Neurotrophin Receptors in Brain Development and Gliomas

Investigating neurotrophin receptors in neural development and as gene fusions that are potential drug targets

Technical overview

Dr. Siobahn S. Pattwell, PhD

Normal brain development and brain tumors are linked, as demonstrated by the dysregulation in some cancers of the Wnt, Hedgehog, or Notch signaling pathways that are required for normal neural development. Another key process in normal nervous system growth, function, and maintenance is interactions between neural growth factors called neurotrophins and their corresponding receptors. This interaction also appears to be disrupted in cancers, including pediatric brain cancers.

Dr. Pattwell studies how neurotrophic factors and their receptors (TrkA, TrkB, TrkC, p75) function in normal brain development and how aberrant receptor variants contribute to cancer, specifically gliomas. In normal neural development, the receptors undergo specific RNA transcript splicing. Aberrant splicing can result in alternative isoforms with altered functions that contribute to cancer development. Dr. Pattwell is currently studying a kinase-deficient splice variant of one neurotrophin receptor, tropomyosin receptor kinase B (TrkB), that is the most abundantly expressed neurotrophin receptor in a range of tumors. Dr. Pattwell showed that overexpressing TrkB.T1 in mice leads to cancer.

In previous work, Dr. Pattwell developed a TrkB.T1-specific mouse monoclonal antibody as a research tool for studying this splice variant across developmental stages of normal neural development and brain cancers. Using a human microarray screen, Dr. Pattwell used the antibody to demonstrate that the splice variant is expressed in many adult tumors of diverse origin, raising the potential of using TrkB.T1 as a biomarker or for tumor-agnostic treatment approaches. The monoclonal antibody has also been engineered as a rabbit antibody.

Current drugs targeting neurotrophin receptors have multiple interactions and broad effects. Since the receptors are involved in normal neural development and brain function, treating children with these pan-receptor inhibitors could potentially have an impact on neurodevelopment or cognitive development. The Pattwell group is studying the origin and expression of TrkB.T1 and other variants, both to characterize their developmental functions and their aberrant splice variants and to identify factors that interact with TrkB.T1 and other neurotrophin receptors as potential drug targets.

Dr. Pattwell has expertise with in vitro and in vivo oncology and neuroscience research as well as in molecular properties associated with learning and memory in humans and in mouse models. She has experience with comprehensive expression analyses using single-cell RNAseq for analyzing transcriptomes across developmental stages. Other research tools and experience that Dr. Pattwell can contribute to a partnership are generation of engineered mice using the RCAS-TVA system. Advantages of this system over others for generating mouse cancer models include tumor development that more closely mimics the typical origin and progression of cancers. The TVA mice used in this system are immunocompetent, providing the opportunity to study the immune response to cancer development and treatment, including in the tumor microenvironment.

Dr. Pattwell is particularly interested in working with partners with biochemistry and protein-structure knowledge, to complement her expertise in characterizing drug targets for neurotrophin receptor fusions or splice variants, such as TrkB.T1.

Stage of Development

• Preclinical in vitro
• Preclinical in vivo

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Mouse model development
• Mouse and rabbit monoclonal research tool access and collaboration
• Molecular and behavioral neuroscience assays

Publications

1. Pattwell SS, Arora S, Cimino PJ, et al. A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways. Nat Commun. 2020;11(1):2977.
2. Randles A, Wirsching HG, Dean JA, Cheng YK, Emerson S, Pattwell SS, et al. Computational modelling of perivascular-niche dynamics for the optimization of treatment schedules for glioblastoma. Nat Biomed Eng. 2021;5(4):346-359.
3. Arora S, Pattwell SS, Holland EC, Bolouri H. Variability in estimated gene expression among commonly used RNA-seq pipelines. Sci Rep. 2020;10(1):2734.
4. Pattwell SS, Konnick EQ, Liu YJ, et al. Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) alterations in low-grade gliomas: Report of a novel gene fusion partner in a pilocytic astrocytoma and review of the literature. Case Rep Pathol. 2020;2020:5903863.
5. Jones RM, Pattwell SS. Future considerations for pediatric cancer survivorship: Translational perspectives from developmental neuroscience. Dev Cogn Neurosci. 2019;38:100657.
6. Pattwell SS, Liston C, Jing D, et al. Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat Commun. 2016;7:11475.
7. Pitter KL, Tamagno I, Alikhanyan K…Pattwell SS, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139(Pt 5):1458-1471.

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Siobahn S. Pattwell, PhD