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研究摘要：
In children, high-risk medulloblastoma (MB) includes metastasis at diagnosis and tumor recurrence during or after radiotherapy treatment and/or cytotoxic chemotherapy. The efficacy of conventional treatment is poor, mortality is high, and causes detrimental influence to neurocognitive function and quality of life in survivors. The current therapy is an unmet need for medical and parent’s expectation. This integrated project consists of three subprojects. We aim at the development of precision targeted therapy for more effective but less traumatic therapy in children suffering from high-risk MB.
Subproject 1. Identification/selection of therapeutic targets (tumor cell surface targets, therapeutic targets) and validation of efficacy of the selects therapeutic targets through cell model and animal (mice) model testing.
In subproject 1, pilot molecular-clinical analysis has performed that include molecular classification of childhood MBs (a cohort series of 52 cases), molecular-clinical analysis for subgroup specific genes and receptors relating to tumor metastasis and recurrence. We find that the expression genes in tumors with metastasis and recurrence potential are subgroup specific. Further analysis of subgroup specific tumor cell surface genes, interleukin genes, and interleukin receptor are performed. Specific high expression of IL32, IL33, IL34 are observed in tumors with metastasis and recurrent potential are observed. High expression of IL4 receptor is found in SHH β tumors and general high expression of IL17RA in MB tumors is observed. Therapeutic targets are also explored through analysis of immune landscapes, metastasis-associated genes, and DNA damage response (DDR) gene expression/mutations. A metastasis MB orthotopic xenograft mice model has been developed through the establishing of a Daoy-MYCN cell line for in-vivo testing.
Subproject 2. Establishment novel drug delivery, the placenta mesenchymal stem cells (P-MSCs) and/or MSC exosome cargo (PEG-SPIO labeled P-MSCs and/or PEG-SPIO labeled P-MSC exosome) and conjugate ligand, to carry targeted therapeutic agent(s) to tumor for novel therapy.
In subproject 2. We have previously demonstrated the tumor-homing property MSCs and established an MRI-based platform for real-time monitoring of in vivo administrated MSCs. By extension of our previous work on MSC-based tumor targeted therapy, the goal of Subproject (SP2) is to develop engineered MSC-exosomes as theranostic nanoparticles of treating MB. The main objectives are (1) to manipulate MSC-exosomal cargoes for miRNAs or antisense oligonucleotides as therapeutic biomaterials, (2) to engineer the external exosome surface of MSC-exosomes with MB-specific binding peptides and MRI contrast agents for MB targeting and imaging, and (3) to evaluate the translational potential of engineered MSC-exosomes for MB in orthotopic xenograft and PDX animal models.
Subproject 3. Application the technology of radiogenomics in the study of CNS embryonal tumors in children and prediction / validation the therapeutic efficacy of the selected targeted therapeutic agents.
We apply radiomics to find the imaging surrogates of genomic event in tumor tissue for non-invasive tissue dissection and evaluation of the macro and microenvironment of brain tumor. Our preliminary results on the radiomic-based machine learning model to predict molecular subtypes of medulloblastoma showed overall accuracy of 71%. Our aim in subproject 3 are: (1) To Extract MB radiomic features and establish the prediction model, (2) Linking the target lncRNA, drugable mRNA (cancer driver) and high-risk gene (metastasis-related) expression to Radiomics features to find imaging surrogates, and (3) To extract Radiomics features in animal medulloblastoma models.
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