Multiple genes simultaneously regulate growth, survival and the propensity for cancer cells to disseminate to other body sites. We are currently focused on the functional mechanisms that co-ordinate these phenotypes in cancers of bone and soft tissues (sarcomas). Ultimately, our aim is to identify and validate functional co-dependencies and to evolve the experimental basis of co-targeting strategies that improve precision (personalisation) of treatment.
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IGF2 TRAP
TKI Ewing sarcoma
Our previous work mainly concerned gene dosage interactions between two reciprocally imprinted genes (mono-allelic expression) that are disrupted in cancers. The genes for the 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). The relative dosage of both genes is critical for normal mammalian development and is the reason for mammalian sexual reproduction. We showed that in murine cancer models disruption of IGF2 supply (both loss of imprinting and mutation of IGF2R) results in tumour progression. IGF2R negatively regulates IGF2 by binding with high affinity and selectivity. Following structural determination of the IGF2 binding domain, we discovered that IGF2R domain 11 evolved prior to genomic imprinting in monotremes. Directed evolution then led to the generation of Fc-domain 11 mutated versions that act as specific and high affinity soluble ligand traps for IGF2, reversing IGF2 induced hypoglycaemia in vivo (IGF2-TRAP). IGF2-TRAP is the basis of a novel human therapeutic that can reverse excess IGF2 in tumour associated hypoglycaemia syndrome and where IGF2 acts as a resistance mechanism to single target signalling blockade.
Our current work is focused towards sarcomas, at least 80 different and complex cancers derived from mesenchyme. Through investigation of functional co-dependencies of oncogenic gain of function and tumour suppressor loss of function, we aim to define the contexts for both lethality and the immune recognition of cancer as non-self. Exploiting cancer specific functional vulnerabilities is a pre-requisite for effective personalisation of cancer therapy. For example, using functional screens in human sarcoma cell lines based on whole genome CRISPR/Cas12a dual sgRNA libraries, we have validated novel dependent mechanisms to a receptor tyrosine kinase inhibitor identified in a human clinical study in Ewing sarcoma (expressing EWS-FLI1 fusion genes). Further investigation of genomic based co-dependencies such as synthetic lethality is ongoing in a variety of sarcoma subtypes. Moreover, we have utilised a genome wide discovery pipeline in Ewing sarcoma, Rhabdomyosarcoma and MPNST to select for somatic genomic target MHC presentation and immune T-cell based selection. This work is integrated with our translational Oxford Precision Oncology for Sarcoma (OxPOS) programme.
2022
Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial).
Barnes, D.J., Dutton, P., Bruland, Ø., Gelderblom, H., Faleti, A., Bühnemann, C., van Maldegem, A., Johnson, H., Poulton, L., Love, S., Tiemeier, G., van Beelen, E., Herbschleb, K., Haddon, C., Billingham, L., Bradley, K., Ferrari, S., Palmerini, E., Picci, P., Dirksen, U., Strauss, S.J., Hogendoorn, P.C.W., Buddingh, E., Blay, J.Y., Cleton-Jansen, A.M. and Hassan, A.B.
BMC Cancer – 22(1):269.
2020
Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9.
Bochel, A. J., Williams, C., McCoy, A.J., Hoppe, H.J, Winter, A.J., Nicholls, R.D., Harlos, K., Jones, E.Y, Berger, I., Hassan, A.B. and Crump, M.P.
Structure – 28(12): 1300-1312.e5.
2019
Maternal transmission of an Igf2r domain 11: IGF2 binding mutant allele (Igf2r(I1565A)) results in partial lethality, overgrowth and intestinal adenoma progression.
Hughes, J., Surakhy, M., Can, S., Ducker, M., Davies, N., Szele, F., Buhnemann, C., Carter, E., Trikin, R., Crump, M.P., Frago, S. and Hassan, A.B.
Scientific Reports – 9(1): 11388.
2016
Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent.
Matheson, J., Bühnemann, C., Carter, E.J., Barnes, D., Hoppe, H.J., Hughes, J., Cobbold, S., Harper, J., Morreau, H., Surakhy, M. and Hassan, A.B.
Oncotarget – 7(43): 69883-69902.
2016
Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.
Frago, S., Nicholls, R.D., Strickland, M., Hughes, J., Williams, C., Garner, L., Surakhy, M., Maclean, R., Rezgui, D., Prince, S.N., Zaccheo, O.J., Ebner, D., Sanegre, S., Yu, S., Buffa, F.M., Crump, M.P. and Hassan, A.B
Proc Natl Acad Sci USA. – 113(20): E2766-75.
2012
An exon splice enhancer primes IGF2:IGF2R binding site for structure and functional evolution.
Williams, C., Hoppe, H., Rezgui, D., Strickland, M., Frago, S., Forbes, B., Gutzner, F., Ellis, R.Z., Wattana-Amorn, P., Prince, S.N., Zaccheo, O.J., Jones, E.Y., Crump, M.C. and Hassan, A.B.
Science – 338(6111): 1209-13.