PROTECT (Harnessing PROTEin degradation for Advanced Childhood Tumors)

ABSTRACT Background Survival rates for children with solid tumors, including brain, have largely plateaued over the past three decades making them the most common cause of disease-related mortality in this age group. After decades of opƟmizing chemotherapy and radiotherapy protocols, higher cure rates for

childhood solid tumors will no longer be achieved by “more of the same.” Rather, cures will require innovaƟve intervenƟons that specifically target the unique biology of these tumors, which are often driven by oncogenic fusions and other pediatric-specific oncoproteins historically considered difficult

drug targets. With advances in targeted protein degradaƟon and chemical intervenƟons to inhibit protein-protein interacƟons, it has recently become tractable to target these proteins previously thought to be “undruggable”. Moreover, unbiased funcƟonal screening approaches, such as CRISPRCas9, have revealed new pediatric cancer syntheƟc lethal liabiliƟes in need of targeted

inhibitors. Aims We aim to lead the transformaƟon of delivering such specific treatments to our young paƟents harnessing the power of a highly interdisciplinary and collaboraƟve team of world-leading experts in pediatric oncology, targeted protein degradaƟon, high-throughput chemical screening, medicinal

chemistry, structural biology, tumor biology, preclinical drug tesƟng, and clinical trials, complemented by a trans-AtlanƟc group of engaged paƟent representaƟves. Methods A bold plan will be pursued with a portiolio of projects that balance very high-risk efforts with others nearing clinical implementaƟon. We will focus on drivers/targets in the following diseases: Ewing

sarcoma, neuroblastoma, synovial sarcoma, ependymoma and high-grade glioma. We will explore different approaches to target these as yet undrugged paediatric drivers/dependencies, to overcome resistance to available targeted inhibitors, and to improve the efficacy and therapeuƟc window of CAR-T treatments.

How the results will be used The aspiraƟon of our team is to establish a sustainable platiorm for repeated developmental cycles of paediatric specific drug development for emerging targets including a viable financial model to de- risk such developments for such rare pediatric tumors to the direct benefit of our paƟents.

Specifically, we anƟcipate success through (i) delivering at least one opƟmised protein degrader for its applicaƟon in early-phase clinical trials, (ii) enabling the druggability of previously “undruggable” targets, (iii) providing mechanisƟc insights into disease, novel targets, and therapy resistance

mechanisms and ways to tackle them.