Abstract A030: Accelerating Therapeutic Discovery for Pediatric Cancer: Optimization of 80S Ribosome Inhibitors for T-Cell Acute Lymphoblastic Leukemia

Abstract Cancer remains the leading cause of disease-related death in children across many regions of the world. Yet, despite this urgent medical need, the discovery and development of novel therapies for pediatric cancers continues to progress slowly. Current treatment protocols often still rely on decades-old chemotherapy regimens. Moreover, the initiation of clinical trials for pediatric patients typically lags 6–7 years behind comparable trials in adults. Key barriers to innovation include the rarity of childhood cancers and the ultra-rare nature of many subtypes, which contribute to small trial populations, perceived low return on investment, and recruitment challenges. Historically, children have also been viewed as a uniquely vulnerable group, complicating drug development efforts. However, current evidence shows that, aside from their disease, children are generally healthier than adults with cancer and often tolerate higher relative doses of chemotherapy, challenging these outdated assumptions. To address these challenges, at Sanofi, we are committed to transforming outcomes for children with cancer through our dedicated Sanofi Childhood Cancer Program, part of the company’s broader societal impact strategy. A central element of this program is the formation of strong academic-industry partnerships to jointly advance the development of novel pediatric therapies. One such collaboration is with Jean-François Peyron and his team at the C3M–U1065 INSERM Institute in southern France. This partnership focuses on T-cell acute lymphoblastic leukemia (T-ALL), a highly proliferative disease that, unlike B-ALL, lacks effective targeted therapies, immunotherapies, and robust biomarkers for risk and relapse. Given the high rate of protein synthesis required for T-ALL cell proliferation, inhibiting translation emerges as a promising therapeutic strategy. Within the framework of this research project, the team has used cryo-EM-guided design to optimize 80S ribosome inhibitors. These compounds were further refined for potency and drug-like properties, resulting in a series of lead molecules with low-nanomolar in vitro efficacy in T-ALL cell lines and demonstrable in vivo activity in T-ALL patient-derived xenograft (PDX) mouse models. Additionally, the project has included efforts to identify and characterize pharmacodynamic biomarkers for these compounds. This research is funded by the Sanofi i-awards program and serves as a compelling example of how public–private collaboration can successfully accelerate the early discovery of targeted therapies for pediatric cancers, particularly for high-risk and underserved patient populations. Citation Format: Iris Valtingojer, Jean-François Peyron, Véronique Imbert, Marielle Nebout, Celia Durano, Muhamad Mustafa, Jean-Yves Winum, Bruno Klaholz, Marie-Pierre Harnist, Loreley Calvet, David Machnik, Sasha Lievre, Joe Kiwan, Valeria Fantin. Accelerating Therapeutic Discovery for Pediatric Cancer: Optimization of 80S Ribosome Inhibitors for T-Cell Acute Lymphoblastic Leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A030.