Sensitizing Treatments for Pediatric Medulloblastoma

Identifying, screening and developing novel targets for combination therapies that reduce toxicities and sensitize patients to standard therapy

Technical Overview

Myron K. Evans II, PhD
Dr. Myron K. Evans II

Brain tumors are the leading cause of cancer-related death in children. The most common malignant pediatric brain tumors are medulloblastomas, for which the standard treatment is high doses of chemotherapy and craniospinal irradiation. Recurrence is high, though, and standard treatment in children can cause long-term treatment-induced adverse effects such as neurodevelopmental toxicities and cognitive deficits. Thus, strategies for lower-toxicity treatments are needed.

Brain development and pediatric neuro-oncology researcher Myron K. Evans II, PhD, has expertise in preclinical identification and validation of novel candidates for targeted therapies that could be added to the current standard treatment. This work aims to reduce treatment-associated toxicities via combination therapy with a targeted drug.

Dr. Evans and team are particularly focused on group 3 medulloblastomas, which often have amplification of the MYC oncogene as a prognostic marker. MYC-driven medulloblastomas represent the most aggressive and deadly subgroup of medulloblastoma. For patients with these tumors, 5-year survival rates are less than 50%. The MYC oncogene has multiple functions, some of which are required for normal cellular function, so direct targeting of it is not an easy approach.

To circumvent direct targeting of MYC, the Evans Lab is looking for targets that are associated with MYC function in cancer cells, which would enable more specific treatment of group 3 medulloblastomas and possibly extend applications to other cancers with MYC amplification. Approaches to identify novel targets include:

  1. Using data from functional genomic screens. Using a dataset from the Broad Institute Pediatric Cancer Dependency Map, Dr. Evans has identified several potential medulloblastoma-specific drug targets. One drug target is the Mediator complex, which is a central integrator of transcription that is associated with MYC amplification in pediatric medulloblastomas. The Evans Lab is determining the mechanisms by which the Mediator complex is involved in medulloblastoma, such as via transcription factor regulation or direct chromatin binding.

  2. Whole-genome CRISPR-Cas9 library screening of mouse and human medulloblastoma models. The Evans Lab has identified multiple drug targets in the pyrimidine nucleoside pathway, including a de novo pyrimidine synthesis enzyme called CTP synthase (CTPS1), which as the final and rate-limiting step in the pathway is a unique vulnerability in MYC-driven medulloblastoma. Dr. Evans has shown that targeted inhibition of CTPS1 by glutamine antagonists leads to decreased tumor cell proliferation and markedly reduces MYC expression in group 3 medulloblastoma models.

    This approach demonstrates potent synergy against patient-derived medulloblastoma xenografts in vivo and could lead to better tumor targeting and enhanced blood-brain barrier (BBB) penetrability. (A major challenge for medulloblastoma therapeutics is their ability to cross the blood-brain barrier.) This work demonstrates the Evans Lab’s expertise and capacity for large-scale drug candidate testing.

  3. Epigenetic studies on proteins required for initiation and/or progression of tumors. The Evans Lab is currently testing the first small molecule inhibitor of the DNA-RNA binding protein YBX1 as a possible therapeutic agent. The Evans team demonstrated that inhibition of YBX1 — alone or combined with radiation or standard of care chemotherapy — reduced tumor proliferation in vivo and in vitro, likely by targeting oncogenic MYC. Thus, YBX1 inhibition may sensitize medulloblastoma to standard treatment.

    Similarly, Evans and team showed that a small molecule CDK8 inhibitor enhanced the efficacy of radiotherapy on MYC-amplified medulloblastoma cells in vitro. In vivo, pretreatment with CDK8 inhibitor enhanced craniospinal irradiation efficacy, preventing relapse/recurrence.

The Evans Lab is prepared to screen additional small molecules, alone or in combination with other drugs that cross the BBB, for effectiveness in sensitizing tumor cells to standard treatments, which could enable lower doses and thereby ameliorate the adverse side effects. The team can also investigate potential mechanisms of action, such as DNA damage repair and apoptosis.

With expertise in drug screening with small molecules and other compounds, the Evans Lab has an array of 2D and 3D pediatric brain models for in vitro and in vivo assays, including animal models and patient-derived human cell lines and organoids. Both immunocompromised and immunocompetent animals are available for characterizing how drugs will work with patients, including after standard treatment and after lower-toxicity combination therapies.

Dr. Evans is interested in partnerships that combine his expertise in drug screening with a partner’s medicinal chemistry knowledge and compound library access. Dr. Evans also has experience collaborating on clinical trials.

Stage of Development

  • Preclinical in vitro
  • Preclinical in vivo

Partnering Opportunities

  • Collaborative research and development
  • Sponsored research agreement
  • Consultation agreement
  • Research tool license agreement
  • Tissue samples and cell lines
  • Clinical trial collaboration

Publications

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