Targeting extracellular vesicles in neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid pediatric cancer and is one of the leading causes of cancer-related deaths in children. Despite the current multi-modal treatment regimens, majority of patients with advanced-stage NBs develop therapeutic resistance and relapse, leading to poor disease outcomes. There is a large body of knowledge on pathophysiological role of small extracellular vesicles (EVs) in progression and metastasis of multiple cancer types, however, the importance of EVs in NB was until recently not well understood. Our recently published studies along with new preliminary data have demonstrated the involvement of EVs in various aspects of NB pathogenesis, including pre-metastatic niche (PMN) formation, metastasis, and immune responses. Tumor-derived EVs (TEVs), being important regulators of NB progression, thus could become efficient targets for developing novel therapies for NB treatment. We have demonstrated that Tipifarnib (a potent, selective, and orally bioavailable inhibitor of farnesyltransferase that can inhibit the secretion of EVs from cancer cells) prevents the immunosuppressive effects of TEVs and sensitizes high-risk NB to therapy. We have also recently reported that SEMA3A mediates the pro-metastatic effects of NB TEV, that depends on SEMA3A receptor-NRP1. These data support an overarching hypothesis that targeting biogenesis and function of NB- derived TEV should elicit potent anti-metastatic effects and improve the efficacy of anti-cancer therapy. We will test this hypothesis in the following Specific Aims: Aim 1: To define the mechanism by which Tipifarnib suppresses TEV production in NB. We will analyze the stages at which Tipifarnib impedes TEV production and identify the molecular targets of Tipifarnib involved in the regulation of TEV biogenesis or secretion. Aim 2: To determine the role and mechanisms of TEV-mediated SEMA3A signaling in NB progression. We will use genetic, molecular, and pharmacologic approaches to determine TEV-mediated function of SEMA3A in NB pathogenesis. Mechanisms of TEV-mediated SEMA3A actions will be investigated. Aim 3: Targeting TEV production and function for NB therapeutics. We will determine the anti-metastatic effects of Tipifarnib and anti-NRP1 antibodies as mono-agents and in combination to suppress spontaneous or chemotherapy-induced NB metastasis. Completion of these studies should gain the insight on the importance of TEV in NB metastasis, characterize the mechanisms of TEV regulation and function in NB, and develop novel strategies to suppress TEV-mediated NB metastasis. Project Number: 1R01CA304343-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Vladimir Spiegelman (+1 co-PI) | Institution: PENNSYLVANIA STATE UNIV HERSHEY MED CTR, HERSHEY, PA | Award Amount: $690,013 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics C Study Section [MCTC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11216953