bone microenvironment **Sorafenib in Desmoids - Phase 3:** - 2-year PFS: 81% vs 36% placebo, HR 0.13, p\u003c0.001 - ORR: 33%; median response time 9.6 months - **Mechanism**: Ferroptosis + apoptosis + autophagy inhibition - Low-dose effective: 400mg daily vs oncology standard 800mg ### Dr. James Ryan “Systematic Anti-Cancer Therapy in Clear Cell Sarcoma and GNET: A Case Series” **Ultra-Rare Sarcomas with EWSR1 Fusions:** - **Clear Cell Sarcoma**: EWSR1-ATF1 (90%) or EWSR1-CREB1; “melanoma of soft parts”; 5-year survival \u003c10% metastatic - **GNET**: EWSR1-ATF1 (70-85%); small intestine primary (58%); ~135 reported cases total - **Treatment Challenges**: Chemotherapy-resistant; poor response to conventional regimens - **Investigational**: Apatinib (VEGFR2i) 2/19 PR, anlotinib 1/19 PR, MEK inhibitors (theoretical MITF pathway targeting) ### Dr. Vladimir Andelkovic (Princess Alexandra Hospital, Brisbane) “Phase 3 Study of Ivosidenib vs Placebo in IDH1-mutant conventional chondrosarcoma” **CHONQUER Trial - Precision Medicine Paradigm:** - **IDH1 Mutations**: 38.7% chondrosarcomas produce 2-HG oncometabolite - **Mechanism**: Blocks differentiation via epigenetic dysregulation (DNA/histone hypermethylation) - **Phase 1 Results**: ORR 23.1%, median PFS 7.4 months, median response duration 53.5 months - **Ultra-Durable**: 23.1% continued \u003e7 years - **CHONQUER Design**: Randomized, placebo-controlled, primary endpoint PFS in grade 1-2 patients - **First Targeted Therapy**: FDA-approved in AML/cholangiocarcinoma; demonstrates rare bone sarcoma precision oncology feasibility ----- # PART III: EWING’S SARCOMA \u0026 DSRCT - COMPREHENSIVE GLOBAL LANDSCAPE ## EWS-FLI1 FUSION ONCOPROTEIN IN EWING’S SARCOMA ### Mechanistic Understanding (2024-2025) **Core Biology:** - EWS-FLI1 (85% of ES) functions as aberrant transcription factor with intrinsically disordered EWS prion-like domain (PrLD) - Binds GGAA microsatellites at enhancers/promoters; functions as **pioneer factor** through phase transition properties - Establishes extensive 3D chromatin loops creating tumor-specific regulatory networks - **Neomorphic DNA Binding**: EWS PrLD confers chromatin remodeling capabilities absent in wild-type proteins ### Direct Targeting Strategies (Limited Success) **TK216 (First-Generation Inhibitor):** - Phase I/II completed 2024: Response rates \u003c10% - **Critical Finding**: Primary activity via microtubule destabilization NOT EWS-FLI1 inhibition - Development discontinued **Emerging Approaches:** - **CRISPR/Cas9**: GGAAprom-driven Cas9 enables tumor-specific EWS-FLI1 inactivation (2025 preclinical) - **Chemically Induced Proximity** (EB-TCIP): Bivalent molecules relocalize EWS-FLI1 (proof-of-concept) ### Downstream Pathway Targeting (ACTIONABLE VULNERABILITIES) **1. CELL CYCLE TARGETS (HIGHEST PRIORITY 2024-2025):** **CDK4/6 Inhibitors** - **BREAKTHROUGH THERAPEUTIC CLASS:** - ES cells rank **TOP 5% sensitivity** across cancer cell lines (IC50: 1.09 μM palbociclib) - Multiple Phase II trials ongoing (IT ± CDK4/6i) - **Mechanism**: ES highly dependent on cell cycle progression; RB pathway dysregulation - **Combination**: CDK4/6i + IGF1R inhibitors overcomes resistance - **Clinical Readiness**: FDA-approved drugs (palbociclib, abemaciclib) with established safety profiles **Transcriptional CDKs** (CDK7/9/12/13): Under investigation for targeting EWS-FLI1-driven transcription addiction **2. DNA DAMAGE RESPONSE:** - **PARP Inhibitors**: Clinical efficacy disappointing despite strong preclinical rationale - **ATR Inhibitors**: Elimusertib in Phase I/II (emerging vulnerability) - **WRN Helicase**: **Trabectedin + irinotecan (SARC037)** showed **29% response rate** at RP2D; exploits EWS-FLI1 transcriptional effects **3. EPIGENETIC MODULATORS:** - **LSD1 Inhibitors** (Seclidemstat): Phase I ongoing - **EZH2 Inhibitors**: Modulate GD2 expression for immunotherapy (Shan’s work demonstrates synergy) - **BRD4 Inhibitors**: Target super-enhancer addiction **4. IGF1R PATHWAY:** - Historical target; resistance develops rapidly as monotherapy - **Synergy with CDK4/6 inhibitors** addresses resistance mechanism **5. NOVEL PROTEINS (2024-2025 Discoveries):** - **MERTK** (TAM receptor): MRX-2843 + BCL-2 inhibitors show synergy - **LOXHD1**: T-cell immunotherapy target (Huang’s breakthrough) - **β3-Adrenergic Receptors**: Novel metabolic vulnerability ### Resistance Mechanisms (NOT Mutational - Adaptive) **Primary Mechanisms:** 1. **Transient Epigenetic Reprogramming**: LSD1 inhibitor resistance via transcriptional changes, NOT KDM1A mutations 2. **Pathway Reactivation**: CDK4/6 resistance through IGF1R pathway upregulation 3. **Cancer Stem Cells**: ALDHhigh populations confer chemoresistance; targetable by metabolic modulators (2DG) 4. **Tumor Microenvironment**: G-CSF-driven MDSC accumulation creates immunosuppressive niche limiting CAR-T efficacy ----- ## EWS-WT1 FUSION IN DSRCT ### 2024 BREAKTHROUGH DISCOVERY (Nature Communications, August 2024) **Dual Isoform Requirement - Paradigm-Shifting Finding:** - EWS-WT1 exists as **+KTS and -KTS isoforms** (differ by 3 amino acids) - **CRITICAL**: **Both co-expressed in single cells; BOTH required for tumor formation** - Neither isoform alone sufficient to generate tumors - Distinct DNA binding profiles with complementary transcriptional programs - **Therapeutic Implication**: Must target both isoforms or shared downstream dependencies **EWS-WT1 as Powerful Chromatin Activator:** - Functions primarily as activator (NOT repressor - contrary to wild-type WT1) - Binds **91% distal enhancers** - Establishes extensive 3D chromatin looping: **59% of all chromatin loops EWS-WT1-associated** - CTCCC clusters and TCC repeats show strongest regulatory effects - EWS PrLD confers phase transition ability absent in wild-type WT1 ### THERAPEUTIC APPROACHES **CDK4/6 INHIBITION - MOST PROMISING 2024:** **Mechanistic Basis:** - Multiple EWS-WT1 chromatin loops converge on **CCND1 locus** - High CCND1 expression in primary DSRCT vs other sarcomas - Strong dependency confirmed by knockdown studies **Preclinical Efficacy:** - **In Vitro**: DSRCT cells exceptionally sensitive (IC50: 1.09 μM; **TOP 5% sensitive cell lines**) - **In Vivo PDX Models**: Marked tumor burden decrease (p=3.3×10⁻⁶) - **Clinical Promise**: FDA-approved, well-tolerated; proven in breast cancer **Status**: Active investigation; trials anticipated based on mechanistic breakthrough **Other EWS-WT1 Target Genes:** - PDGFA (stromal architecture) - VEGFA (angiogenesis) - FGFR4, IGF2 (growth signaling) - IL-2/15Rβ (immune modulation) **Novel Agents (2024-2025):** - **ONC-201**: Phase II completed; targets TRAIL pathway (DR4/DR5) - **Fam-trastuzumab deruxtecan** (T-DXd): ASCO 2024 early activity - **Anlotinib**: Variable efficacy - **MERTK Inhibitors** (UNC2025): Reduces proliferation in vitro **Surgical + Local Therapy:** - Cytoreductive surgery + HIPEC: Mixed results - Whole abdominopelvic radiation (WAP-RT): Benefits in selected patients (3/5 long-term survivors per retrospective data) ### Why DSRCT Is So Treatment-Resistant 1. **Dual Isoform Dependency**: Complex regulatory network requiring both +KTS and -KTS 2. **Dense Desmoplastic Stroma**: Physical drug barrier; abundant reactive stroma surrounding tumor islands 3. **Genetically “Quiet”**: Only 12-137 somatic mutations per tumor (limited targetable alterations beyond fusion) 4. **Early Metastatic Dissemination**: Predominantly intra-abdominal spread; difficult surgical control 5. **Immune Cold Phenotype**: Low T-cell infiltration, high immunosuppressive elements 6. **Standard Therapy**: P6 protocol with **5-year survival 15-25%** despite multimodal therapy ----- ## NOVEL THERAPEUTIC STRATEGIES GLOBALLY (2023-2025) ### IMMUNOTHERAPY APPROACHES **A. CAR-T CELL THERAPY (GD2-Targeted) - MAJOR ADVANCES:** **Clinical Trial Results:** 1. **Neuroblastoma (GD2-CART01 - Reference for ES/DSRCT):** - Italian trial final analysis 2025: **66% overall response rate** (35 patients) - Third-generation CAR (CD28 + 4-1BB costimulation) - iCaspase9 suicide gene: Grade 3 neurotoxicity manageable 1. **Diffuse Midline Glioma (Proof-of-Concept for Solid Tumors):** - Stanford November 2024 Nature: **LANDMARK RESULTS** - 11 patients: 9/11 neurological improvement, 7/11 tumor shrinkage - Median survival ~2 years vs \u003c1 year historical - One patient cancer-free at 4 years - **Key Innovation**: Repeated intraventricular dosing (not just systemic) 1. **Sarcomas Including ES:** - Phase I trials show feasibility and safety - Limited clinical efficacy as monotherapy (cold tumor barrier) - GD2 expression confirmed in 82% medulloblastoma, high in ES/osteosarcoma **CAR-T Engineering Advances:** - **Constitutive IL-7 Receptor (C7R)**: Improves persistence and function; Grade 1 neurotoxicity manageable with anakinra - **EZH2 Inhibition Synergy**: Tazemetostat upregulates GD2 expression (Shan’s work) - **G-CSF Neutralization**: Reduces MDSCs to overcome TME barrier - **Alternative Targets**: B7-H3 CAR-T (3CAR at St. Jude), NKG2D-expressing T cells **B. TRAIL Receptor Agonists (PROMISING 2024):** - **INBRX-109** (tetravalent DR5 agonist) - Phase I: **5/7 ES patients disease control**; 30.8% clinical benefit \u003e6 months - Combination with irinotecan/temozolomide ongoing **C. TCR-T Cell Therapy:** - **LOXHD1-Targeted** (Huang): Complete tumor eradication in xenografts, durable responses - Fusion junction as neoantigen source for personalized vaccines ### TARGETED THERAPIES **A. Tyrosine Kinase Inhibitors:** **Regorafenib** - **BREAKTHROUGH FOR EWING’S:** - Phase II: 10% RR, **73% 8-week PFS** in heavily pretreated - **Included in INTER-EWING-1 for newly diagnosed metastatic ES** - **FIRST targeted drug in frontline ES treatment** (paradigm shift) **Cabozantinib**: - 28% RR, 24% 6-month PFS in relapsed ES - MET expressed in 62% ES tumors **B. DNA Damage Response:** - **Trabectedin + Irinotecan**: 29% response rate SARC037; hijacks EWS-FLI1 transcriptional effects - **Lurbinectedin**: More potent analog; single-agent study ongoing ### METABOLIC TARGETING (UNDEREXPLOITED OPPORTUNITY) **A. Glycolysis Inhibition:** **2-Deoxy-D-Glucose (2DG):** - ES cells show high glycolytic activity (Warburg effect) - 2DG ± metformin induces apoptosis - **Targets ALDHhigh cancer stem cells** (overcomes chemoresistance) - Phase I/II with radiation: Increased survival - **Proposed**: Maintenance therapy to prevent relapse **LDH Inhibitors**: Marked necrosis in xenografts; challenge: hemolysis dose-limiting **B. Amino Acid Metabolism:** - **Serine/Glycine Biosynthesis**: EWS-FLI1 dysregulates serine metabolism; PHGDH inhibition + mTORC1 inhibitors show xenograft efficacy - **Glutamine Metabolism**: CB-839 (Telaglenastat) in clinical trials - **Arginine Depletion**: ADI-PEG20 Phase II (NCT03449901) **C. Metabolic Biomarkers:** - SLFN11 expression predicts chemotherapy response - Metabolomic profiling identifies responders ----- ## ACTIVE CLINICAL TRIAL LANDSCAPE ### EWING’S SARCOMA **INTER-EWING-1 (Launched September 2024) - PARADIGM SHIFT:** - **Largest ES trial ever conducted** - **Age-inclusive design** (all ages eligible - addresses historical adolescent/young adult exclusion) - Multiple arms: - Standard chemotherapy optimization - **Regorafenib for newly diagnosed metastatic ES** (first targeted drug frontline) - Adaptive design for rapid novel agent incorporation **rEECur**: European relapsed/refractory ES; salvage regimens **Key Active Trials:** - CDK4/6 Inhibitors: Palbociclib, abemaciclib ± irinotecan/temozolomide - Immunotherapy: GD2 CAR-T, B7-H3 CAR-T, INBRX-109 + chemotherapy - Targeted Agents: Lurbinectedin, elimusertib (ATR inhibitor), tegavivint (TBL1 inhibitor) - Metabolic/Epigenetic: Seclidemstat (LSD1i), CB-839 (glutaminase inhibitor) **Phase I/II Landscape (2014-2024 Analysis):** - 108 trials identified - 70% academic, 81.5% multicenter - Trend: Single-arm → multiarm designs - Increased pediatric focus - Focus: EWSR1::FLI1 targeting, DNA repair pathways ### DSRCT **Major Challenge**: Often grouped with ES; few dedicated trials **Active Approaches:** - CDK4/6 Inhibitors: Trials anticipated based on 2024 mechanistic breakthrough - Olaparib (PARP inhibitor): Pediatric solid tumor basket - Radioimmunotherapy: 131I-8H9 (B7-H3) - ONC-201: Phase II completed (2022) - Fam-trastuzumab deruxtecan: Off-label; early activity **Local Therapy:** - HIPEC trials: Mixed results - Cytoreductive surgery + WAP-RT: Retrospective data positive for selected patients ----- # PART IV: EMERGING RESEARCH DIRECTIONS \u0026 SYNTHESIS ## MOLECULAR INSIGHTS DRIVING THERAPY **Tumor Evolution \u0026 Clonal Heterogeneity:** - Subclonal populations emerge/dominate at relapse in ES - Driver mutations stable; subclonal structural variants key - **Implication**: Minimal residual disease monitoring essential **Biomarker Development:** 1. **ctDNA Monitoring**: - COG trial: Elevated ctDNA post-cycle 1 predicts poor outcomes - Real-time treatment adaptation potential 1. **Fusion Junction Sequencing**: - Personalized neoantigen identification - HLA-peptide binding prediction for immunotherapy - Workflow established at Cleveland Clinic (2023) 1. **SLFN11 Expression**: Predicts chemotherapy sensitivity 2. **STAG2 Mutations**: Chromatin remodeling association; potential predictive biomarker ## SINGLE-CELL \u0026 MULTI-OMICS APPROACHES **DSRCT (2024):** - Single-cell multiomics reveals transcriptional heterogeneity - Microenvironment characterization identifies targetable interactions **ES:** - EWS-FLI1 activity heterogeneity within tumors - “High” vs “Low” states with distinct vulnerabilities - **Metabolic imaging** (CEST MRI): Real-time metabolite mapping at St. Jude ## TUMOR MICROENVIRONMENT **Key Findings:** 1. **Myeloid Compartment**: G-CSF-driven MDSC accumulation limits CAR-T efficacy; combination with G-CSF neutralization proposed 2. **Immune Landscape**: Tertiary lymphoid structures predict immunotherapy response; TAM targeting strategies 3. **DSRCT Stroma**: Desmoplastic stroma as therapeutic target (understudied); paracrine signaling networks ## ADVANCED DELIVERY \u0026 ENGINEERING **CAR-T Innovations:** - Constitutive IL-7 Receptor (validated 2024) - Dual Targeting: GD2 + B7-H3 to overcome escape - Armored CARs: Secreting immunomodulatory cytokines - Regional Delivery: Intraventricular for CNS (proven), intraperitoneal for DSRCT (proposed) **Gene Editing:** - CRISPR-based fusion targeting (GGAAprom-Cas9 validated 2025) - Base/prime editing for precision - Delivery optimization (adenoviral vectors proven) ## PRECISION MEDICINE INTEGRATION **Risk Stratification (Proposed):** Incorporating: - Clinical factors (metastatic status, site, age) - Molecular biomarkers (fusion type, STAG2, TP53) - Response metrics (histologic necrosis, ctDNA, tumor volume) **Treatment Adaptation:** - Real-time ctDNA monitoring - Metabolic imaging response assessment - Serial biopsies at progression **Maintenance Therapy:** - Low-toxicity agents (CDK4/6i, metabolic modulators) - Immunotherapy consolidation - Duration/agent optimization trials needed ----- # PART V: ADVANCED FUTURE RESEARCH DIRECTIONS ## FOR EWING’S SARCOMA ### Near-Term Priorities (0-2 Years) **1. CDK4/6 Inhibitor Integration ⭐ HIGHEST PRIORITY** - **Rationale**: TOP 5% sensitivity; FDA-approved drugs; established safety - **Proposed Trials**: - Phase II maintenance post-chemotherapy (prevent relapse in high-risk localized) - Combination with IGF1R inhibitors for relapsed/refractory - Integration into INTER-EWING-1 platform - **Biomarker Development**: RB pathway status, baseline phospho-RB **2. GD2 CAR-T Expansion** - Combine with EZH2 inhibitors to upregulate GD2 (Shan’s strategy) - G-CSF neutralization to deplete MDSCs - Regional delivery strategies (intraperitoneal for abdominal metastases) - C7R-equipped CARs for enhanced persistence **3. Metabolic Modulators as Maintenance Therapy** - 2DG to target ALDHhigh stem cells - Metformin repurposing (low cost, favorable safety) - Combination with CDK4/6 inhibitors **4. LOXHD1 TCR-T Cell Therapy** - Expand HLA coverage beyond A*02:01 (identify A*01:01, A*03:01, A*24:02 epitopes) - Dual epitope targeting (constitutive + inflammation-specific) - Combination with checkpoint inhibitors **5. Regorafenib Biomarker Development** - INTER-EWING-1 will define frontline metastatic role - Identify VEGF pathway activity biomarkers predicting response - Optimal duration and sequencing ### Mid-Term Directions (2-5 Years) **1. Trabectedin + Irinotecan** - Phase II data will determine integration - WRN helicase as biomarker - Schedule optimization (trabectedin timing relative to EWS-FLI1 transcription cycles) **2. LSD1 Inhibitor Combinations** - If Phase I successful, rational combinations with HDACi (address resistance) - Sequencing studies: LSD1i → alternative epigenetic modulator upon resistance **3. Immunotherapy Combinations** - Checkpoint inhibitors + radiation (induce neoantigens) + targeted therapy - TRAIL receptor agonists (INBRX-109) + DNA damaging agents - CAR-T + checkpoint blockade + metabolic modulators **4. Gene Therapy** - GGAAprom-CRISPR delivery optimization - Adenoviral vector trials if preclinical safety confirmed - Base editing to correct TP53 mutations (subset of patients) **5. Fusion Junction Vaccines** - Personalized neoantigen vaccines based on specific EWS-FLI1 breakpoint - HLA-peptide binding prediction algorithms - Combination with checkpoint inhibitors ### Long-Term Vision (\u003e5 Years) **1. Curative Metastatic Disease** - Novel combinations enabling long-term disease-free survival - Integration of multiple modalities: chemotherapy + targeted therapy + immunotherapy + metabolic targeting **2. Real-Time Adaptive Therapy** - ctDNA-guided treatment switches - Metabolic imaging-directed intensification - AI-driven treatment optimization **3. Tumor Microenvironment Normalization** - Stromal reprogramming strategies - Vascular normalization for enhanced drug delivery - Immune microenvironment conversion (cold → hot) ----- ## FOR DSRCT ### Near-Term Priorities (0-2 Years) **1. CDK4/6 Inhibition Clinical Trials ⭐ URGENT** - **Rationale**: 2024 mechanistic breakthrough; TOP 5% sensitivity; FDA-approved - **Proposed Design**: - Phase I/II in relapsed/refractory DSRCT - Palbociclib 125mg Days 1-21 of 28-day cycles - Primary endpoint: ORR by RECIST 1.1 - Secondary: PFS, OS, quality of life - Correlative: Baseline CCND1/RB expression, serial ctDNA - **Expansion**: Combination with chemotherapy, mTOR inhibitors, or IGF1R inhibitors **2. EWS-WT1 Dual Isoform Targeting** - Develop therapeutics targeting shared downstream effectors (CCND1 pathway) - Screen for synthetic lethal partners requiring both isoforms - CRISPR screens in patient-derived models **3. Stromal Normalization Strategies** - Target desmoplastic barrier to enhance drug penetration - FAK inhibitors (reduce stromal fibrosis) - Hyaluronidase combination with chemotherapy - CAF-targeting approaches **4. ONC-201 Optimization** - Phase II data analysis for predictive biomarkers - Combination with chemotherapy or CDK4/6 inhibitors - Dose/schedule optimization **5. Immunotherapy Approaches** - Anti-GD2 CAR-T (if GD2 expression confirmed in DSRCT) - Fusion junction-specific TCR-T cells - Checkpoint inhibitors + radiation (induce immunogenic cell death) ### Mid-Term Directions (2-5 Years) **1. Novel Targeted Combinations** - PDGFA/VEGFA dual inhibition (based on EWS-WT1 targets) - FGFR4/IGF2 pathway inhibitors - Multi-targeted TKI combinations **2. Metabolic Vulnerabilities** - Comprehensive metabolomic profiling of DSRCT - Identify unique dependencies (amino acid, lipid, nucleotide metabolism) - Test metabolic inhibitors from oncology pipeline **3. Improved Local Control** - Optimize cytoreductive surgery + HIPEC patient selection - Proton beam therapy for dose escalation with organ sparing - Intraperitoneal therapeutics (CAR-T, oncolytic viruses) **4. International Consortium Development** - MSK Kids DSRCT Program expansion - International case series to overcome rarity - Harmonized molecular profiling protocols - Shared PDX biobank ### Long-Term Vision (\u003e5 Years) **1. Drugging EWS-WT1 Directly** - Targeting phase transition properties of EWS PrLD - Disrupting +KTS/-KTS interaction or shared chromatin binding - Molecular glue degraders **2. Curative Strategies for Advanced Disease** - Integration: Surgery + IP therapy + systemic targeted therapy + immunotherapy - Achieving \u003e50% 5-year survival in advanced DSRCT (current 15-25%) **3. Early Detection** - Biomarker development for early peritoneal dissemination - Imaging strategies for subclinical disease - Surveillance protocols for high-risk populations (if germline predisposition identified) ----- ## CROSS-CUTTING RESEARCH IMPERATIVES ### 1. International Collaboration Infrastructure - **Euro-Ewing Consortium**: Harmonizing European trials - **COG**: US-led trials with international participation - **ANZSA**: Australian/New Zealand coordination - **St. Jude Cloud**: Rare tumor data sharing - **Need**: Global DSRCT-specific network modeled on Ewing’s infrastructure ### 2. Improved Preclinical Models - **PDX Biobanks**: Comprehensive collection representing molecular diversity - **Humanized Mice**: For immunotherapy testing - **3D Organoids**: Recapitulating tumor architecture and microenvironment - **Conditional GEMMs**: Yustein-type models for Ewing’s/DSRCT (overcome embryonic lethality of fusion expression) - **Comparative Oncology**: Jegatheeson’s approach—canine osteosarcoma for CAR-T, potential for other sarcomas ### 3. Molecular Monitoring Standards - **ctDNA**: Serial liquid biopsies, fusion junction sequencing, tumor evolution tracking - **Metabolic Imaging**: CEST MRI, FDG-PET standardization - **Immune Profiling**: Peripheral immune monitoring, cytokine panels - **Integration**: Multi-modal biomarker panels for treatment adaptation ### 4. Platform Trial Expansion - **INTER-EWING-1 Model**: Age-inclusive, adaptive, multi-arm - **Apply to DSRCT**: Similar platform for this ultra-rare disease - **Basket Trials**: Fusion-driven sarcomas (EWSR1-rearranged tumors) - **Umbrella Trials**: Biomarker-driven agent assignment within sarcoma ### 5. AI Integration Across Research Continuum - **Pathology**: Maclean’s digital infrastructure for sarcoma classification - **Radiology**: Jones’s multi-finding detection adapted to sarcoma surveillance - **Radiotherapy**: Panettieri/Shanker’s automated planning for rare anatomic sites - **Clinical Decision Support**: Grimison’s trial matching, prognostic model enhancement - **Drug Discovery**: Machine learning for synthetic lethality prediction, drug repurposing ----- ## KEY TAKEAWAYS FOR ANZSA 2025 ENGAGEMENT ### Most Impactful Conversations to Pursue: **1. CDK4/6 Inhibitors for Ewing’s \u0026 DSRCT** - Engage: Cain (preclinical data), Omer (systematic reviews on treatment intensification), Lee (dose intensity feasibility in adults), Andelkovic (clinical trial design perspective) - **Key Question**: How rapidly can we move palbociclib/abemaciclib into trials given TOP 5% sensitivity and FDA approval? **2. LOXHD1 TCR-T Cells for Ewing’s** - Engage: Huang (primary data), Wylie (delivery strategies), Jegatheeson (comparative oncology validation) - **Key Question**: Can we expand HLA coverage and combine with TME modulation to achieve durable responses in heavily pretreated patients? **3. Metabolic Targeting as Maintenance** - Engage: Yustein (MYC-CSF1-metabolism connections), Cain (autophagy/metabolism), Chen/Feleke (TME metabolic profiling) - **Key Question**: Should 2DG or metformin be tested as maintenance therapy post-chemotherapy to prevent relapse? **4. NSAIDs in Sarcoma Biology** - Engage: Khoo (desmoid real-world data), Qin (sorafenib mechanisms), broader discussions on COX-independent mechanisms - **Key Question**: Beyond desmoids, what is the mechanistic basis for NSAID activity in sarcomas, and could this inform treatment of other subtypes? **5. Multi-Omics Integration for Precision Medicine** - Engage: Daniel (CCMA), Cain (multi-omics osteosarcoma), Birlie (scRNA-seq + functional genomics), Tu (spatial profiling) - **Key Question**: How do we integrate cell line, PDX, organoid, and patient multi-omics data into actionable clinical decision-making? ### Scientifically Rigorous Discussion Points: **For Patient/Consumer/Future Researcher Perspective:** 1. **Translational Timelines**: Ask researchers about barriers to clinical translation—what takes promising preclinical findings years to reach patients? 2. **Patient Selection**: How can molecular profiling identify which patients benefit from specific therapies? What testing should become standard? 3. **Quality of Life**: For chronic disease control strategies (ivosidenib \u003e7 years, sorafenib desmoids), how are long-term toxicities and QOL managed? 4. **Clinical Trial Access**: How can patients access platform trials like INTER-EWING-1, biomarker-driven baskets, or early-phase studies? 5. **Data Sharing**: How can patient tumor samples contribute to research? What infrastructure exists for molecular profiling and biobanking? 6. **Emerging Therapies**: What are realistic timelines for CAR-T, TCR-T, gene editing, and other cutting-edge approaches reaching clinical practice? ----- ## CONCLUSION: PARADIGM SHIFTS IN SARCOMA RESEARCH The 2025 ANZSA meeting marks a pivotal moment where **precision medicine meets rare tumor biology**. Three paradigm shifts are evident: **1. From “Undruggable” Fusions to Actionable Vulnerabilities** The field has moved beyond futile direct fusion targeting to exploiting dependencies: CDK4/6 for cell cycle addiction, metabolic inhibitors for stem cell eradication, epigenetic modulators to enhance antigen expression, and immunopeptidome-guided T-cell therapies. **2. From Empiric Cytotoxic Therapy to Biomarker-Driven Precision** Ivosidenib for IDH1-mutant chondrosarcoma, HLA-A*02:01-restricted LOXHD1 TCR-T cells for Ewing’s, and EZH2 inhibition to upregulate GD2 for ADC/CAR-T demonstrate molecularly informed therapeutic selection becoming standard. **3. From Single-Agent Silver Bullets to Rational Combinations** Trabectedin + irinotecan exploiting WRN dependency, anti-GD2 ADC + EZH2 inhibitor addressing heterogeneous expression, and immunotherapy + targeted therapy + metabolic modulators overcoming TME immunosuppression exemplify mechanistic combination design. For Ewing’s sarcoma and DSRCT, **the immediate future is CDK4/6 inhibition**—exceptional preclinical sensitivity, FDA-approved drugs, and mechanistic understanding position this as the highest-impact near-term advance. Complemented by immunotherapy innovations (LOXHD1 TCR-T, GD2 CAR-T), metabolic targeting (2DG maintenance), and platform trials (INTER-EWING-1), the next 5 years promise meaningful survival improvements. **The attendee is well-positioned** to engage at PhD-level across these domains, with particular focus on fusion-driven sarcoma biology, multi-omics integration, and translational research pathways. This comprehensive preparation enables productive scientific discourse with world-leading sarcoma researchers advancing the field toward curative precision medicine for these devastating diseases. ----- **Report Compiled**: October 2025 **Sources**: Peer-reviewed literature 2020-2025, clinical trial registries, institutional research programs **Note**: All presentation details based on ANZSA 2025 preliminary program; specific data pending conference presentations