Exploiting nuclear envelope mislocalisation as an immunotherapeutic vulnerability in MYC-Driven Medulloblastoma

Primary supervisor: Sheila Singh, King’s College London

Secondary supervisor: John Anderson, UCL

Project

Medulloblastoma (MB) is the most common malignant pediatric brain tumour comprised of four molecular subgroups (WNT, SHH, Group 3, and Group 4). Among these, MYC-driven Group 3 MB (MYC-G3MB) represents an aggressive subtype characterized by resistance to standard of care (SoC). Effective and brain-sparing therapeutic strategies for this high-risk population remain an urgent unmet need. The Singh lab has applied our non-canonical target discovery platform comprising site-specific proteomics to reveal nuclear envelope (NE) proteins lamin B receptor (LBR) and thymopoietin (TMPO) are highly expressed in MYC-G3MBs and aberrantly localize to the plasma membrane only in this MB subtype, and not in normal cells. Orthogonal validation confirms restriction of this unexpected finding to MYC-G3MBs, with expected nuclear membrane and intracellular expression in human neural stem cells (hNSCs) and other MB subgroups. High resolution imaging and transcriptomic profiling associate mislocalization with hyperproliferative tumour cell states and features of NE dysregulation, including NE fracture, excessive DNA damage and chromosomal instability. Leveraging this cancer-specific vulnerability, we generated single domain antibodies (sdAbs) against the exposed N-termini of LBR and TMPO and now proposed to engineer novel chimeric antigen receptor (CAR) T cell therapies against these dynamic NE targets. CAR T cell engineering principles that address low-density targets that are dynamically expressed on the cell surface will be considered in the design of a new therapeutic strategy and it is here the expertise of the Anderson lab is employed. Anderson laboratory has proven expertise in addressing low density but very specific targets such as ALK with both endodomain CAR library and ScFv library approaches. They have also developed other elegant and innovative methods to allow dimerization of two separate CARs in the same cell, which mitigates antigen loss variants (via an OR gate). This project will thus use the strengths of the Singh and Anderson labs to generate novel CARs that target nuclear envelope proteins aberrantly mislocalized to the cell surface that mark a hyperproliferative, treatment-resistant, recurrent MB tumor cell population. Collectively, this project will exploit aberrant surface exposure of NE proteins as an immunotherapeutically actionable vulnerability in MYC-G3MB, establishing a previously unrecognized class of cancer cell state-specific surface targets for clinical translation.

Candidate background

The candidate should possess a strong background in molecular biology and biochemistry, and prior experience in cell and tissue culture, cloning or other molecular biology techniques will be valuable. Prior experience in cancer biology, developmental biology, neuroscience or immunology would be assets for this project. An interest in brain cancer, childhood cancers, immunotherapy development or CAR T cell engineering would be welcome.

Potential placements

1. Karin Straathof, Institute of Child Health, UCL
2. Laura Donovan, Institute of Child Health, UCL
3. Denise Sheer, Centre for Genomics and Child Health, Queen Mary University of London

References

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