Designing modulators of PI 3-kinase delta (PI3Kdelta) for the treatment of haematological malignancies

Lead Research Organisation: University College London

Abstract

This proposal is aimed at creating medicines that can control a protein called PI3Kdelta, for use in the treatment of blood cancers such as acute lymphoblastic leukaemia (ALL). It is based on clinical insight provided by our team, who are treating patients with this disease and recognise the need for improved therapies. We discovered PI3Kdelta and have long-term expertise on this molecule. We believe we have found news ways to modulate PI3Kdelta to treat leukaemia, and would now like to turn these concepts into a medicine, with the help of AstraZeneca.

Technical Summary

We propose to generate modulators of the leukocyte-expressed PI3Kdelta, for the treatment of haematological malignancies such as acute lymphoblastic leukaemia (ALL). ALL is a relatively rare cancer for which 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 (Profs Mansour & Khwaja), who are treating patients with this disease and recognise the need for improved therapies. It exploits our expertise in PI3Kdelta biology (Prof Vanhaesebroeck pioneered the exploration of PI3Kdelta biology and drug discovery applications) and our proof-of-principle success in generating similar modulators of the ubiquitously-expressed PI3Kalpha isoform, developed in collaboration with AstraZeneca under an Open Innovation collaboration. Our team has unrivalled understanding of the structural requirements associated with modulation of this kinase family (Dr Williams).

We propose to carry out a high throughput screen for PI3Kdelta modulators using the AstraZeneca proprietary compound library. Primary assay development has been completed by the Academic Partners 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.

Planned Impact

Patients, Academics, Clinicians, commercial private sector and charities will benefit from this research.
1. Patients will benefit from this research. Acute Lymphoblastic Leukemia (ALL) is a relatively rare cancer which develops
rapidly over a matter of weeks or months. If caught early, prognosis is good for most patients. However, for a significant
number of adult patients, the prognosis is poor. Relapse leading to death is common (>50%) amongst this group. Current
treatments are either chemotherapeutics or cell therapies, both of which carry significant toxicities. A need remains for a
selective agent that targets the tumour biology specific to these cells. This proposal is based on the clinical insight provided
by our team (Prof Marc Mansour & Prof Asim Khwaja), who are treating patients with this disease and recognize the need
for improved therapies. We will exploit biology specific to this cell type (Prof Bart Vanhaesebroeck) to develop our drug
molecules. 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 anticancer
therapeutics. Academics interested in the research areas of cell signalling and oncology will benefit from our
research. Manipulation of cell signalling pathways in the manner described within this proposal enables exploration of
additional therapeutic settings, including immune activation ahead of vaccination and rheumatoid arthritis. Both these settings are outside the scope of this application but would be the subject of a thorough investigation with small molecule
hit compounds in hand. This widens the impact of this research plan beyond the ALL patients envisaged here.
Demonstration that our scientific concept is achievable, in combination with previous successes in related family members,
opens up an entirely novel way of addressing this protein class, currently only possible through complex biological
manipulations. We believe, as a concept, it will be of wide-spread interest to the research community, both academic and
commercial. Our results will be published in high impact scientific journals and our tools compounds will enable a more
complete understanding of the biological role of PI3K family members.
3. Clinical academics interested in treating patients currently poorly served by existing therapies will benefit from this
research, particularly those treating ALL patients.
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.
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.

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