New Treatments for Pediatric Brain Cancers
Identifying new drug targets and screening compounds using patient-derived in vitro and in vivo tools
Technology Overview
Dr. Myron K. Evans II
Brain tumors are the leading cause of pediatric cancer deaths. The standard treatments of high-dose chemotherapy and radiation have long-term adverse effects on children, including severe developmental delays and cognitive problems.
Brain development and pediatric neuro-oncology researcher Myron K. Evans II, PhD, identifies novel targets and drugs for more effective, less toxic treatment of pediatric brain tumors. His laboratory has a broad array of 2D and 3D pediatric brain tumor models for in vitro and in vivo assays, including patient-derived cell lines and organoids, and immunocompromised and immunocompetent xenograft animal models.
One focus of the Evans Lab is epigenetic drug targets, based on major epigenetic dysregulation (e.g., changes to histone modifications) seen in most pediatric brain tumors. In diffuse intrinsic pontine glioma (DIPG), an aggressive brain cancer with a postdiagnosis survival of under 1 year, Drs. Evans and pediatric neuro-oncologist Nick Vitanza demonstrated striking antitumor effects in vitro and in vivo using histone deacetylase (HDAC) inhibitors that reach the brain. Dr. Evans is interested in partnerships to identify other novel DIPG therapeutic targets.
The Evans Lab identified the DNA/RNA-binding protein YBX1 as an epigenetic modulator in normal brain development. YBX1 is highly expressed in solid and blood cancers in children and adults and often correlates with poor prognosis. Dr. Evans is interested in partnerships to further his work determining how YBX1 functions in cancer and exploring its therapeutic promise.
Using large datasets, the Evans Lab demonstrated YBX1 overexpression in nearly all pediatric brain tumors, both primary and relapse. They showed that small molecule antagonism of YBX1, alone or combined with radiation or standard chemotherapies such as gemcitabine, vincristine, and/or cisplatin (GVP), reduced tumor proliferation in vivo and in vitro. Dr. Evans is interested in working with industry partners to define the YBX1 mechanism of action, to support developing the small molecule as a new therapeutic.
The Evans Lab has the capability to screen additional small molecules that cross the blood-brain barrier for effectiveness against aggressive cancers. They are testing small molecules that sensitize tumor cells to chemotherapeutic agents and radiotherapy, which would enable lower doses of these standard treatments.
Using whole-genome CRISPR-Cas9 screening of animal and human medulloblastoma models, Dr. Evans has identified multiple drug targets in the pyrimidine nucleoside pathway. His team showed that targeted inhibition of CTPS1, the rate-limiting enzyme in pyrimidine synthesis, decreases tumor cell proliferation in vitro and in vivo by targeting hyperactive MYC. After linking CTPS1 inhibition to a cell-survival pathway mediated by the checkpoint kinase CHK1, the researchers found that combination therapy targeting CTPS1 and CHK1 effectively kills tumor cells in vitro and increases animal model survival in vivo. This work demonstrates the Evans Lab's expertise and capacity for large-scale drug candidate testing.
Dr. Evans is interested in partnerships to identify targets and optimize hits; determine mechanisms of action; and develop screening assays in animal models, patient-derived cell lines and organoids. His lab has expertise in screening compounds and libraries for effectiveness against an array of pediatric brain cancers, particularly for drugs targeting epigenetic modifications or metabolic pathways including, but not limited to, pyrimidine synthesis. 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
- Hathaway MR, Gadek KE, Jaganal HL … Evans MK. CTPS1 inhibition synergizes with replication stress signaling inhibition in MYC-amplified Group 3 medulloblastoma. bioRxiv. 2024:06.03.597242.
- 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.
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