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​

Cancer Res. 2020 Dec 1;80(23):5393-5407. doi: 10.1158/0008-5472.CAN-20-1655. Epub 2020 Oct 12.

ABSTRACT

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients’ tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

PMID:33046443 | PMC:PMC7718387 | DOI:10.1158/0008-5472.CAN-20-1655

Cold Spring Harb Mol Case Stud. 2019 Oct 23;5(5):a004572. doi: 10.1101/mcs.a004572. Print 2019 Oct.

ABSTRACT

Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G>A canonical splice donor site variant in GNAS was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing GNAS, consistent with predicted biallelic loss of GNAS in the tumor specimen. This case strengthens the evidence implicating GNAS as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility.

PMID:31624069 | PMC:PMC6824258 | DOI:10.1101/mcs.a004572

Sci Signal. 2018 Sep 11;11(547):eaau5147. doi: 10.1126/scisignal.aau5147.

ABSTRACT

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

PMID:30206138 | PMC:PMC6475502 | DOI:10.1126/scisignal.aau5147

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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