Search results
Found 10744 matches for
The Department of Oncology has been awarded a Bronze Employer Award from Science Oxford for our contributions to STEM week in 2018.
Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer.
Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment.
Neomorphic mutations and drugs can elicit unanticipated effects that require mechanistic understanding to inform clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. Here, we identify that these neomorphic interactions are mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 capture 2:1 and 2:2 KBTBD4-HDAC2 complexes, as well as a 2:1:1 KBTBD4-HDAC2-CoREST1 complex, at resolutions spanning 2.7 to 3.3 Å. The mutant and drug-induced complexes adopt similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 is identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshapes the same surface of KBTBD4 providing an example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4, while structure-activity relationship (SAR) analysis of UM171 reveals analog S234984 as a more potent molecular glue for future studies.
Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations.
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma3, the most common embryonal brain tumour in children4. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST5. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3-neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions.
Radiobiology of High Dose Fractions
Advances in the technology of radiotherapy delivery have resulted in deliberate radiation fluence and dose displacement away from designated normal tissues, and with improved conformity of tumour dose. This applies to normal tissues outside the planning target volume (PTV) in most es. The prospects for hypofractionation improve in these circumstances provided that loss of function of the normal tissue included in the PTV is not considered harmful or deleterious to the subsequent health and well-being of the patient. The radiobiology of large fractions is considered in the context of the linear quadratic (LQ) model of radiation effect and the concept of the biological effective dose (BED). One feature of the model is that it might overestimate high fractional dose effects especially in tumours or tissues which have low α/β ratios. For normal tissues, this is probably advantageous since the model provides a ‘worst e scenario’, and protects against overdosage. Substantial benefits in the therapeutic ratio with increasing fractionation only apply where there is a marked difference between the α/β ratios of the tumour and relevant normal tissues. Thus slow growing tumours with low α/β ratios are preferred candidates for hypofractionation. Where high dose fractions are employed it is vital to ensure that the prescribed dose is not exceeded in relevant normal tissue where overdosage can be harmful. Some worked examples are given to illustrate these principles, using BED calculations, with examples of how to include straightening out of the dose response curve.
Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer.
Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting polycomb-group (PcG) epigenetic regulators, EZH2 and ASXL1 frequently found in haematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. While there is clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progresses. Here we show that genetic inactivation of Asxl1 and Ezh2 in murine haematopoietic stem/progenitor cells results in highly penetrant haematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and non-coding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF mutated cells, which create a novel vulnerability for PARP inhibitors (PARPi)-induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2 mutated cells are highly sensitive to PARPi that induce excessive DNA damage and significantly extend disease latency. Intriguingly the observed PARPi-sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target-site primed reverse transcription (TPRT) and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.
Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Investigating the therapeutic potential of FLASH radiotherapy - a treatment planning study.
PURPOSE/BACKGROUND: Ultra-high dose rate radiotherapy (RT) has shown potential for differential normal tissue (NT) sparing (a phenomenon termed the "FLASH effect"), particularly for larger fraction doses (>5 Gy). However, transitioning to hypofractionation may increase late-reacting NT toxicity, counteracting the FLASH effect. This study evaluates whether FLASH-RT can provide netsparing for organs at risk (OARs) and NT within the PTV under the assumption of standard-of-care dose-conformity. MATERIAL/METHODS: Five patients per tumor-site (breast, head-and-neck, prostate, and glioblastoma) were analyzed. Using the Linear-Quadratic model, dose-distributions with higher dose per fraction were derived from standard schedules while maintaining tumor control efficacy. FLASH-modified dose-distributions were simulated voxel-by-voxel using logistic regression-based dose-modifying factors modeled from preclinical data. These plans were converted to standard fractionation equivalents for radiobiological comparisons of NT damage. Netsparing was defined as the difference in OAR dose-volume histogram parameters between standard and FLASH-modified plans, normalized to the prescribed dose. Commonly used α/β-ratios for tumors and late-reacting NT were applied. RESULTS: The netsparing for OARs and PTV varied strongly by tumor location. Breast and prostate cases showed positive netsparing, indicating that the FLASH effect outweighed increased toxicity. Even under a conservative scenario (higher α/βT vs. α/βNT), most OARs showed positive netsparing. In glioblastoma and head-and-neck cases, no netsparing was observed, indicating increased toxicity even with FLASH induced NT-sparing. CONCLUSION: FLASH-RT appears to be beneficial for tumor sites where α/βT ≲ α/βNT, such as breast and prostate. However, not all tumor sites may benefit from FLASH-RT, highlighting the need for site-specific consideration for FLASH-RT implementation.
FLASH-induced DNA damage reduction measured in vitro correlates with effective oxygen depletion determined in silico: further support for oxygen depletion contributing to FLASH's reduced damage burden in vitro.
OBJECTIVES: FLASH irradiation demonstrates notable normal-tissue protective effects, including reduced damage in vitro. Radiochemical mechanisms proposed include radical-radical recombination and transient oxygen depletion (TOD), but the relative contributions remain unclear. This study compares FLASH-mediated DNA damage reduction in vitro with oxygen depletion for FLASH radiotherapy modelled in silico, to i) investigate the contribution of TOD towards the reduced damage burden in vitro, and ii) evaluate its contribution to the broader FLASH effect in vivo. METHODS: An in silico model was used to identify and compare the parameter space for FLASH-induced oxygen depletion in an in-vitro setup with experimental DNA damage reduction data, previously determined using the alkaline comet assay. RESULTS: Correlation analysis revealed a strong relationship between model-predicted oxygen depletion and experimentally-observed DNA damage reduction (Spearman's = 0.87, p = 2 x 10-6; Pearson's = 0.85, p = 4 x 10-6). CONCLUSIONS: Findings support a significant role for TOD in the FLASH-induced reduction in damage in vitro at low oxygen tensions. However, parameter spaces identified, for both oxygen depletion in silico and DNA damage reduction in vitro, suggest that TOD may only partially contribute to the wider-ranging FLASH sparing effects in vivo. Further work is required to clarify this. ADVANCES IN KNOWLEDGE: Findings support TOD as a key mechanism for the reduced damage burden of FLASH in vitro. However, further work is required to demarcate the sparing effects of FLASH in vivo.
Impact of Long-Term Chemotherapy on Outcomes in Pancreatic Ductal Adenocarcinoma: A Real-World UK Multi-Centre Study.
Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival (OS) and best overall response (BOR) to chemotherapy were assessed using the Wilcoxon test, Kaplan-Meier test, and univariate and multivariate Cox regression models. Results: We screened 237 patients, and 135 patients met the study criteria. Among these patients, 25 had resectable disease, and 110 had unresectable/metastatic disease (13% borderline resectable (BRPC), 20% locally advanced (LAPC), 10% localised developing metastases, 57% de novo metastatic). Ten patients (7%) underwent genetic profiling; KRAS aberrations (N = 4), actionable PLAB2/BRCA2/FGFR2 mutations (N = 3), ATM/BRIP1 alteration (N = 1). Two patients were managed with PARP inhibitors after receiving multiple lines of chemotherapy. Median PFS1 and OS were concordant with the published literature, but select patient groups achieved prolonged survival outcomes. Among the 36 BRPC/LAPC patients, we observed >1-year PFS1 in 9 (25%) patients and >2-year OS in 3 (8%) patients. Among the 63 de novo metastatic patients, we observed >1-year PFS1 and >2-year OS in 6 (10%) patients. Among patients with localised disease, smoking history was a poor prognostic factor with respect to OS (p = 0.03). Improved PFS1 and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥3.66 months, and local treatment after first chemotherapy (p < 0.05 for all). Stereotactic body radiotherapy following first-line chemotherapy was delivered in N = 6 (27%) and N = 1 (7%) of patients with LAPC and BRPC, respectively. Chemotherapy interruption duration, but not number, was associated with PFS1 and OS only in the localised cohort (p < 0.05). In patients with de novo metastatic disease, prevalence of type 2 diabetes was adversely associated with OS (p = 0.03). Improved PFS and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥4.37 months, and BOR to it (only in this cohort) (p < 0.05 for all). A favourable OS was associated with >1 line of chemotherapy (p = 0.003). Conclusion: Despite challenges, extended chemotherapy and multiple treatment lines may improve survival, with localised treatments benefiting select patients.
A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation.
PURPOSE: The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [177Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an in vitro screen of potential novel synergistic drug combinations with [177Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts. METHODS: In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC50), compared to incubations of the test drug plus [177Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [177Lu]Lu-rhPSMA-10.1 (0-25 MBq/mL) on drug IC50. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores >5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α >0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated in vivo: intravenous [177Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed. RESULTS: In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [177Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α>3). Combination treatment significantly suppressed tumor growth in vivo versus untreated controls (from Day 13-30; p<0.01) and [177Lu]Lu-rhPSMA-10.1 (from Day 17-30; p<0.001). Median survival was significantly longer with combination treatment (49 days) versus untreated controls (23 days; p=0.001) and [177Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [177Lu]Lu-rhPSMA-10.1 was observed. CONCLUSIONS: The combination of cobimetinib and [177Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.
Pan-Asia adapted ESMO Clinical Practice Guideline for the management of patients with newly diagnosed and relapsed epithelial ovarian cancer.
The European Society for Medical Oncology (ESMO) Clinical Practice Guideline for the diagnosis, treatment and follow-up of patients with newly diagnosed and relapsed epithelial ovarian cancer (EOC), published in 2023, was adapted in July 2024, according to established standard methodology, to produce the Pan-Asian adapted ESMO consensus guideline for the management of Asian patients with EOC. The adapted guideline presented in this manuscript represents the consensus opinions reached by a panel of Asian experts in the treatment of patients with EOC representing the oncological societies of China, Indonesia, India, Japan, Korea, Malaysia, the Philippines, Singapore, Taiwan and Thailand, coordinated by ESMO and the Indian Society of Medical and Pediatric Oncology. Voting was based on scientific evidence and was independent of current treatment practices, drug access restrictions and reimbursement decisions in the represented countries. Drug access and reimbursement across Asia are discussed separately in the manuscript. The Pan-Asian consensus aims to guide the optimisation and harmonisation of management of patients with EOC in Asia, drawing on the evidence provided by both Western and Asian trials. Attention is drawn to the disparity in the drug approvals and reimbursement strategies between countries.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q ('chr. 21amp') in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Megavoltage photon FLASH for preclinical experiments.
BACKGROUND: FLASH radiotherapy using megavoltage (MV) photon beams should enable greater therapeutic efficacy, target deep seated tumors, and provide insights into mechanisms within FLASH. PURPOSE: In this study, we aim to show how to facilitate ultra-high dose rates (FLASH) with MV photons over a field size of 12-15 mm, using a 6 MeV (nominal) preclinical electron linear accelerator (linac). Our intention is to utilize this setup to deliver FLASH with MV photons in future preclinical experiments. METHODS: An electron linear accelerator operating at a pulse repetition frequency of 300 Hz, a tungsten target, and a beam hardening filter were used, in conjunction with beam tuning and source-to-surface distance (SSD) reduction. Depth dose curves, beam profiles, and average dose rates were determined using EBT-XD Gafchromic film, and an Advanced Markus ionization chamber was used to measure the photon charge output. RESULTS: A 0.55 mm thick tungsten target, in combination with a 6 mm thick copper hardening filter were found to produce photon FLASH dose rates, with minimal electron contamination, delivering dose rates > 40 Gy/s over fields of 12-15 mm. Beam flatness and symmetry were comparable in horizontal and vertical planes. CONCLUSION: Ultra-high average dose rate beams have been achieved with MV photons for preclinical irradiation fields, enabling future preclinical FLASH radiation experiments.
Cancer vaccine trial evaluations: immunobridging and potential immunological endpoints.
Therapeutic cancer vaccines are an emerging class of immunotherapy, but challenges remain in effectively adapting approved vaccines to a growing number of adjuvants, combination therapies, and antigen-selection methods. Phase III clinical trials remain the gold standard in determining clinical benefit, but are slow and resource intensive, whilst radiological surrogates often fail to reliably predict clinical benefit. Using immunological surrogates of efficacy, deployed in 'immunobridging trials', could present a viable alternative, safely speeding up cancer vaccine development in a cost-effective manner. Whilst this approach has proven successful in infectious disease vaccines, identifying reliable immunological correlates of protection has proven difficult for cancer vaccines. Most clinical trials, which present the richest source of data to establish a correlate, rely on peripheral blood samples and standard immunoassays that are ill-equipped to capture the complexity of the vaccine-induced anti-tumour response. This review is the first to outline the importance and challenges of establishing immunological surrogates for cancer vaccines in the context of immunobridging trials, evaluating current immunoassay methods, and highlighting the need for techniques that can characterize tumour-infiltrating lymphocytes and the suppressive tumour microenvironment across a range of patients. The authors propose adapting trial designs for surrogate discovery, including combining phase I/II trials and the use of multi-omics approaches. Successful immunological surrogate development could enable future immunobridging trials to accelerate the optimization of approved cancer vaccines without requiring new phase III trials, promoting faster clinical implementation of scientific advances and patient benefits.
A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol.
BACKGROUND: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma. METHODS/DESIGN: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom. TRIAL REGISTRATION: ISRCTN84434175. Registered 12 November 2018.