QMUL Confidence in Concept 2014
Lead Research Organisation:
Queen Mary University of London
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The Confidence in Concept scheme is a key part of MRC’s translational research strategy and provides annual awards to institutions, to be used flexibly to support the earliest stages of multiple translational research projects. The award can be used by the institution to support a number of preliminary-stage translational projects. The projects supported should aim to provide sufficient preliminary data to establish the viability of an approach –– before seeking more substantive funding. It is intended to accelerate the transition from discovery research to translational development projects by supporting preliminary work or feasibility studies to establish the viability of an approach.
People |
ORCID iD |
Publications
Ogbe A
(2015)
Early Growth Response Genes 2 and 3 Regulate the Expression of Bcl6 and Differentiation of T Follicular Helper Cells.
in The Journal of biological chemistry
| Description | Industrial award |
| Amount | £490,000 (GBP) |
| Funding ID | New targets in IBD |
| Organisation | Johnson & Johnson |
| Sector | Private |
| Country | United States |
| Start | 01/2015 |
| End | 02/2019 |
| Description | Industrial collaboration |
| Amount | £93,000 (GBP) |
| Funding ID | Oncostatin M in IBD |
| Organisation | GlaxoSmithKline (GSK) |
| Sector | Private |
| Country | Global |
| Start | 01/2018 |
| End | 09/2019 |
| Description | Industrial funded PhD |
| Amount | £64,221 (GBP) |
| Funding ID | A new drug target for the combined treatment of inflammatory disorders and emotional wellbeing' |
| Organisation | UCB Pharma |
| Sector | Private |
| Country | United Kingdom |
| Start | 05/2018 |
| End | 04/2021 |
| Description | MR/N009185/1 Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation. |
| Amount | £380,207 (GBP) |
| Funding ID | MR/N009185/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2016 |
| End | 05/2019 |
| Description | Response Mode |
| Amount | £330,000 (GBP) |
| Organisation | Barts Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 03/2019 |
| Description | Response mode |
| Amount | £560,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2017 |
| End | 12/2019 |
| Description | Response mode funding |
| Amount | £200,000 (GBP) |
| Funding ID | Development of an effective vaccine regimen particularly targeting triple-negative breast cancer |
| Organisation | Breast Cancer Now |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2016 |
| End | 04/2018 |
| Description | Confidence in Concept-Crnogorac-Jurcevic |
| Organisation | Cancer Research Technology (CRT) |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | M1. Successfully radiolabelled the two monoclonal mouse anti-human AGR2 antibodies (P1G4 and P3A5) using 125Iodine (P1G4: 90% radiolabelling efficiency; P3A5: 30%). Using a subcutaneous pancreatic cancer xenograft model we showed a good intratumoral uptake of the purified antibodies 48h after injection, as shown by SPECT/CT imaging for P3A5. These data proved that AGR2 expressing-pancreatic cancer cells can be specifically immunotargeted in vivo using the two antibodies. M2. The biodistribution experiment was performed with both AGR2 mAbs (P1G4, P3A5) and one control IgG antibody using three groups of mice (two mice per group). A high uptake of P3A5 mAb in the tumours was noticed (> 40% injected dose) as well as some uptake in lungs and spleen after 48 hours. M3. P1G4 mAb appeared to show a very poor uptake, and was low even in blood. This was highly likely due to initial low specific activity of injected radiolabelled antibody. However, data were available from only one mouse as the second one died during the experiment. The Immunotherapy experiment has not yet been completed but is being undertaken at St Georges medical. Completion is predicted within the next few weeks. Arumugan et al. showed that AGR2 blocking antibodies could inhibit in vivo pancreatic tumour growth and metastasis leading to increased survival in xenograft mouse models (Arumugam et al., PMID:25646014). These results provided a strong independent proof of concept that AGR2 antibodies are indeed promising tools for PDAC therapy. For pre-clinical validation of our immune strategy, a Patient Derived Xenograft (PDX) model is used, which is the most clinically relevant PDAC model. Tumours derived from primary cell lines of PDAC patients are currently growing subcutaneously in immunodeficient CD1 mice. Treatment with P1G4 and P3A5 antibodies (15g/kg of body weight) alone or in combination with Gemcitabine, the standard first-line chemotherapy drug used in clinic, will start shortly. Animals will be treated by intraperitoneal injection twice a week for 4 weeks. The results of this in vivo therapeutic experiment will be obtained in the next few weeks. The delay was faced as work had to be transferred to St George's due to the flooding of the BSU at the William Harvey Institute and re-building works will not be completed for a few months. |
| Collaborator Contribution | Two of our translation partners have arranged to discuss this project: SBC and CRT/CRUK. The meeting is planned with CRT on 19 October to explore the potential for collaboration. We are also discussing the possibility of licensing the biomarker PDAC technology into a spin-out company with a well- known VC and this project could be offered as part of the package to provide the therapeutic component with the diagnostic analysis. |
| Impact | None |
| Start Year | 2015 |
| Description | Confidence in Concept-D'Acquisto |
| Organisation | Medannex |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | M1. Six rats have been subjected to genetic immunization with immuno-moodulin (Imud) construct generated by Aldveron. Splenocytes from each rat were used to create hybridomas and their supernatants used for screening against Imud-transfected cells. 15 clones were selected and tested in vitro using western blotting and immunoprecipitation. Among all the screened antibodies we identified two of interest. M2. BLP-1B10 was the clone that 1) immunoprecipitated the native recombinant Imud; 2) did not recognise the protein in Western blotting and 3) selectively recognised the 25kDa form of Imud. Conversely, BLP-1C4 was the clone that 1) immunoprecipitated the native recombinant Imud; 2) worked in western blot and 3) selectively immunoprecipitated the 31kDa form of Imud. M3. These two clones were selected for the final step i.e. the purification of the antibody and the testing of these in vivo. Purified antibodies were tested against home-made recombinant Imud produced by the research team. Both recombinant Imud and purified antibodies (BLP-1B10 and BLP- 1C4) were tested in vivo using the light/dark shuttle box as mouse model of anxiety like behaviour. In this test the exploratory activity reflects the combination of hazard and risk avoidance. Administration of recombinant Imud (500ng, i.p.) in male C57BL/6 mice caused a significant reduction (at least 50%) in the number of transitions (i.e. the number of passages between the dark and light boxes) or in the time spent in the lit compartment (both parameters being an index of increased anxiety). Conversely, administration of1B10 or 1C4 antibodies caused a significant increase in the time spent in the lit side of the box and in the number of crossings. Together these results show that modulation of Imud levels in vivo significantly alters anxiety-like behaviour in mice |
| Collaborator Contribution | Prof D'Acquisto has, with QMI, been successful in out-licensing an immunomodulatory antibody and associated IP to spin-out company Medannex Ltd, which generated revenues for QMUL for £257,000. Antibody-based therapies such as this would offer a step change against current therapies that are based on small molecules: a biologic will require a single administration which is very desirable in patients suffering from mental disorders (often showing poor compliance as result of their very own disease). |
| Impact | None |
| Start Year | 2015 |
| Description | Confidence in Concept-Sharp |
| Organisation | Prestwick Chemical Library |
| Country | France |
| Sector | Private |
| PI Contribution | Purchase Prestwick Drug library (collection of 1080 small molecules, 100% approved drugs (e.g. FDA, EMA). Also the Selleckchem FDA approved library (1177). In addition, at no extra cost, we obtained 500 compounds/drugs chemical tools from IRC Sutton. |
| Collaborator Contribution | 1. Purchase Prestwick Drug library (collection of 1080 small molecules, 100% approved drugs (e.g. FDA, EMA). Also the Selleckchem FDA approved library (1177). l In addition, at no extra cost, we obtained 500 compounds/drugs chemical tools from IRC Sutton. |
| Impact | Drug screening to inhibit LIMD1 in cancer |
| Start Year | 2015 |
| Description | Confidence in Concept-Wang |
| Organisation | Medical Research Council (MRC) |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Synthesis of cell permeable Egr2 functional domain. YPCPAEGCDRRFSRSDELTRHIRIH peptide will be commercially synthesised and tested for cell membrane permeability before use. The interaction of this peptide with Egr2 binding sequence will be tested by EMSA (electrophoretic mobility shift assay) to confirm its binding ability to Egr2 binding sites. EMSA is one of the working technologies established in this group. M2. Inhibition of IFNg and IL17 production in human CD4 T cells by Egr2 peptide. The peptide can effectively inhibit the production of IFNg in Egr2 deficient mouse CD4 T cells and also reduces production of IFNg in normal human CD4 T cells following activation in vitro. The results may suggest a screening model for selection of anti-inflammation drugs. PCR analysis showed reduced Il-17 production in Egr2- deficient cells following peptide treatment although it was less marked than IFNg. It was demonstrated that the peptides can restore Egr2 function in suppression of IFNg production in Egr2 deficient T cells. From titration assays, the peptides can achieve 50% suppressive effect for IFNg production at a concentration of 10nM. Wang et al have carried out a test assay for inhibition of IFNg production by T cells from inflammatory bowel disease patients and MS patients. With limited cases, it is not possible to firmly conclude their efficacy. However, the peptide achieved similar rate of permeability in human T cells as in mouse T cells. Wang et al have now accumulated 20 cases for IBD and 7 for MS and will carry out tests for all peptides over the next few weeks. M3. It was found that Egr2 did not affect the development of Th1 and Th17 cells in vitro under artificial conditions, but reduced production of IFNg and IL17 in activated CD4 T cells in general. M4. It was successfully shown that the peptide did not affect normal function of T cells in proliferation and production of Il-2. M5. Reverse inflammatory phenotype of CD4 T cells from MS patients by Egr2-peptides. Cells from five patients were tested and three of them had an inflammatory response in their CD4 T cells indicated by over- production of Il17 and IFNg. Peptide reduced the production of both cytokines in two patients (ie 2./3). Wang et al are in the process of testing and are addressing ethical and materials issues associated with the use of primary human tissues before proceeding. M6. Screening model. An early screening model has been developed in vitro with human T cell line Jurkat cells which is being developed and which has generated preliminary interest from MRCT- to allow us to further screen for small molecules as an additional approach to the peptide therapy. |
| Collaborator Contribution | Funding for more studies on egr2 |
| Impact | none |
| Start Year | 2015 |
| Description | Confidence in Concept-Wang Y |
| Organisation | Cancer Research Technology (CRT) |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Progress against Milestones M1. Identification of potential kinases that phosphorylate t-Darpp at Thr75 and Ser137 (M1 met). By constructing a mutant t-Darpp plasmid (in which t-Darpp cannot be phosphorylated at Ser137), Wang's group has identified that phosphorylation of Darpp at Ser137 is important for t-Darpp- mediated Herceptin resistance: this is a new and possibly patentable finding. Ser137 can be phosphorylated by Casein Kinase (CK)1, DNA PK, CK2 and ATM kinase (ATM). Phosphorylation at Thr75 is effected by CDK5. The CK1 and CK2 inhibitors were first used to analyse cell survival and reduction of phosphorylation of t-DARPP both at Thr75 and Ser137. Firstly, it was observed that CK1, CK2 inhibitors and UO126 (a MEK inhibitor that blocks ERK phosphorylation) treatments sensitise cancer cells to Herceptin reducing cell survival by 40-60% when individual inhibitors were combined with Herceptin. These cellular responses were associated with inhibition of Ser137 phosphorylation by blocking the CK1, CK2 or ERK pathways. The three inhibitors could be used as potential therapeutic agents to overcome Herceptin resistance. In vivo validation of anti-tumour efficacy by combination of CK1 or CK2 inhibitor and Herceptin using BT-474 HerR xenografts tumour models are ongoing. : M2. Evaluation of anti-tumour efficacy by combination of kinase/phosphatase inhibitor and Herceptin in vitro) and new milestone Validation of t- Darpp as a direct target for Herceptin resistance. Given that Darpp-32 is an unstructured protein, it is difficult to directly target Darpp-32 to design a drug. Using computational software, Wang et al. made a predicted structure of t-Darpp, which suggests that HEME is a potential ligand to t- Darpp. The effect of HEME (clinically used drug for treating porphyria) on Herceptin treatment was tested in vitro on Herceptin resistant cell lines. Strikingly it was found that HEME alone has no effect on the cell survival but 20µM Hemin sensitises Herceptin treatment with reduction of survival by 30-50%. In vivo validation of anti-tumour efficacy by combination of Hemin and Herceptin using BT-474 HerR xenografts tumour models are in the process of development. M3. Evaluation of a new cancer therapeutic regime to overcome Herceptin resistance in vivo. Due to the refurbishment of Biological Service Unit at QMUL, this milestone has been delayed. In summary, this project has provided new biology to guide the identification of CK1 and CK2 as potential targets for development of new therapeutics overcoming Herceptin resistance. Screen or design new small compounds that specifically target CK1 and CK2 kinase for overcoming Herceptin will be sought resistance with one of our translation partners. Additionally, t-Darpp itself might be targetable: Heme could be repositioned as a potential drug for overcoming Herceptin resistance although the in vivo anti-tumour efficacy by combination of Heme with Herceptin has yet to be tested. |
| Collaborator Contribution | We have met with a CRO small molecule provider, Selcia who have asked to re-engage when the PoC studies in the in vivo xenograft model have been completed. There are also plans to meet with Domainex, CRT and MRCT to discuss the potential for identifying a new small molecule drug(s) that can modify the effect of t-Darpp. |
| Impact | None |
| Start Year | 2015 |