Preclinical Development of a First-in-Class PCNA Inhibitor for Treating Neuroblastoma
Lay Summary: This project is focused on developing a safe and effective therapy for treating high-risk neuroblastoma (NB). NB is one of the most common childhood neoplasms and accounts for 15% of all pediatric cancer deaths. The single most important factor determining the treatment options and prognosis of NB patients is risk stratification. Survival is excellent in low- and intermediate-risk groups. Localized perinatal adrenal tumors often regress spontaneously. In contrast, there is currently no effective treatment for high-risk NB, in part because of a limited drug development effort for this disease type. Whereas more than 80% of children with cancer now survive five years or more, most patients with high-risk NB are not expected to survive for more than five years. We discovered a novel small molecule (AOH1996) that selectively targets a cancer-associated protein isoform. AOH1996 effectively inhibits the growth of NB tumors but causes no observable side-effects, including weight loss in experimental animals. Here, we propose to perform a comprehensive toxicology study on AOH1996 according to the FDA’s guidelines. Such a study is critical to gain regulatory approval to start clinical trials. Through proposed studies, we will also create a patient-friendly dosage form that can be used in the clinic and gain information such as bioavailability, dosage, therapeutic window, and predictive biomarkers, which will inform the design of clinical trials. At the completion of this proposal, we expect to meet the FDA’s regulatory requirement for investigational drugs (IND) and file an IND application.