Therapies for patients with rare tumors and genetic tumor predisposition

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

A large focus of my group has been on neurofibromatosis type 1 (NF1). People with NF1 develop multiple tumors including cutaneous neurofibromas (cNF), which never transform to malignancy; plexiform neurofibromas (PN), which are histologically benign but can cause substantial morbidity and transform to highly aggressive cancers called malignant peripheral nerve sheath tumors (MPNST); atypical neurofibromas (AN), which are histologically borderline lesions and at risk for transformation to MPNST. Our NIH NF1 natural history study allowed us to comprehensively characterize the growth rate of PN in NF1 and the development of associated morbidities. In addition, we have conducted a series of interventional clinical trials directed at cNF, PN, AN and MPNST using novel trial designs and endpoints. Key achievements from our team (in collaboration with intramural and extramural investigators include: 1) Development of volumetric magnetic resonance imaging (MRI) analysis, now used in nearly all trials conducted for NF1 PN in the United States, using the criteria proposed by PETS (Dr. Eva Dombi) with central review at POB, 2) Identification and clinical and MRI characterization of distinct nodular lesions (DNL) as the imaging correlate of AN, which are premalignant lesions, allowing earlier intervention for MPNST prevention, 3) Recommendation for marginal resection of AN as a strategy to prevent MPNST from a state of the science workshop on MPNST, which has directly impacted patient care, 4) New pathological criteria to aid identification of concerning lesions and treatment decision making Innovative clinical trials directed at PNST that take patient age, tumor type (AN/PN), precise volume measurements, and patient reported and functional outcomes into consideration, 5) Developing and coordinating a multi-site a phase II registration trial of selumetinib for children with NF1and inoperable, symptomatic PN (SPRINT), which resulted in FDA approval of selumetinib for children with inoperable, symptomatic PN in 2020, and subsequent regulatory approval in. more than 50 countries, 6) Conducting the first adult phase II trial of a MEK inhibitor with serial tumor biopsies demonstrating similar response rate to the SPRINT Trial, feasibility of serial biopsies and providing pharmacodynamic insights into mechanisms of response, (7) Development of a secondary prevention trial of selumetinib for young children with NF1 and asymptomatic PN in high-risk locations. This trial will be coordinated through the NF Clinical trials Consortium and has DoD and Alexion funding. The PI will be Dr. Gross and trial enrollment will begin in 2025. We also developed a new longitudinal observational trial for people with NF1 and peripheral nerve sheath tumors, who are at increased risk for malignant transformation of their tumors. Patients are followed with whole body MRI and other imaging studies as well as cell free DNA to assess risk for malignant transformation. In collaboration with Dr. Prashant Chittiboina, NINDS neurosurgeon, lesions at increased risk are removed with surgical excision, as clinically indicated. My team has substantially contributed to the development of cell free DNA (cfDNA) as liquid biomarker for malignant transformation of peripheral nerve sheath tumors in NF1. Dr. Jack Shern is the PI for this project and he and his team have established the largest PNST single cell atlas. I am collaborating extensively with extramural investigators and participate in the Developmental and hyperactive RAS Tumor SPORE (DHART) directed by Drs. Kevin Shannon and Wade Clapp as a clinical investigator. In collaboration with intramural and extramural investigators I have expanded my effort to understand the natural history of RASopathies and develop interventional trials for RASopathies and RAS pathway driven tumors (PI Drs. Marielle Yohe, Andrea Gross, Douglas Stewart, Gina Ney). For NF1 and non NF1 rare tumors we are closely collaborating with the NCI Adult Developmental Therapeutics Clinic (Director, Dr. Alice Chen) to allow enrollment of pediatric and adolescent patients on clinical trials designed primarily for adult patients, when there is a strong scientific rationale to do so and, vice versa, to allow adult patients to participate in clinical trials primarily designed for pediatric patients. Learning from NF1, we also developed a natural history of rare solid tumors study, which is actively enrolling patients and are engaged in several interventional trials for patients with rare solid tumors conducted in the Pediatric Oncology Branch of the NCI. Key advances in 2024 included a state of the science symposium focused on the classification of AN as precursors for MPNST. The consensus classification now includes molecular features in addition to pathologic features. These criteria will allow for better detection of tumors at risk for malignant transformation and improved clinical management. We also hosted a workshop with the goal to develop criteria which will allow comparison of responses in clinical trials developed for patients with NF1 PN. Finally, I am working with the NCI Childhood Cancer Data Initiative (CCDI) and POB and extramural collaborators in the development of a national strategy to study rare tumors. A national registry study is in development with the goal to study rare tumors more efficiently and advance better therapies. This study will likely open for enrollment soon.