Targets and Treatments for Pediatric Brain Tumors

Identifying novel targets for combination therapies that reduce toxicities of treating childhood medulloblastomas

Technical overview

Dr. Myron K. Evans IIBrain tumors are the leading cause of death among pediatric cancers and show substantial disparities in occurrence and survival. The most common pediatric brain tumors are medulloblastomas, for which the standard treatment is high-dose chemotherapy and radiation. These intensive therapies have long-term effects on children, including severe developmental delays and cognitive problems. Medulloblastoma recurrence is also high. Dr. Evans has expertise in preclinical identification and validation of novel candidates for targeted therapies that could be added to the current standard treatment. Combination therapy with a targeted drug has the potential to reduce treatment-associated toxicities.

Dr. Evans is particularly focused on Group 3 medulloblastomas, which often have amplification of the MYC oncogene as a prognostic marker. For patients with these tumors, 5-year survival rates are less than 50%. However, MYC itself has multiple functions, some of which are required for normal cellular function, so the Evans lab is circumventing the direct targeting of MYC and taking three approaches to identify novel targets. Some of these targets are associated with MYC function in cancer cells, allowing for more specific treatment of Group 3 medulloblastomas and creating the possibility of applications in other cancers with MYC amplification.

Using data from functional genomic screens, including from the Broad Institute Pediatric Cancer Dependency Map, Dr. Evans identified several potential medulloblastoma-specific drug targets. For example, the Mediator complex, a central integrator of transcription, is associated with MYC amplification in pediatric medulloblastomas. The Evans group is determining the mechanisms by which the Mediator complex is involved in medulloblastoma, for example through regulating transcription factors or direct chromatin binding. As an additional unbiased method for identifying novel druggable targets, Dr. Evans is conducting whole-genome CRISPR/Cas9 library screening of mouse and human medulloblastoma models.

Dr. Evans also studies the epigenetics of pediatric brain tumors, based on work showing alterations such as histone modifications in Group 3 medulloblastomas. Dr. Evans has identified factors including DNA- and RNA-binding proteins that interact with epigenetic modifiers. He is investigating these factors and the histone methyltransferase, EZH2, as potential drug targets.

Metabolic pathways are another rich area of potential targets. MYC-driven cell proliferation depends on pathways such as glycolysis, oxidative phosphorylation, and biosynthesis of certain amino acids. Dr. Evans is exploiting synthetic lethalities between genes required for medulloblastoma growth and metabolic enzymes to identify additional actionable targets for pharmacological interventions.

Dr. Evans has expertise in drug screens with small molecules and other compounds. His lab is equipped for 2-D and 3-D in vitro studies with human cell lines and organoids. His group's main in vivo model is mice with patient-derived xenografts. Both immunocompromised and immunocompetent mouse models are available for fully characterizing how drugs will work with patients, including after treatment.

Dr. Evans is interested in partnerships that combine his expertise with in vitro and in vivo drug screening with a partner's medicinal chemistry knowledge and compound library access. The Evans group is building a library of treatment-naïve and post-treatment patient tissues, for example for mouse xenograft models. 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

• Langdon CG, Gadek KE, Garcia MR, Evans MK, et al. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity. Nat Commun. 2021;12(1):5520.
• Evans MK, Matsui Y, Xu B, et al. Ybx1 fine-tunes PRC2 activities to control embryonic brain development. Nat Commun. 2020;11(1):4060.
• Yang X, Xu B, Mulvey B, Evans M, et al. Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1. Nat Neurosci. 2019;22(3):362-373.
• Evans MK, Brown MC, Geradts J, et al. XIAP Regulation by MNK links MAPK and NFκB signaling to determine an aggressive breast cancer phenotype. Cancer Res. 2018;78(7):1726-1738.
• Evans MK, Sauer SJ, Nath S, et al. X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity. Cell Death Dis. 2016;7(1):e2073.
• Allensworth JL, Evans MK, Bertucci F, et al. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol Oncol. 2015;9(6):1155-1168.
• Evans MK, Tovmasyan A, Batinic-Haberle I, et al. Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death. Free Radic Biol Med. 2014;68:302-314.

Learn More

• Myron K. Evans II, PhD