Discovering inhibitors of gain-of-function Phospholipase C gamma1 for T-cell lymphomas

This proposal is aimed at creating medicines that can control a protein called Phospholipase Cgamma1, for use in the treatment of a subtype of blood cancers, known as T-cell lymphomas. It is based on clinical insight provided by our team, including those treating patients with this disease and the recognition of a need for improved therapies. We have long-term expertise on the proposed target molecule. We believe we have established a set of interconnected experimental and screening approaches that will provide the route to new treatment options, and would now like to turn these advances into a medicine, with the help of the access to the AstraZeneca screening collection to start our drug discovery efforts. Although this proposal focuses on T-cell lymphomas, drugs obtained for this purpose will be also useful for a range of other diseases caused by deregulation of the same target.

We propose to generate inhibitors to target gain-of-function PLCgamma1 variants in the context of dysregulated T-cell signalling, for the treatment of T-cell lymphoma. This is a relatively rare cancer, with dismal prognosis for more aggressive forms. A need remains for a selective agent that targets biology specific to these cells.

This proposal is based on clinical insight provided by our team. Dr Lucy Cook is not only treating the patients but recently led a consensus for a best practice and has opened clinical trials while Professor Charles Bangham has the long-term involvement in defining the mechanism of leukaemogenesis in T-cell lymphoma (in particular ATL). Notably, the proposal also exploits our expertise in PLCgamma enzymes in physiology and pathology and a focus on structural and mechanistic aspects of their regulation, provided by the Katan team. Based on our recent structural insights (collaboration with AstraZeneca) and further characterization of the variants supporting a distinct conformation of gain-of-function proteins, we are in a leading position to take the proposed approach. This proposal also builds on our current, MRC-funded project (Assessing new therapeutic opportunities linked to TCR signalling in mature T-cell lymphomas with unmet need) led by Professors Katan and Bangham.

Dr Richard Angell has participated in generating leads for a number of novel targets at UCL, including two Open Innovation collaborations with AstraZeneca. The team has extensive experience of working effectively with the AstraZeneca team.

We propose to carry out a high throughput screen for PLCgamma inhibitors using the AstraZeneca proprietary compound library. Primary assay development has been completed by the Academic Partners (Dr Trevor Askwith, Dr Tom Bunney) and the downstream cascade assays identified. Small-scale reagent generation has also been performed and we are in a position to generate the reagents required for a high throughput screen.

Patients, Academics, Clinicians, commercial private sector and charities will benefit from this research.

1. Patients will benefit from this research. Many forms of T- cell lymphoma, including ATL, remain a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. A recent review of current clinical practice proposed a new consensus for a best practice that would result in improvements but would not be sufficient to overcome dismal prognosis. Importantly, this expert consensus highlights the need for additional test compounds and clinical trials to develop novel standard therapies for the treatment. I particular, there is a need for a selective agent that targets the tumour biology specific to these cells.

Successful identification of hit molecules from this screening proposal will be the first step towards identification of novel treatments for this group of poorly treated patients. Success of this approach will improve quality of life and make a positive contribution to the economy by alleviating the financial burden on the NHS and by generating new jobs. Such advances would strengthen the UK's position in terms of international research leadership that would in turn attract new economic investment.

2. This award will allow the Academic Partners to initiate a drug development programme, with a view to generating anti-cancer therapeutics. Academics interested in the research areas of cell signalling and oncology will benefit from our research. Furthermore,

In addition, the inhibitors generated in this study will provide currently missing tools in the PLC- field. General lack of reliable pharmacological inhibitors for PLC enzymes hampered efforts to fully assess their biological roles and complement data using other approaches such as knockout and knockdown of PLC proteins or inhibition of other components in the pathways. We believe that these new reagents will be of wide-spread interest to the research community, both academic and commercial.


3. Clinical academics interested in treating patients currently poorly served by existing therapies will benefit from this research, particularly those treating T-cell lymphoma patients. Additionally, those involved in other diseases linked to mutations in PLCgamma enzymes (PLCgamma1 in angiosarcoma and PLCgamma2 in immune disorders and CLL resistant to Btk-inhibitors) will also benefit from this research.

4. New IP and know-how generated could be licensed by the commercial private sector to generate future economic return for the University and the companies involved.

5. Charities may also benefit by having a tangible benefit against which to raise funds.

Finally, the researchers working on the project will benefit from engaging with scientists from different backgrounds. This will seed new ideas, forge further new collaborations and secure future research funding.