Progamme title: Chromosomal translocation genes and their protein interactions in cancer
Summary: Specific chromosomal translocations are found in tumours of all human cancer types and often involve activation of transcription factors that function in protein-protein and/or protein-DNA interaction. These features are pivotal in understanding how the proteins contribute to normal development and to tumourigenesis. Many oncogenic proteins are intracellular and involved in disparate functions. The work will involve studies of LMO2 and MLL transcription complexes as well as CMYC protein and mutant RAS. We will implement new fast throughput translocator methods to add tracking devices specifically to cancer initiating cells and use new technologies involving single antibody domains as drug surrogates to study function. The programme will contribute to understanding of basic problems in haematopoiesis and cancer biology and to the unmet need of cancer target validation and corroborating protein complexes as targets for therapy.
Awarding Body: Medical Research Council Programme Grant
Dates: 2012- 2017
Awarding Body: Wellcome Trust Senior Investigator Award
Summary: This grant will allow us to use models of cancer progression to determine the changes associated with the development of cancer from initiation to overt cancer. We will be comparing the genes and proteins that are expressed as tumours evolve in these different cancer models using next generation sequencing RNA-seq with special emphasis on expression of genes for surface proteins and transcription factors. These studies will identify new markers for diagnosis and new targets for therapy
Progamme title: Tracing cancer evolution using mouse models
Dates: 2012- 2018
Awarding Body: Bloodwise (formerly known as Leukaemia & Lymphoma Research) Programme Grant
Progamme title: Targeting protein-protein interactions in leukaemia for novel therapeutics
Dates: 2013- 2018
Summary: Many therapeutic targets in leukaemia are intracellular proteins and not enzymes that can be targeted by active site inhibitors, but rather they function via protein-protein interaction (PPI) networks. In this programme, we will use methods involving small antibody fragments, selected from diverse libraries, for use inside cells to block specific PPIs.. Further, we will use these antibody fragments as templates for isolating small compounds (as drug progenitors) that mimic the interaction surface, using a combination of small molecule library screening and in silico modeling. The Programme will implement and develop translational research objectives, focused on LMO2, RAS and MLL protein complexes.
Awarding Body: Wellcome Trust Seeding Drug Development Award
Summary: The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, we have characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Small molecules will be identified that bind to RAS at the same point of contact as the anti-RAS VH. The Award will be used to develop these hits through to leads and ultimately the identification of preclinical development candidates.
Progamme title: Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using single antibody domain surrogate emulators
Dates: 2013- 2017
Awarding Body: EPSRC
Programme Title: OxCD3: Oxford Centre for Drug Delivery Devices
Co-Investigator: Professor Constantin Coussios, (PI)
Dates: 2014 - 2019
Summary: Our group will be part of the new Oxford Centre for Drug Delivery Devices, starting in July 2014, to develop new methods for drug delivery. New techniques have produced many macromolecules (e.g. antibody fragments) that function in the intracellular environment and these have potential to be drugs but the limitation is in delivering these macrodrugs to their site of action. The OxCD3 work will allow us to interact with experts in the Oxford Centre working with new drug delivery techniques to implement clinical delivery of our high affinity antibody fragments for cancer treatment.