Prof Gary Middleton
Chair
Prof Gary Middleton is a clinical academic with a clinical practice in thoracic and colorectal cancer and an active lab programme. He is the Chief Investigator, National Lung Matrix Trial (NLMT). This is the flagship lung cancer CR-UK funded stratified medicine trial aligned to the national Stratified Medicine Programme 2. The trial was highlighted in the recent DHSS document ‘Saving and Improving Lives: The Future of UK Clinical Research Delivery’ as a trial that “shows the power of collaboration, through the UK’s integrated health research System”. It is the largest and most ambitious signal of activity study examining potential genotype matched targeted therapies in lung cancer globally. Data from 19 biomarker:drug cohorts was presented in the Presidential Symposium at the World Lung Cancer Conference, 2019 and published in Nature, 2020 (Middleton G, et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature. 2020 Jul;583(7818):807-812). There are several further high impact papers to come from this trial which will incorporate the large ctDNA analysis from this study. In particular these include the results from the palbociclib treated patients where the ctDNA analysis of KRAS mutant patients will be mapped to the results of transgenic models of KRAS mutant lung cancer in which multiple barcoded genes are knocked down with CRISPR to identify concomitant sensitising or resistance aberrations in collaboration with D2G (Stanford).
It is clear from the outputs of NLMT that the genomic context of targeted genomic aberrations, the degree of genomic complexity and instability, are critically important in determining the outcome with genotype-matched targeted therapies (Middleton G. Towards personalized treatment of smoking related lung cancers. Nature. 2021 Jun 18. doi: 10.1038/d41586-021-01113-90). The learnings from the trial have led to a key publication which represents a blueprint for future precision medicine trials in cancer (Middleton G, et al. A state-of-the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer. Ann Oncol. 2022 Feb;33(2):143-157). In part this is explicitly a call for a more contextualised stratified medicine, one which takes into account the genomic, transcriptional and immunobiological context on which the targeted genomic aberration is inscribed. It builds on important work on how the transcriptional and immunological landscape of canonical oncogenic drivers shapes both biology and response to targeted therapy (Middleton G, et al. BRAF-mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer. Clin Cancer Res. 2020 Feb 11. pii: clincanres.3579.2019 and Lal N, White BS, Goussous G, Pickles OJ, Mason M, Beggs AD, Taniere P, Willcox BE, Guinney J, Middleton G. KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer. Clin Cancer Res. 2018 Jan 1;24(1):224-233). This concept of target context as supplemental biomarker for outcome forms the key translational component of the CR UK sponsored DETERMINE trial in which WGS and RNAseq will be performed to establish the impact on outcome with genotype matched-therapies of the genomic, transcriptomic and immunological context on which the targeted aberrations are inscribed . It is also a superb opportunity to discover novel targets in rare and paediatric cancers in both the exome and in the non-coding genome where we will analyse alternative polyadenylation, pseudogenes and somatic non-coding mutations in regulatory regions. Middleton is translational lead of the DETERMINE trial which will commence recruitment later this year with the translational work being performed in Birmingham.
As a result of NLMT it is also apparent that squamous lung cancer is not susceptible to genotype matched targeted therapy and that other approaches are needed for this disease of huge unmet therapeutic need. Middleton is leading on KETO-LUNG, a feasibility trial exploring the addition of a ketogenic diet to standard chemo-immunotherapy in LUSC, to harness the unique metabolic vulnerability of squamous lung cancer (a strict reliance on anabolic glycolysis for the provision of redox potential). This trial in effect inaugurates metabolic Precision Medicine – stratification for metabolic intervention by histology. We have huge buy-in from the ECMC and the expertise of our ECMCs will be integral to the successful prosecution of this complex intervention trial. The trial design is an exemplar of PPI and our PPI rep is a co-investigator. We will analyse metabolic and redox shifts using tumoral 13C tracing at the Metabolic Tracer Analysis Core at the University of Birmingham (Tennant) for the first time in any clinical trial in advanced disease using biopsy samples. This technology could prove invaluable to other metabolic intervention trials being run across the network.
Middleton is Chief Investigator, PePS2: A phase II study of pembrolizumab in patients with advanced non-small lung cancer and a performance status of 2. This is the first ever study to prospectively assess the activity of anti-PD-1 agents in patients with PS2 and thus is of pivotal importance in opening up such therapies to a large number of patients. Results were presented at ESMO, 2018 and published in Lancet Respiratory Medicine in 2020 (Middleton G, et al. Pembrolizumab in patients with non-small-cell lung cancer of performancestatus 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med. 2020 Mar 19:S2213-2600(20)30033-3.) and are being used to seek CDF approval for this pembrolizumab in this large group of lung cancer patients with huge unmet therapeutic need.
Of potentially huge impact is the recent work from the Middleton group looking at predictive biomarkers for immune related adverse events in lung cancer patients treated with checkpoint blockade. Using CyTOF and B cell functional assays we have demonstrated that patients developing severe toxicity have significant baseline qualitative and quantitative defects in B regulatory cells. The manuscript has been accepted for publication in Nature Communications. We have patent protection on this potentially crucial and game changing biomarker. We also have patent protection on a highly predictive autoantibody signature for outcome following resection of early stage lung cancer and are validating this data using TRACERx samples with a view to designing a trial of adjuvant vaccination against the candidate antigens which include a large proportion of ctAgs (Patel AJ, Tan TM, Richter AG, Naidu B, Blackburn JM, Middleton GW. A highly predictive autoantibody-based biomarker panel for prognosis in early-stage NSCLC with potential therapeutic implications. Br J Cancer. 2022 Feb;126(2):238-246.)
