Our Research
Neuro-Oncology Research
In 2014, the Center for Cancer and Immunology Research (CCIR) established the Medulloblastoma Special Interest Group, which aims to understand causative mechanisms and improve treatment of medulloblastoma. The group performs translational research to integrate advances in molecular biology with clinical trials, taking research from the bench to the bedside.
Medulloblastoma
The lab of Yanxin Pei, Ph.D., is interested in elucidating the molecular and cellular mechanisms underlying initiation, progression and therapeutic resistance in medulloblastoma and identifying novel therapeutic approaches to medulloblastoma treatment. Currently, the lab focuses on three major research areas:
Generating Diverse Preclinical Mouse Models of Medulloblastoma
Medulloblastoma is a heterogeneous disease that has been classified into four major molecular groups (WNT, SHH, Group 3 and Group 4), each characterized by distinct genetic and molecular alterations and clinical features. Despite this heterogeneity, most medulloblastoma patients currently receive the same therapy, resulting in overtreatment and toxic side effects for those with a good prognosis and insufficient treatment for patients with more malignant tumors who ultimately succumb to their disease. A major goal of our research is to generate diverse preclinical mouse models for each subgroup of medulloblastoma and discover new therapeutic strategies that are tailored to the specific subgroups. To this end, we have used an orthotopic transplantation approach to generate mouse models of both Group 3 medulloblastoma, associated with MYC amplification, and SHH medulloblastoma, associated with GLI2 amplification. Using our newly developed models, we have identified novel therapeutic targets that are specific to the corresponding subgroup of medulloblastoma.
Elucidating the Molecular Mechanisms of Metastasis, Therapeutic Resistance and Tumor Relapse
Approximately one-third of patients with Group 3 medulloblastoma present with metastases at diagnosis, and nearly all have metastatic disease at relapse. Treatment-resistant, metastatic medulloblastoma tumors pose a daunting therapeutic challenge as they are neither amenable to surgical resection nor responsive to radiation or currently available chemotherapy. Identifying the signaling pathways involved in metastatic progression will facilitate the development of an effective strategy to prevent and treat metastasis. Using patient-derived xenograft mouse models of Group 3 medulloblastoma, we have isolated treatment-resistant metastatic tumor cells and discovered that a subpopulation of OLIG2+ tumor cells in primary tumors have a unique ability to metastasize along the leptomeninges. We are currently testing several novel therapeutic approaches to eliminate the metastatic tumor cells, including targeted drug therapy and cellular immunotherapy with CAR T cells and adoptive natural killer (NK) cells.
Exploring Novel Approaches to Enhance Delivery of Therapeutic Drugs to the Central Nervous System
The blood-brain barrier (BBB) is a major obstacle to the delivery of effective therapies for brain tumors. To address this problem, we are collaborating with bioengineers specializing in nanotechnology. By encapsulating drugs in nanoparticles and delivering them directly to the central nervous system, we hope to improve the delivery of sufficient, effective concentrations of drugs to the brain tumor site and reduce accumulation of the drugs in other tissues, thereby mitigating systemic side effects. Additionally, we are collaborating with bioengineers using either high-frequency irreversible electroporation (H-FIRE) or ultrasound to transiently disrupt the BBB in order to deliver effective intratumoral concentrations of anticancer drugs. We have already identified several drugs that effectively kill medulloblastoma cells in vitro; if we can develop strategies to effectively deliver these drugs to tumors, we can markedly improve outcomes for patients with medulloblastoma.