Bass Hassan

Sarcomas are a rare group mesenchymal derived cancers that arise in bone and soft tissues are frequently difficult to diagnose and treat. They each exhibit 80-100 different genotype-phenotype mechanistic drivers that range from either gain of function (oncogenic) driver events or loss of function (tumour suppressor).  We first became interested in sarcomas as they frequently disrupt epigenetically regulated imprinted genes.  Gene dosage interactions between two reciprocally imprinted genes (mono-allelic expression) disrupted in cancers such as sarcomas was the basis of our initial genetic, structure and functional approach.  Here, growth promoting Insulin-like growth factor 2 ligand and its negative regulator, the IGF2/ Mannose 6-phosphate receptor (IGF2R) are reciprocally imprinted (parent of origin dependent allelic silencing).  IGF2R acts as a tumour suppressor by binding IGF2 with high affinity and selectivity and targets it for degradation.  Structural determination of the IGF2 binding domain led to an IGF2R domain 11 directed evolution screen that led to the generation of Fc-domain 11 mutated versions as high affinity soluble ligand traps for IGF2.  Sarcoma’s can be very large tumours (kgs) and supply so much IGF2 that blood levels become sufficient to activate the insulin receptor and induce hypogylcaemia (tumour associated hypoglycaemia).   IGF2-TRAP administration reverses IGF2 induced hypoglycaemia in vivo and is the basis a selective human therapeutic.

In the last few years, we have developed human in vivo discovery clinical trials in bone sarcoma and established in vitro functional perturbation screens with CRISPR.  The former has led to ‘bedside to bench’ experimental studies in Ewing sarcoma and the latter to a series of isogenic sarcoma cell line screens. Using enAsCas12a and multi-plex gRNAs, the functional co-dependencies of oncogenic gain of function and tumour suppressor loss of function exploits cancer specific functional vulnerabilities. Genomic based co-dependencies, such as synthetic lethality are ongoing in a variety of sarcoma subtypes, e.g. osteosarcoma, MPNST, leiomyosarcoma, rhabdomyosarcoma and Ewing sarcoma.  Moreover, we have utilised a genome wide neoantigen discovery pipeline in selected sarcomas (Ewing sarcoma, Rhabdomyosarcoma and MPNST) to select for peptides derived from somatic driver genomic targets for MHC presentation and immune T-cell based selection.  These projects are currently integrated with a translational project called the Oxford Precision Oncology for Sarcoma (OxPOS) programme, where the basis for genomic based selection of co-targeting strategies and mRNA-based sarcoma vaccines can be corroborated in a real world human high grade sarcoma cohort prior to future mechanistic clinical studies.  For the work on neoantigen-TCR recognition, we have recently focused on translocation driven fusion gene neoantigens in sarcoma’s such as Rhabdomyosarcoma and Ewing sarcoma, the former funded by a grant from Alice’s Arc RMS charity.