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.
Project Goal: 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.
Project Update 2022: Towards this goal, we completed safety evaluation studies required by the US Food and Drug Administration and demonstrated that this compound doesn’t cause any observable side toxicities at 6 times its effective dose. In addition, we developed a drug product that can be used in an outpatient setting in the clinic. These results enable us to obtain FDA approval and start clinical trials. In fact, patient enrollment started in August 2022. In addition, we discovered promising biomarkers (pChk1 and ?H2A.X) whose expression indicates response to AHO1996 treatment and may predict whether a patient is likely to benefit from AOH1996 treatment. These biomarkers will enable us to design an “enhancement” trial, in which patients are pre-screened and enrolled based on their biomarker status. Such a trial will enable us to carry out clinical trials on a small enrollment size and spare patients who are unlikely to respond to AOH1996 from the burden of participation.
