Assessing new therapeutic opportunities linked to TCR signalling in mature T-cell lymphomas with unmet need

Knowledge about the specific molecular and genetic makeup of a patient's tumour provides valuable guide for diagnosis and for decisions about the treatment. This approach, described as personalized or precision medicine, has recognized benefits for patients, drug development and healthcare. However, linking information that describes genetic aberrations in tumours with successful new treatments requires considerable research effort.

In this proposal we outline our plan to assess new potential drug targets in T-cell lymphomas where patient's outcome with current treatments remains bleak and where recent genetic studies highlighted changes that could be linked to cancer development. We will combine expertise in a close collabariton that we believe is necessary to provide definitive supporting evidence. This expertise covers long standing involvement in studies of the development of particular forms of T-cell lymphomas and an extensive expertise and contribution to structural and mechanistic understanding of potential targets which will both facilitate ongoing efforts in drug development. This will bring together in-depth insights from studies of isolated proteins, findings from the analysis of cells from actual patient's tumours and initial generation and characterization of potential drugs, all using the latest methodological advances in respective research areas. If confirmed as feasible, the new treatment options will have a wider relevance, including some other cancer types, drug-resistance in specific cancers and a range of immune disorders.

Comprehensive insights into genetic changes in a variety of malignancies over the past decade have provided a basis for identification of new targets and personalized treatments. Lagging behind some of the more prevalent cancer types, mutations associated with T-cell lymphomas, including those with limited treatments, have only been described within the last two years.
We now propose to extend structural insights into some of the key components mutated in these cancers (such as PLCgamma) using latest developments in cryoEM and methods for mapping molecular interactions (HDX-MS) as well as to establish the exact contribution of genetic alterations to pathogenesis. Our approaches will be based on the expertise and available clinical material for two related CD4+ T-cell malignancies with different aetiology, CTCL and ATL which is virally (HTLV-1) transformed. In addition to already acquired data for bioinformatics, we also have access to primary cells from individual patients from longitudinal studies of these malignances and we obtained cell lines from ATL patients with PLCG1 mutations; for comparison, we also have Btk-inhibitor resistant cell lines with PLCG2 mutations. In these systems, we plan to assess broader genetic changes and apply gene editing (CRISPR modification) and pharmacological inhibitors to a range of components involved in TCR signalling and establish those that are critical as well as their links in pathology. Overall, we aim to identify mechanisms that contribute to oncogenesis and maintenance of malignancy and key components that can be therapeutic targets. PLC and/or other components that we identify will guide new routes to treatment.
Use of pharmacological inhibitors is important in assessing potential drug targets. However, there is no reliable inhibitor that specifically targets PLC enzymes. To address this limitation, we have established a collaboration with a GSK team that will provide us with relevant material.

Who will benefit and how:

One group of beneficiaries will be scientists working in the fields of the molecular basis of cellular regulation and dysregulation as well as in cancer research and immune disorders and potentially other human diseases. In particular, this work will provide the first insights into the scope and role of cancer mutations in signaling components implicated in T-cell malignancies with very limited treatment options.

Notably, the data accumulated during this project will provide essential guidance to inform development of new drugs. Therefore, the outcomes of this project could be of significant commercial interest to pharmaceutical companies and the drug discovery industry with a further impact on healthcare and patient benefits. The work proposed here has the potential to validate new targets and assist drug discovery against established and a new class of targets (such as PLC) and also provide the tools and reagents required to determine or predict the effects of drugs targeting. Further applicability could be in biomarker discovery for early diagnosis by linking genetic aberrations to likely disease outcomes and treatments. With the several clinical areas of application, including lymphoma, leukaemia, angiosarcoma and forms of inherited and widespread immune disorders, the new treatment options could have wide impact in healthcare.