Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

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Therapeutic targeting of NTRK2 rearrangements in diffuse midline glioma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Lay Summary

 

Diffuse midline glioma (DMG) is a malignant brain tumour arising in children representing a major unmet clinical need, with a 2-year survival rate close to zero. We recently discovered a proportion of children with DMG to have small genetic alterations in a gene called NTRK2. Although not previously seen in DMG, this gene is found in other cancer types, including brain tumours, and there are drugs available in the clinic which have proved beneficial in these cases. We wish to find out what these NTRK2 alterations are doing in the context of DMG, and to see whether such drugs will work here too. We predict that any benefit received may be short-lived, as DMG are complex tumours and may evolve ways to become resistant to the drugs. We will therefore also try to work out the way they do this, and design new combination treatments to overcome it. 

 

Executive Summary

Executive Summary 

We identified structural rearrangements involving NTRK2 to be enriched in H3.3K27M-mutant diffuse midline glioma (DMG), representing a potential novel therapeutic option in these otherwise incurable tumours. We will carry out a systematic bioinformatic re-evaluation of all extant data in DMG to further characterise the nature and prevalence of these alterations. We will also generate novel in vitro and in vivo models to test targeted inhibitors, with a view to identifying possible resistance mechanisms to single agent treatment, and novel combinatorial approaches to overcome them.  

 

Scientific Merit

We have recently undertaken several large-scale genomic analyses of high grade gliomas of children spanning all locations and ages. A striking finding was the frequent occurrence of gene fusions driving a large proportion of gliomas in patients under 12 months old, predominantly NTRKs, ALK, ROS1 and MET. Notably, NTRK2 was found with numerous novel partners (e.g. KCTD16:NTRK2 and AGBL4:NTRK2) but were largely seen in other glioma subtypes occurring in the appropriate anatomical locations, especially with H3.3K27M mutations in midline regions, suggesting an important difference compared to NTRK1/3 fusion-positive cases. Using a custom NGS fusion panel applied to the HERBY clinical trial cohort of non-brainstem glioma in children aged 3-18 years old, we identified eight cases presenting novel structural variants involving NTRK2. In addition to a novel inter-chromosomal translocation producing the fusion gene SLC4A4:NTRK2, seven cases were found to harbour novel somatic internal tandem duplications of NTRK2 (ITD-NTRK2), spanning the kinase domain and predicted to be activating. Additionalcases have been identified anecdotally in other laboratories and datasets, supporting our discovery of a novel therapeutically targetable ITD-NTRK2 with a potential enrichment in K27M positive DMG, and represent an exciting novel therapeutic option for these incurable tumours. We plan to complete a systematic bioinformatic re-evaluation of all extant sequencing data in DMG in order to fully characterise structural variation in NTRK2. We propose to explore the functional consequences of these ITDs through mouse modelling via in utero electroporation. We will use both engineered and patient-derived models for preclinical evaluation of relevant inhibitors in vitro and in vivo, and take advantage of our existing funded collaborations to explore resistance mechanisms via high-complexity barcoding, as well as approved drug screening to identify novel combinatorial approaches that may be rapidly translated to the clinic.

 

Feasibility

All bioinformatic, cell biology, and preclinical techniques are well established within the Jones lab and the ICR’s Biological Services Unit and Centre for Cancer Imaging. The proposal contributed towards a bioinformatician and an experienced laboratory scientist with the relevant expertise required for the success of this project. We are building on previously funded infrastructure in respect of preclinical screening (INSTINCT), CRISPR modelling (Brain Tumour Charity) and in utero electroporation (DIPG Collaborative), providing added value to the proposal. This initial grant is aimed at generating an achievable amount of data which would then be much more widely validated across multiple labs in a future application.

 

Expertise

The Jones lab is an international leader in the genomic characterisation of pGBM / DIPG samples, and has published extensively on the molecular profiling of these tumours as well as detailed functional assessment of their defining mutations. Chris Jones is biology lead on the HERBY and BIOMEDE clinical trials, former Chair of the Biology Subcommittee of the SIOPE HGG / DIPG Working Group, preclinical lead for the CONNECT consortium, and Steering Committee member for ITCC-Brain, allowing rapid dissemination of results and clinical translation. 

Description of Research Proposal

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

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