Pan Pantziarka

The fourth Paediatric Therapeutic Development Workshop focused on osteosarcoma, the most common primary bone cancer in children and young adults. Current treatment of osteosarcoma comprises surgery and chemotherapy. Outcome has shown very little improvement over the last four decades and there are substantial unmet needs including improving survival, especially in metastatic or relapsed disease, and reducing treatment toxicity. There is a lack of new therapeutics in osteosarcoma, with the evaluation of new treatments challenged by complex biology and variation in chemotherapy standard of care regimens. An antibody-drug conjugate (ADC) targeting LRRC15 with an osteosarcoma-relevant payload is a promising therapeutic approach. Small molecule inhibitors and degraders targeting SMARCAL1 should be considered as a very high priority, as it is a target applicable to several high unmet need malignancies. Preclinical evaluation of KIF18A in osteosarcoma models is required. An early phase study of an eIF4A1 inhibitor is warranted. Further preclinical validation of RUNX2 using PROTACs or ADCs is required. Targeting MYC, either indirectly or directly is a high priority. Osteosarcomas have significant genomic instability and impaired DNA repair mechanisms and efforts are ongoing to exploit this vulnerability therapeutically. The goal is that these therapeutic developments will improve survival for patients with osteosarcoma.

Despite tremendous advances in new drug development over recent decades, the medical needs of an ever increasing and ageing global population are still significantly unmet. Drug repurposing (DR)—finding new therapeutic uses for existing medicinal substances and products—offers a promising strategy by potentially reducing development time, costs and risk. However, currently, significant hurdles restrict broader application of DR. This study was conducted within the European Commission funded REMEDi4ALL consortium to systematically identify and analyse the key policy obstacles perceived to be hindering the success of DR. A systematic literature review was conducted using PubMed and Embase, supplemented by grey literature searches and expert interviews within the consortium. The extracted data underwent thematic analysis. A barrier tree was developed and validated through five workshops with 80 experts from seven stakeholder groups. From 4059 hits, 192 were included for data extraction, resulting in the identification of 33 key barriers grouped into nine main themes: perception of off‐patent medicines, business case for on‐patent DR, business case for off‐patent DR, non‐industry‐funded DR, ecosystem for non‐profit or small and medium‐sized enterprise‐driven repurposing, market authorisation, exclusivity rights, health technology assessment and pricing. This comprehensive analysis provides a foundation for prioritizing the main areas for future interventions. Surprisingly, there were considerable differences in how different stakeholders perceived the importance of a number of key barriers. Such multidimensional aspects of DR barriers will need to inform future development of actionable policy recommendations to enhance the DR ecosystem and facilitate broader access to repurposed medicines.

PURPOSE: Updated analysis of phase I/II trials in recurrent/refractory (R/R) Ewing sarcoma (EwS) over the past 11 years. METHODS: A systematic review was performed to identify phase I/II trials for R/R EwS in three databases (WHO, US National Library of Medicine, and European Clinical Trials Database) and/or published in PubMed/ASCO/European Society for Medical Oncology websites from 2014 to 2024. The search criteria included EwS OR bone sarcoma OR sarcoma AND Phase-I OR Phase-II. Eligibility and data extraction were performed independently by three reviewers, with priority given to trials with EwS specified data. Trials were categorized by therapeutic intervention, including targeted therapies, immunotherapy, chemotherapy, and combined therapies. RESULTS: One hundred eight trials met inclusion criteria, predominantly academic (70%) and multicenter (81.5%), with significant US and European collaboration. Trial designs were mainly single-arm, with an increase in multiarm trials in the recent years and increased focus on the pediatric population. Trial modalities emphasized targeted therapies with tyrosine kinase, poly-ADP ribose polymerase, EWSR1::FLI1, and cell cycle inhibitors. Immunotherapy with monoclonal antibodies and CAR-T cells as primary agents is also under investigation. The COVID-19 pandemic coincided with a marked reduction in trial initiation in 2020. Among evaluable data, disease control rates averaged 44% and response rates 8%. CONCLUSION: This review highlights evolving therapeutic directions in R/R EwS, with increased emphasis on targeted therapies and immunotherapies. Despite pandemic-related delays, trials have progressed in exploring novel targets, including EWSR1::FLI1 oncogenic fusion and DNA repair pathways. These findings underscore ongoing global efforts to address critical unmet needs in EwS treatment, offering a foundation for future trial designs, especially international, randomized phase‐II trials across all age ranges.

Intratumoral microbiota, the diverse community of microorganisms residing within tumor tissues, represent an emerging and intriguing field in cancer biology. These microbial populations are distinct from the well-studied gut microbiota, offering novel insights into tumor biology, cancer progression, and potential therapeutic interventions. Recent studies have explored the use of certain antibiotics to modulate intratumoral microbiota and enhance the efficacy of cancer therapies, showing promising results. Antibiotics can alter intratumoral microbiota’s composition, which may have a major role in promoting cancer progression and immune evasion. Certain bacteria within tumors can promote immunosuppression and resistance to therapies. By targeting these bacteria, antibiotics can help create a more favorable environment for chemotherapy, targeted therapy, and immunotherapy to act effectively. Some bacteria within the tumor microenvironment produce immunosuppressive molecules that inhibit the activity of immune cells. The combination of antibiotics and other cancer therapies holds significant promise for creating a synergistic effect and enhancing the immune response against cancer. In this review, we analyze several preclinical studies that have been conducted to demonstrate the synergy between antibiotics and other cancer therapies and discuss possible clinical implications.

Intratumoral microbiota, the diverse community of microorganisms residing within tumor tissues, represent an emerging and intriguing field in cancer biology. These microbial populations are distinct from the well-studied gut microbiota, offering novel insights into tumor biology, cancer progression, and potential therapeutic interventions. Recent studies have explored the use of certain antibiotics to modulate intratumoral microbiota and enhance the efficacy of cancer therapies, showing promising results. Antibiotics can alter intratumoral microbiota’s composition, which may have a major role in promoting cancer progression and immune evasion. Certain bacteria within tumors can promote immunosuppression and resistance to therapies. By targeting these bacteria, antibiotics can help create a more favorable environment for chemotherapy, targeted therapy and immunotherapy to act effectively. Some bacteria within the tumor microenvironment produce immunosuppressive molecules that inhibit the activity of immune cells. The combination of antibiotics and other cancer therapies holds significant promise for creating a synergistic effect and enhancing the immune response against cancer. In this review we analyze several preclinical studies that have been conducted to demonstrate the synergy between antibiotics and other cancer therapies and discuss possible clinical implications.

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes.