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Updates on radiotherapy-immunotherapy combinations: Proceedings of 8th Annual ImmunoRad Conference.
No full textThe annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference
End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer.
No full textPURPOSE: The evolving treatment landscape of muscle-invasive bladder cancer (MIBC) increasingly warrants novel trial design to evaluate perioperative strategies aimed at bladder preservation. To establish standardized outcome measures for evaluating organ preservation strategies in MIBC, the International Bladder Cancer Group (IBCG) and the Global Society of Rare Genitourinary Tumors (GSRGT) assembled an international, multidisciplinary consensus panel. METHODS: The IBCG and GSRGT gathered global bladder cancer experts and patient advocates to establish a framework for risk-adapted bladder-sparing treatment approaches for MIBC. Working groups reviewed the literature and developed draft recommendations, which were discussed at a live meeting in December 2024 in Milan. This was followed by voting by the members using a modified Delphi process. Recommendations achieving ≥75% agreement during the meeting were further refined and presented. RESULTS: Clinical complete response (cCR) definition should encompass the absence of high-grade malignancy on pathology and malignant cells on urine cytology and no evidence of local or metastatic disease on cross-sectional imaging. Although cCR remains immature as a primary or coprimary end point in registrational trials, it could serve as a suitable end point in early-phase studies and risk-adapted investigations. Event-free survival (EFS) remains the preferred primary end point as it could reliably capture the durability of clinically meaningful benefit after omittance of surgical consolidation or chemoradiation. Given the composite nature of EFS, events should be prespecified, evaluated in an intention-to-treat approach, and meticulously collected. Continuous assessment of individual patient preferences should begin at the outset of perioperative therapy discussions, with informed decision making prioritized throughout. CONCLUSION: The consensus definition of cCR and the framework presented in this study can serve as a foundation for thorough testing of risk-adapted bladder-sparing treatment paradigms for MIBC
Adiposity Status Close to Diagnosis and Its Association with Prostate Cancer Survival in the UK Biobank.
No full textUNLABELLED: Substantial evidence links higher adiposity to prostate cancer development. The relationship between adiposity and outcomes after a prostate cancer diagnosis, however, is unclear. This study aimed to investigate the association between adiposity measured close to prostate cancer diagnosis and all-cause and prostate cancer-specific mortality in a prospective cohort study. Cox regression analyses estimated HRs and 95% confidence intervals (CI) for mortality in 3,760 men in the UK Biobank who had first primary prostate cancer and complete data on body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (measured up to 2 years before or up to 5 years after diagnosis), and on covariates (diagnosis age and year, smoking, Townsend deprivation index, exercise, sedentary activities, and alcohol). The waist-to-height ratio and body fat percentage (assessed by bioelectrical impedance) were also evaluated as adiposity measures. Each 5-U increment in pre- or post-diagnosis BMI (N = 3,760) was associated with a 30% (95% CI, 1.18-1.44) higher rate of all-cause mortality (deaths = 680), a 33% (95% CI, 1.15-1.52) higher rate of prostate cancer-specific mortality (deaths = 331), and a 28% (95% CI, 1.12-1.47) higher rate of non-prostate cancer mortality (deaths = 347). Positive associations of similar magnitude were observed for separate analyses by pre- and post-diagnosis BMI and for waist and hip circumference, waist-to-hip ratio, waist-to-height ratio, and body fat percentage. Obesity assessed close to prostate cancer diagnosis is associated with higher mortality. More studies are needed to strengthen the evidence and clarify the mechanisms behind the observed associations. SIGNIFICANCE: Patients with prostate cancer might improve their chances of survival by avoiding obesity
Fluctuating DNA methylation tracks cancer evolution at clinical scale.
No full textCancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour
AI-augmented reconstruction provides improved image quality and enables shorter breath-holds in contrast-enhanced liver MRI.
No full textBACKGROUND: To compare liver image quality and lesion detection using an AI-augmented T1-weighted sequence on hepatobiliary-phase gadoxetate-enhanced magnetic resonance imaging (MRI). METHODS: Fifty patients undergoing gadoxetate-enhanced MRI were recruited. Two T1-weighted Dixon sequences were utilized: a 17-s breath-hold acquisition and an accelerated 12-s breath-hold acquisition (reduced phase resolution), both reconstructed using neural network (NN) and iterative denoising (ID), NN-alone, ID-alone, and the standard method. Contrast-to-noise ratio (CNR) was assessed quantitatively for all series (ANOVA). Two blinded radiologists independently analyzed three image sets: 17-s acquisition reconstructed with NN and ID (17-s NN + ID), 12-s acquisition reconstructed with NN and ID (12-s NN + ID), and 17-s acquisition with standard reconstruction (17-s standard). Overall image quality, qualitative CNR, lesion edge sharpness, vessel edge sharpness, and respiratory motion artifacts were scored (4-point Likert scale) and compared (Friedman test). Lesion detection was compared between 12-s NN + ID and 17-s standard reconstructions (Wilcoxon signed-rank test). RESULTS: Quantitative liver-to-portal vein CNR was significantly higher for 17-s NN + ID than 17-s standard or 17-s NN-alone images (p = 0.001). Scores for overall image quality, qualitative CNR, vessel edge sharpness, and lesion edge sharpness were significantly higher for 17-s NN + ID and 12-s NN + ID than standard reconstruction (p < 0.001); there was no significant difference between 17-s and 12-s NN + ID. There was no significant difference in respiratory motion artifacts and number of lesions or diameter of the smallest detected lesion using 12-s NN + ID or 17-s standard reconstruction. CONCLUSION: AI-augmented reconstructions can improve image quality while reducing breath-hold duration in T1-weighted hepatobiliary-phase gadoxetate-enhanced MRI, without compromising lesion detection. RELEVANCE STATEMENT: AI-augmented reconstruction of T1-weighted MRI improves image quality and lesion detection in hepatobiliary phase liver imaging, reducing breath-hold duration without compromising clinical lesion detection. KEY POINTS: Liver-to-portal vein CNR was significantly higher for 17-s NN + ID. AI-augmented reconstructions scored higher for image quality, contrast-to-noise, vessel-edge, and lesion-edge sharpness. No significant difference in lesion detection between 12-s NN + ID and 17-s standard reconstructions
Dissecting the Role of MYCN in Neuroepithelial Stem Cells towards the Pathogenesis of Embryonal Brain Tumours
No full textThis thesis investigates the roles of neuroepithelial stem (NES) cells and the transcription factor MYCN in embryonal brain tumours, specifically embryonal tumour with multilayered rosettes (ETMR) and medulloblastoma (MB). It aims to elucidate how MYCN overexpression in NES cells contributes to the development of these tumours, addressing a gap in our understanding of the connection between early neural development and oncogenesis. NES cells, essential for neural development, differentiate into various neural cell types. The dysregulation of crucial genes that govern the state of NES cells can lead to abnormal development, such as tumorigenesis. This research underscores the importance of NES cells as a potential origin of these tumours and examines the role of MYCN, a gene pivotal for cell cycle regulation and neurogenesis, which is pathologically overexpressed in several paediatric brain tumours. The study emphasises the critical early signalling pathways, such as Sonic hedgehog (Shh) and Wnt, that regulate neural development. MYCN, a downstream target of these pathways, is frequently deregulated in ETMR and MB, implicating it in the pathology of these diseases. Through exploring the interplay between MYCN function, NES cell biology, and tumourigenesis, this thesis provides insights into the molecular mechanisms driving these cancers. Utilising in vitro and in vivo models to replicate the disease processes, this work not only clarifies the oncogenic role of MYCN and NES cells in embryonal brain tumours but also pioneers the identification of the cell of origin for ETMR. This achievement introduces a robust humanised model, addressing a significant gap in the field. It paves the way for further exploration into tumourigenesis and the development of targeted therapies, promising to enhance our understanding and management of these devastating rare childhood brain tumours
Expanding access to cancer immunotherapy: A systematic review of low-dose PD-(L)1 inhibitor strategies.
No full textBACKGROUND: Anti-PD-(L)1 inhibitors have transformed cancer treatment. However, their high costs severely restrict their accessibility, especially in low- and middle-income countries (LMIC). Low-dose regimens, inferior to weigh-based or flat dosings, may help address this barrier. Our aim is to evaluate their dosing strategies, clinical outcomes, and potential cost savings. METHODS: WebOfScience, ASCO and ESMO conference databases were systematically searched until January 31st, 2025, for post- commercialization use of anti-PD-(L)1 agents at reduced doses compared to FDA- and/or EMA- approved weight-based regimens. RESULTS: Five clinical trials and 27 observational studies, including 2055 patients, met the review criteria. Two studies had non-inferiority designs, and 26 grouped patients across various treatment lines in the metastatic setting among them. Most studies originated from LMIC (53 %), focusing on head and neck (30 %) and lung cancers (15 %). Low-dose anti-PD-(L)1 use reported radiological responses in 16 (ranging 5-100 %), observing similar responses than pivotal trials in refractory Hodgkin lymphoma, lung and kidney cancers. Risk of bias was serious in 56 % of the studies, while rest was moderate. Nivolumab was the anti-PD-(L)1 most frequently investigated (k = 27). Nivo40mg Q2W (k = 8) and Nivo20mg Q3W (k = 6) were the most assessed doses. More than two-thirds of the studies achieved estimated savings of ≥ 80 % compared to list prices. CONCLUSION: Low-dose anti-PD-(L)1 regimens show promising radiological responses, including as monotherapy, especially in lymphoma, lung and kidney cancers. However, the high risk of bias in available studies limits definitive conclusions. Prudent use may be considered in resource-limited settings. Ongoing non-inferiority trials or near-equivalence are essential to confirm clinical validity
MEK inhibitor sensitivity and resistance in MAPK-altered diffuse midline gliomas
No full textTargeted therapies inhibiting MAPK pathway activation have recently been approved for
use in paediatric low-grade glioma. Pre-clinical evidence suggests these therapies could
be translated in MAPK-altered diffuse midline glioma (DMG). In this thesis, I determine the
frequency of MAPK pathway alterations in DMG and assess the utility of the MEK inhibitor
trametinib in patient-derived models. Both PIK3R1-mutant B181-3D and the NF1-mutant
B184-3D models show ~500-fold increased trametinib sensitivity compared to their
isogenic non-MAPK-altered counterparts, suggesting MAPK pathway alterations
specifically confer sensitivity to trametinib. Furthermore, drug screening revealed antiapoptosis
inhibitors could sensitize non-MAPK-altered B181-2D to trametinib. Three
independent trametinib resistant cell lines were also generated from parental B181-3D
cells, drug screening of which exhibited 100% increased sensitivity to progesterone
compared to parental cells. Trametinib resistance was also investigated in the BRAFmutant
B169-2D model using coupled lineage tracing and single cell RNA sequencing
(scRNA-seq). A subset of clones was reproducibly enriched across several technical
replicate experiments, suggesting deterministic patterns of selection and expansion.
Linking clonal identity with transcriptional output suggests resistant cells are phenotypically
plastic and shuttle between astrocyte-like and neural precursor-like cell states. Previously
reported trametinib resistance-conferring MAP2K1 mutations were also detected in this
model and seem to arise from phenotypic plasticity that is reminiscent of drug tolerant
persisters (DTP). In the same model, a subpopulation of resistant cells were distinctly
characterized by epithelial to mesenchymal transition, suggesting two transcriptionally and
clonally disparate resistance mechanisms occur simultaneously. Optimization experiments
were also conducted to allow for downstream retrieval of resistant clones from pretreatment
barcoded cells to determine whether resistance was pre-existing. Overall, I
investigated trametinib resistance in two MAPK-altered DMG models by utilizing
conventional resistance modelling techniques and development of novel tools that shed
light on the role of clonal evolution in resistance. To our best knowledge, this coupling of
lineage tracing and scRNA-seq is the first time this technique has been used to study
targeted therapy resistance in DMG
Barriers to publishing early phase clinical trials: the oncologists' perspective.
No full textINTRODUCTION: Findings from early phase studies are not always placed in the public domain. This study aims to explore why many early phase clinical oncology studies are not published, as well as identify the potential barriers investigators encountered in the publication process. METHODS: Semi-structured interviews were conducted among investigators with experience in early phase clinical oncology studies. Interviews were analyzed using reflexive thematic analysis. RESULTS: Twenty-one investigators were interviewed. The majority worked in Europe (n = 13), while other investigators were based in North America (n = 4), Asia (n = 2) or Oceania (n = 2). We identified three reasons why investigators believed publishing early phase clinical trial results was important: (1) there is an ethical and moral responsibility; (2) there should be no loss of knowledge to society; and (3) there should be no waste of resources. Four main barriers in the publication process of early phase clinical trials were identified: (1) practical barriers (eg, an increased complexity of number of trials/trial sites), (2) insufficient resources (eg, money, time and human), (3) limited motivation (eg, limited intrinsic motivation of the investigator or limited prospect of return for the sponsor), and (4) inadequate collaboration (eg, different interests between industry partners and investigators). Finally, five major stakeholders were identified that can potentially contribute to improving the publication process: (1) journal editors, (2) sponsors, (3) investigators, (4) regulatory bodies, and (5) society. Investigator suggestions for improving this process, for each stakeholder, are presented. CONCLUSIONS: This study highlights the barriers experienced in publishing early phase clinical trials. Recognizing and acknowledging these barriers is crucial to devise effective strategies to improve the publishing and public sharing of early phase clinical trials
Structural and biochemical investigations into the anaphase-promoting complex regulation during mitosis
No full textThe APC/C is a master regulator of the cell cycle, it is an E3 ubiquitin ligase responsible for the ubiquitination of numerous cell cycle related proteins through mitosis and G1. A key mitotic substrate of the APC/C is cyclin B1, its
timely degradation at the metaphase to anaphase transition is necessary for sister chromatid separation. Because of its pivotal role in the cell cycle, and its numerous substrates, the activity of the APC/C is tightly regulated to ensure correct progression through the cell cycle. This regulation is achieved by several different mechanisms
acting directly on the APC/C, such as association with coactivators, inhibitors and E2 enzymes as well as PTMs
and differing substrate affinities. In addition to this the inhibitors, coactivators, substrates and E2 enzymes
themselves are also regulated in a cell cycle related manner.
In this thesis I explore some aspects of APC/C regulation further. First, I investigate the regulation of the APC/C via localisation. I use a combination of EMSAs and XL-MS to identify arginine anchor motifs in both the APC/C and in cyclin B1 which localise them to nucleosomes during mitosis. I also visualise the acidic patch interaction of both cyclin B1 and the APC/C using cryo-EM. I then use protein purification to show that the APC subunit involved in nucleosome localisation is also implicated in nuclear localisation via an interaction with importin-4 and have begun to structurally determine this interaction using cryo-EM. Finally, I have investigated the regulation of the APC/C by its mitotic inhibitor the MCC, specifically looking at an interaction interface formed by the CRY box of CDC20MCC, BubR1KNOT and CDC20APC/C. Mutations to this interface do not affect complex formation but do effect APC/C inhibition. I have also used an improved cryo-EM sample preparation pipeline to make cryo-EM grids
of the APC/CMCC and am attempting to improve the current resolution of the solved structure to resolve more of the sidechain interactions to improve our understanding of APC/C inhibition by the MCC