Medulloblastoma (MB) is the most common form of primitive neuroectodermal tumor of the pediatric central nervous system (CNS). The standard treatment of MBs includes surgical resection, followed by chemo- or radiation treatments. Dissemination of cancer cells and subsequent metastasis is one of the major causes of treatment failure. Early identification of MB metastases is important in applying timely and proper follow-up treatment and improving outcome of MB patients. Current clinical methods for detection of MB metastases are: 1) magnetic resonance imaging (MRI) of spine, and 2) cytology or flow cytometry analysis of cerebrospinal fluid (CSF) samples collected through the lumbar puncture procedure. Neither method is sensitive enough for the early detection of metastases and well-tolerated by pediatric patients. More importantly, they are not easily accessible and available in low-resource areas. Without early detection, aggressively treating pediatric patients can lead to over-treatment caused CNS damage. Therefore, there is a critical need in highly sensitive and robust methods for detecting rare MB cells spread in CSF and blood, especially for patients having no or limited access to imaging and complicated hospital procedures. The goal of this phase I STTR project is to develop an ultra-sensitive liquid biopsy technology to capture MB cells in blood samples of MB patients, with the readout simply done with minimal training and resources. While various circulating cancer cells (CTCs) detection methods have been developed, sensitivity and specificity of current technologies are limited by the unwanted interactions between detecting systems and non-specific biomaterials and cells in blood samples, e.g., the formation of protein corona and adsorption of non-cancerous cells on the surface of cell capturing devices. Such biofouling effect not only attenuates the affinity of targeting ligands, causing loss of biomarker specificity, but also generates undesirable background, leading to inaccurate results. Consequently, there is no CTC detection method currently available to detect MB spread in the blood. This STTR project will address these problems with several patented technologies, including: (1) anti-biofouling coating polymer for reducing protein corona and non-specific cell uptake to improve biomarker targeting and specificity of cell capture, and (2) high magnetism magnetic iron oxide nanorods (IONRs) for efficient immuno-magnetic cell capturing. The project aims to: (1) develop and optimize an anti-biofouling ultra-magnetic IONR as a cell capturing agent; (2) determine and optimize the effectiveness of developed IONRs for capturing circulating GFP tagged MB cells in the blood of GFP transgenic MB mice; and (3) test the developed immuno-magnetic capturing technology for detecting MB cells in blood samples from patients with clinically confirmed MB metastases. If successful, proposed technology for early detection of MB metastasis will be further developed in the Phase II with a product to make a practice- changing impact on the clinical management of MB patients, especially those in low-resource settings.
Public Health Relevance Statement: PROJECT NARRATIVE Early detection of metastasis of medulloblastoma (MB), the most common pediatric brain tumor, is important to improve the outcome and life quality of pediatric brain tumor patients. The goal of this phase I STTR project is to develop an ultra-sensitive liquid biopsy technology to capture circulating MB cells in blood samples readily collected from MB patients. This practice-changing and paradigm shifting approach will replace insensitive, complicated and expensive MRI and CSF cytology based detection methods in the current clinical management of MB patients, especially for those with limited access to the resources needed in the current clinical practice.
Project Terms: Address; Adsorption; Affinity; Archives; Area; Attenuated; base; Binding; Biocompatible Materials; Biological Markers; Blood; Blood specimen; Blood Tests; cancer cell; Cell Communication; Cell surface; Cells; Central Nervous System Neoplasms; Cerebrospinal Fluid; chemotherapy; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Primitive Neuroectodermal Tumor; circulating cancer cell; Clinic; Clinical; clinical Diagnosis; Clinical Management; clinical practice; Clinical Trials; cost; Cytology; Detection; Development; Devices; Diagnosis; Early Diagnosis; Early identification; Effectiveness; ethylene glycol; Excision; Flow Cytometry; follow-up; glycidyl ethers; Goals; Health Professional; Hematogenous; Hospitals; Image; improved; improved outcome; innovative technologies; instrument; iron oxide; Lead; Legal patent; Leptomeninges; Ligands; liquid biopsy; magnetic beads; Magnetic Resonance Imaging; Magnetism; Medical; medulloblastoma; Metastatic Neoplasm to the Central Nervous System; Metastatic Neoplasm to the Leptomeninges; Methods; mouse model; Mus; nanoparticle; nanorod; Neoplasm Circulating Cells; Neoplasm Metastasis; neoplastic cell; Nervous System Trauma; Neuraxis; Operative Surgical Procedures; overexpression; overtreatment; Patients; pediatric patients; performance tests; Phase; Polymers; Primary Neoplasm; Primitive Neuroectodermal Tumor; Procedures; Proteins; Puncture procedure; Quality of life; Radiation; Radiation therapy; Resources; Route; Sampling; Scheme; Sensitivity and Specificity; Serum; Shapes; Signal Transduction; Small Business Technology Transfer Research; Specificity; Spinal Puncture; standard care; Surface; System; targeted biomarker; Technology; Testing; TFRC gene; Time; tool; Training; Transferrin; Transgenic Organisms; Treatment Failure; Treatment outcome; uptake; Vertebral column
