Project 4: Secondary Cancers among NF1 cancer survivors

Investigator: Jean L. Nakamura, MD
Sponsor: Indiana University


PROJECT 4 Radiation and alkylating agent chemotherapy are used sparingly in NF1 patients with a primary neoplasm, because of the commonly held belief that NF1 patients may be at increased risk of second malignant neoplasms (SMNs). The overarching goals of this proposal are to define the risk of SMNs for individuals with NF1, and define responsible pathogenetic mechanisms in order to inform therapeutic approaches in NF1. These goals will be addressed by utilizing the resources available through the SPORE, the Childhood Cancer Survivor Study and the Children's Hospital of Philadelphia NF1 Registry, and validated experimental systems comprised of clinically relevant animal models developed specifically in mice heterozygous for Nf1.

Subsequent malignant neoplasms (SMNs) are histologically distinct tumors that develop after successful treatment of a primary neoplasm. Previous small case series indicate that NF1 patients with a primary tumor may be at increased risk of SMNs. However, whether the risk of SMN in NF1 individuals is in excess of that observed in non-NF1 cancer patients is unclear. Furthermore, whether specific genotoxic agents increase the risk of SMNs in NF1 patients is unknown. Nonetheless, radiation is generally avoided for non-malignant tumors in NF1 patients being reserved only as a last resort measure due to concern about radiation-induced malignant transformation;this is despite the fact that for sporadic optic pathway glioma (OPG)/low-grade glioma (LGG) patients, radiation results in improved tumor control when compared to chemotherapy. Furthermore, in NF1 patients with malignant peripheral nerve sheath tumors (MPNST), radiation is used inconsistently (largely based upon regional preferences), despite the knowledge that radiation (when compared to surgery) provides superior nerve-sparing/ improved functional outcomes and is standard therapy in sporadic MPNSTs;this inconsistency in practice is largely because of lack of conclusive evidence regarding the risk of SMNs in this setting. Similarly, alkylators are used sparingly in NF1 patients, because of the potential for increased risk of therapy-related leukemia, thus limiting therapeutic options for OPG patients. We will leverage the resources offered by Childhood Cancer Survivor Study (CCSS) and the Tumor and NF1 Registries at Children's Hospital of Philadelphia (CHOP), to identify two large cohorts: i) Children with NF1 and primary neoplasia (NF1+cohort: n=575);ii) Children with neoplasia, but without NF1 (non-NF1cohort: n=24,000). We will test the hypotheses that NF1 patients with a primary neoplasm are at increased risk of SMNs as compared with non-NF1 patients, and that radiation and alkylating agents increase the risk of SMNs among NF1 patients. To investigate the pathogenesis of radiation-induced SMNs, we developed novel mouse models of SMNs in Nf1+/- mice that function as highly coherent platforms for studying how ionizing radiation promotes tumorigenesis in the Nf1 mutant background. Integrated genomic analysis of tumors from our mouse models suggests enrichment of mutations in discrete biological pathways, which may be similarly enriched in SMNs from individuals with NF1. We propose to define mechanisms that promote radiation-induced tumorigenesis in individuals with NF1 and model radiotherapy to plexiform neurofibromas (PNs) a potential treatment option in NF1 individuals that is poorly utilized. We hypothesize that SMN development in NF1 patients requires genetic alterations in the conserved signaling pathways. We will test this hypothesis by determining whether these pathways are similarly somatically mutated in SMNs from NF1 individuals (as in mouse model) and test their importance to tumor growth. Further, we will test whether fractionated focal irradiation promotes transformation of PNs into MPNSTs in vivo.