Title: Improved Treatment of Childhood Neuroblastoma - Targeting the Oncogene Drivers MYCN and ALK, and Identification of Therapy Resistance Mechanisms
Funder: Cancer Research UK

Abstract: Background. Neuroblastoma is a common solid-tumour that accounts for 15% of cancer deaths in children. This application addresses key deficiencies in modelling neuroblastoma biology, and in drug-development, where, with few exceptions, no new life-extending drugs have been developed targeting the molecular-events that drive tumourigenesis. We evaluate experimental drugs in children with relapsed, metastatic and treatment-resistant tumours, yet we have no experimental models that recapitulate regrowth of spontaneous tumours within a native immuno-microenvironment. These deficiencies contribute to a lack of improvement in survival, where 40% of children still die from high-risk disease, 85% of them within 3-years of relapse. We have hypothesized that amplification of the proto-oncogene MYCN, and kinase-domain mutations in the growth-factor receptor ALK, interact to drive neuroblastoma growth. We developed vital in-vivo models of MYCN- and ALK-driven neuroblastoma, an interactome map of potentially-druggable MYCN-interacting proteins, and small-molecule inhibitors of both MYCN and ALK that reached clinical trials. Clinical evaluation of ALK-inhibitor monotherapy, combinatorial therapy targeting resistant ALK-mutations (Crizotinib/Temsirolimus) and an ICR-developed transcriptional inhibitor of MYCN (CYC065, CDK9) are in progress, and we are using genomic-testing to monitor emergence of treatment-resistance in these patients. To develop future options for these patients we propose 3 aims: Aims. A1. Interrogate therapeutic-resistance to the clinical MYCN and CDK9-inhibitor CYC065 and target additional oncogenic functions of MYCN through blockade of the MYCN-interacting proteins AURKA, EIF4E and USP28. A2. Interrogate therapeutic-resistance to the clinical ALK-inhibitor Lorlatinib and characterise efficacy of novel ALK-binding CAR-T cells and ICR-developed small-molecule dual ALK-BRD4 inhibitors. A3. Interrogate mechanisms of neuroblastoma dissemination using a novel transgenic model of natively-metastatic tumour relapse, and target metastasis using a bicyclic clinical-inhibitor of MMP14. Methods. We will probe established cell-line panels isogenic for MYCN and ALK-expression and in-vivo models of spontaneous and relapsed neuroblastoma, for sensitivity to unique ALK- and MYCN-targeted small-molecule inhibitors, PROTACS and CAR-T therapeutics available to us. We will identify pathways that drive resistance to our established ALK and MYCN-inhibitors, and characterise novel CAR-T, dual small-molecule inhibitors, or combinations thereof for clinical use, using a mouse-hospital approach. How the results of this research will be used. Data from this research will highlight mechanisms by which oncogenic activity of MYCN and ALK and dissemination of neuroblastoma can be targeted. As in our previous work, we will aim to translate our preclinical data and therapeutic agents directly to early-phase, biomarker-driven clinical trials in relapsed patients, using the drugs or combinations identified here.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS