Neuro-Oncology

Dr. Robert Wechsler-Reya talks about his work with RCIGM.

In 2016, the Institute established the Joseph Clayes III Research Center for Neuro-Oncology and Genomics. This was made possible by a generous $10 million endowment from the Joseph Clayes III Charitable Trust. Under the direction of Robert Wechsler-Reya, The Center aims to accelerate the translation of leading-edge genomic research into prevention, diagnosis, treatment and cures.

“The first instinct of parents who have a child diagnosed with cancer is to seek out the best treatments available,” said Stephen Kingsmore, MD, DSc, President and CEO of Rady Children’s Institute for Genomic Medicine.“That’s exactly what our team of scientists, researchers and physicians aim to provide. By sequencing the tumor, we can discover the genomic foundation of the cancer, and develop individualized approaches to treatment.”

The Joseph Clayes III Research Center for Neuro-Oncology and Genomics brings together childhood brain cancer researchers to accelerate the translation of new findings and knowledge into prevention, diagnosis, treatment and cures.

The endowment is divided into three specific programs:

  • The Joseph Clayes III Neuro-Oncology Research Fund that will accelerate research into the understanding of the genomic foundation of childhood brain cancers and help scientists to develop individualized approaches to treatment.
  • The Joseph Clayes III Endowed Chair in Neuro-Oncology Research, allowing Rady Children’s to invest in top leadership talent with the knowledge and skill to lead advanced genomics research.
  • The Joseph Clayes III Neuro-Oncology Research Fellowship and Education Fund, allowing the most promising young scientists to learn the best approaches in pioneering cancer research and preparing them to be future leaders in genomic medicine.

Related Study

Publications​

Int J Cancer. 2022 Aug 27. doi: 10.1002/ijc.34261. Online ahead of print.

ABSTRACT

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA, and histone H3 as compared to serum EVs from healthy volunteers (p value range: <0.0001 – 0.08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.

PMID:36054558 | DOI:10.1002/ijc.34261

Genes Dev. 2022 May 1;36(9-10):514-532. doi: 10.1101/gad.349538.122.

ABSTRACT

Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families.

PMID:35680424 | DOI:10.1101/gad.349538.122

Front Immunol. 2022 Mar 3;13:837013. doi: 10.3389/fimmu.2022.837013. eCollection 2022.

ABSTRACT

Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc-driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1-deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1-deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1+ macrophages, and we show that CD45high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments.

PMID:35309309 | PMC:PMC8928748 | DOI:10.3389/fimmu.2022.837013

Robert Wechsler-Reya (1)

Robert Wechsler-Reya, PhD

Neuro-Oncology Program Director

Robert Wechsler-Reya, PhD is also a professor and researcher at the Sanford Burnham Prebys Medical Discovery Institute (SBP) where he is focused on investigating the genes and nervous system signaling pathways that contribute to medulloblastoma, the most common malignant brain tumor in children.

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