The overall five-year survival of pediatric patients with malignant bone sarcomas and metastatic disease is only 30%. There is an urgent need for new prognostic biomarkers, which could serve as targets for new systemic therapies and help improve outcomes for these patients. Tumor-associated macrophages (TAM) have been recently identified as novel biomarkers, which are associated with tumor progression and poor prognosis in patients with malignant sarcomas. New therapeutic drugs that target TAM are currently being developed and are starting to enter the clinic. To stratify patients who might benefit from these novel TAM- modulating therapies and to monitor treatment responses, it is important to identify patients whose tumors are heavily infiltrated with TAM. We propose to address this unmet clinical need by developing a novel and immediately clinically applicable molecular imaging test for selective detection and quantification of TAMs in pediatric bone sarcomas. This new imaging test relies on off-label use of the iron supplement ferumoxytol, an FDA-approved iron oxide nanoparticle compound, which is phagocytosed by TAM. Since ferumoxytol nanoparticles can be detected with magnetic resonance imaging (MRI), we hypothesize that ferumoxytol- enhanced MRI can be used as an immediately clinically applicable imaging biomarker for TAMs in bone sarcomas. To the best of our knowledge, this is the first attempt to visualize TAMs with FDA-approved nanoparticles in patients. In a two-step approach, we will first investigate whether the proposed ferumoxytol TAM imaging test can detect responses to new immune-modulating cancer therapies in a mouse model. Subsequently, we will provide proof of concept in pediatric patients with bone sarcomas, by correlating ferumoxytol tumor MRI enhancement with histopathological TAM quantities and distribution. This combination of studies in animal models and patients will establish preliminary data for co-clinical imaging research, a new precision medicine initiative of the National Cancer Institute. Developing a TAM imaging test would represent a significant breakthrough for clinicians as a new means for risk stratification and as a gold-standard imaging test for tracking treatment response in cancer immunotherapy trials, including a planned first-in-man anti-CD47 immunotherapy trial at Stanford University in 2016.
Pediatric patients with metastatic bone sarcomas have a very poor prognosis, with an overall survival rate of less than 30%. It has been recently discovered that specific immune cells, tumor-associated macrophages (TAM), initiate and maintain a chronic inflammation in malignant bone sarcomas, which promotes tumor growth and metastasis. We propose to develop a novel, non-invasive molecular imaging test for detection of TAM in malignant sarcomas in pediatric patients, which should help to identify tumors with poor prognosis and assign these tumors to novel TAM-targeted therapies, which are currently entering the clinic.
