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Tumor control and immune activation through palliative irradiation and ATR inhibition, PATRIOT Part C: a phase Ib trial.
No full textAtaxia telangiectasia and Rad3-related kinase (ATR) is a rational radiosensitization target. In this study, we explore the combination of the ATR inhibitor, ceralasertib, and palliative radiotherapy, with primary endpoint the identification of maximum tolerated dose, and secondary endpoints the determination of adverse event causality, pharmacokinetics (PK) and anti-tumor activity. Twenty-seven patients were dosed in escalating dose cohorts from 20 to 80 mg twice daily (BD) with concomitant radiation, 20 Gy in 10 fractions or 30 Gy in 15 fractions. Patients were assessed for acute and late toxicities and response after therapy. A non-tolerated dose was not reached. Maximum administered dose was 80 mg BD ceralasertib over 3 weeks with 30 Gy in 15 fractions, at which 1/6 evaluable patients had dose-limiting toxicities (radiation dermatitis and mucositis). PK was comparable to monotherapy. Of 23 efficacy-evaluable participants, 2 (9%) had complete response (CR), 6 (26%) partial response (PR), 13 (57%) stable disease (SD) and 2 (9%) progressive disease (PD) as best response in irradiated tumors. Response was not clearly linked to genomic aberrations. Increased T and natural killer cell activation as observed in peripheral blood as treatment progressed
Technical note: Adaptation of a Small Animal Radiation Research Platform for pre-clinical microbeam irradiations.
No full textComparison of radiation-related cancer risks from the atomic bomb survivors with studies of pediatric medical radiation exposure.
No full textMedical exposures are the largest source of human-made ionizing radiation received by the general population. Cancer risk assessment for medical radiation is often based on the Life Span Study (LSS) of the Japanese atomic bomb survivors. Various assumptions are required to transfer radiation-related cancer risk estimates from the LSS to medical radiation exposures, including dose and fractionation effects. We compared organ-specific cancer risk coefficients from pediatric medical radiation studies (age, <22 years) with the LSS, controlling for average age at exposure, attained age, or time since exposure. We compared 21 studies (including 5 pooled analyses) of brain, breast, thyroid cancer, and leukemia (the most radiosensitive cancers in children), including 6 low-dose (mean < 100 mGy), 7 moderate-dose (mean = 100 mGy to -<2 Gy) and 8 high-dose (mean = 2+ Gy). The high-dose studies all had lower dose-response estimates than the LSS (ratio range = 1.3-37), as did most of the moderate-dose studies (ratio range = 0.4-9.4). In contrast, the dose-response estimates for the low-dose studies were all higher than the LSS (ratio range = 0.1-0.7). These results do not provide strong support for a dose reduction effectiveness factor of 2 for risk assessment for low-dose medical radiation exposures using the LSS. Whilst there is a clear reduction in risk from high-dose fractionated exposures compared with the LSS, the wide variation in ratios makes it difficult currently to quantify these effects
Ultrahypofractionated radiotherapy for localised prostate cancer: The impact of daily MRI-guided adaptive radiotherapy on delivered dose.
No full textINTRODUCTION: Magnetic resonance image-guided adaptive radiotherapy (MRIgART) reduces uncertainties by correcting for day-to-day target and organ-at-risk deformation and motion. This is the first study to examine the dosimetric impact of MRIgART for ultrahypofractionated prostate cancer treatment, compared to standard-of-care image-guided non-adapted radiotherapy. METHODS: Twenty patients with localised prostate cancer, who received ultrahypofractionated MRIgART on the Unity MR linac (Elekta, Sweden) were retrospectively analysed. Online daily MRI was acquired for replanning (MRIsession) and a second for position verification before treatment (MRIverification). To compare delivered dose with and without adaptation, three plans were generated offline per fraction; a session plan (reference plan adapted to MRIsession anatomy), a verification plan (session plan recalculated on MRIverfication anatomy), and a non-adapted plan (reference plan recalculated on MRIverfication anatomy). Target and organ-at-risk doses were calculated, and dose difference evaluated.Secondary analysis, using deformable dose accumulation, estimated verification and non-adapted dose to primary target (CTVpsv) substructures; prostate, gross tumour volume (GTV) and proximal 1 cm of seminal vesicles (1cmSV). Impact of prostate, rectum and bladder volume changes on dose were evaluated. RESULTS: Median dose to 95 % of the CTVpsv was significantly higher with adaptation; 40.3, 40.0 and 38.2 Gy for session, verification, and non-adapted plans. Adaptation achieved a lower median urethra V42Gy dose but bladder V37Gy dose was lower when not adapting. Rectum V36Gy dose was similar for adapted and non-adapted plans.CTVpsv substructure dose difference was greatest for 1cmSV; 40.0 versus 37.5 Gy for verification/non-adapted plans. Adaptation achieved significantly higher prostate only, but not GTV doses. Prostate and rectal volume changes had a negative impact on non-adapted dose only. CONCLUSION: MRIgART, offers significant dosimetric benefit for ultrahypofractionated prostate cancer compared to non-adapted strategies. Greatest benefit is expected for those with SV or high-risk of SV involvement, persistent rectal gas, prostate swelling and for the application of novel dose strategies including GTV dose escalation and non-involved prostate dose de-escalation
Invisible spectrum: a model for minority community public engagement in cancer research.
No full textBACKGROUND: Ethnic minority communities are often recognised as experiencing decreased accessibility to vital medical services as well as increased barriers to participation in research studies. These issues stem from a variety of social, cultural and economic factors, all of which must be taken into consideration when designing engagement initiatives for a particular community. Invisible Spectrum is an annual engagement initiative which seeks to promote effective communication and outreach to often-overlooked ethnic minority communities within Ireland, primarily those of Bangladeshi origin. The programme was developed in response to the traditionally low levels of engagement with healthcare services observed within these communities and seeks to empower communities in their own healthcare decision making. METHODS: This study reports a programme of community participation activity with an embedded empirical research component based on participatory action research. The team included researchers and leaders within the Bangladeshi and Arabic Muslim communities in Ireland. Over the course of four years, feedback polls, pre- and post-event surveys and in-depth interviews gathered the views and recommendations of attendees. RESULTS: We held 4 annual events as part of the Invisible Spectrum programme, from 2019 to 2023. Feedback we collected from participants consistently demonstrated high levels of satisfaction within the target communities while quantitative survey data also indicated improvements in key areas such as recognition of potential cancer symptoms and greater awareness of available screening services. CONCLUSION: There is a significant need to continually promote patient involvement and minority inclusion in healthcare and research initiatives. In line with this goal and after 4 successful years of running the Invisible Spectrum programme, we have developed a set of recommendations and guidelines for the successful development and organisation of minority community engagement initiatives. It is our hope that the Invisible Spectrum programme could be used as a model for future endeavours of a similar nature
Harnessing the Power of Metabolomics for Precision Oncology: Current Advances and Future Directions.
No full textMetabolic reprogramming is a hallmark of cancer, with cancer cells acquiring many unique metabolic traits to support malignant growth, and extensive intra- and inter-tumour metabolic heterogeneity. Understanding these metabolic characteristics presents opportunities in precision medicine for both diagnosis and therapy. However, despite its potential, metabolic phenotyping has lagged behind genetic, transcriptomic, and immunohistochemical profiling in clinical applications. This is partly due to the lack of a single experimental technique capable of profiling the entire metabolome, necessitating the use of multiple technologies and approaches to capture the full range of cancer metabolic plasticity. This review examines the repertoire of tools available for profiling cancer metabolism, demonstrating their applications in preclinical and clinical settings. It also presents case studies illustrating how metabolomic profiling has been integrated with other omics technologies to gain insights into tumour biology and guide treatment strategies. This information aims to assist researchers in selecting the most effective tools for their studies and highlights the importance of combining different metabolic profiling techniques to comprehensively understand tumour metabolism
Understanding the regulation and impact of variant splicing in non-small cell lung cancer
No full textAlternative splicing is a molecular mechanism that allows a single gene to encode multiple proteins. It is a complex and tightly controlled process used to regulate normal gene expression but is often dysregulated in cancer. Compounds that can modulate alternative splicing are currently being explored as a
potential new class of therapeutic agent in cancer, highlighting the need to understand the process of splicing, its regulation, and its impact.
While a growing selection of tool compounds exists to investigate splicing, the knowledge gap in this field is delaying progress. Multiple splicing
modulators with different mechanisms of action have advanced to clinical trials, but toxicity or lack of response have prevented most compounds from
progressing to the clinic. The discovery of new splicing modulator tool compounds with novel targets and mechanisms of action would be beneficial in
helping understand the regulation and dysregulation of splicing in cancer and how this may be exploited therapeutically.
Phenotypic screens using splicing-based reporter assays have produced many splicing modulators, amongst them risdiplam, the first small-molecule
splicing modulator to gain FDA approval. This study describes a similar strategy built around MCL1 splicing in a non-small cell lung cancer background.
MCL1 (myeloid cell leukemia-1 protein) is a regulator of apoptosis in several cancers and was chosen for exploration because of its sensitivity to splicing
modulation through a multitude of signalling pathways and splicing modulators. Constitutive splicing of MCL1 produces the anti-apoptotic variant MCL1L,
which is present in high levels in NSCLC, while alternative splicing produces MCL1S, a pro-apoptotic variant.
In an effort to identify novel splicing tool compounds, the human NSCLC cell line NCI-H1299 was engineered to express a tagged MCL1 that reports on
the generation of the pro-apoptotic MCL1S splice variant using a split luciferase HiBiT reporter assay. Using this model, high-throughput small molecule
phenotypic screening of compound libraries was undertaken. A single screen hit, CCT803, was discovered to increase mRNA and protein levels of
MCL1S and induce splicing changes across the transcriptome. The extensive characterisation and deconvolution of CCT803 suggest a novel mechanism
of action involving splicing factor relocalisation and a molecular target that does not show pan-essentiality. Further investigation of this compound and its effects on splicing may help to narrow the knowledge gap for splicing in NSCLC, providing evidence for splicing as a therapeutic target
PERSEUS1: An Open-label, Investigator-initiated, Single arm, Phase 2 Trial Testing the Efficacy of Pembrolizumab in Patients with Metastatic Castration-resistant Prostate Cancer with Mismatch Repair Deficiency and Other Immune-sensitive Molecular Subtypes.
No full textBACKGROUND AND OBJECTIVE: Some metastatic castration-resistant prostate cancers (mCRPCs) present mismatch repair deficiency (MMRd) and other molecular subtypes potentially sensitive to immune checkpoint inhibitors (ICIs). The PERSEUS1 trial evaluated the response to pembrolizumab in these subtypes. METHODS: This open-label, investigator-initiated, single-arm, phase 2 trial used a two-stage Simon minimax design. Results from stage 1 are presented here. Tumour biopsies from patients with mCRPC progressing on standard therapies were analysed via targeted next-generation sequencing and immunohistochemistry. Patients with MMRd and/or other molecular subtypes associated with ICI sensitivity were treated with pembrolizumab until disease progression or unacceptable toxicity. The primary outcome was response by 24 wk using a composite of radiological objective response; confirmed decrease in prostate-specific antigen ≥50%; or conversion of circulating tumour cell count. The hypothesised desirable response rate was 40%, with 20% deemed unacceptable; >5/24 responses were required for progression to stage 2. KEY FINDINGS AND LIMITATIONS: In total, 25 patients from two centres received a median of 6 cycles (range 2-13) of pembrolizumab, with a response observed in seven (28.0%, 95% confidence interval 12.1-49.4%). Median progression-free survival was 2.8 mo and median overall survival was 16.0 mo. Nineteen patients (76%) experienced treatment-related adverse events, including three (12%) grade 3-4 events. There were no treatment-related deaths. While the prespecified threshold for futility was not met, slow accrual meant the study did not progress to stage 2. CONCLUSIONS AND CLINICAL IMPLICATIONS: Pembrolizumab showed antitumour activity against MMRd and/or other mCRPC molecular subtypes, with a manageable toxicity profile. Genomic and molecular stratification and further translational research are needed to refine patient selection for this therapy in the mCRPC setting
biogrowleR: Enhancing Longitudinal Data Analysis.
No full textTime course measurements are used for many applications in biomedical research, ranging from growth curves to drug efficacy testing and high-throughput screening. Statistical methods used to analyze the resulting longitudinal data, such as t-tests or repeated measures ANOVA have limitations when groups are unbalanced, or individual measurements are missing. To address these issues we developed biogrowleR (https://upbri.gitlab.io/biogrowleR/), a workflow to visualize and analyze data based on Frequentist and Bayesian inference combined with hierarchical modeling. By focusing on effect sizes we enhance data interpretation. The workflow further includes a randomization algorithm important to reduce numbers of experimental animals (RRR) and costs. The workflow and R package were designed to be used by researchers with limited experience in R and biostatistics. Our open-source R package biogrowleR contains tutorials, pipelines, and helper functions for the analysis of longitudinal data and enables non computational scientists to perform more effective data analysis
Use of routinely collected health data (England) to identify subsequent disease-related events in patients with primary breast cancer: a practical alternative to hospital-based follow-up for breast cancer clinical trials.
No full textBACKGROUND: With continued improvements in breast cancer (BC) outcomes and risk of recurrence occurring until at least 20 years post-diagnosis, it is important to continue to follow up clinical trial participants to characterise long-term treatment impact. Traditionally, follow-up has been via hospitals, entailing burden on patients and site staff. Using routinely collected health datasets (RCHD) as an alternative method is attractive, but historically, cancer recurrence is poorly recorded, unlike initial cancer diagnosis. Here we use data collected prospectively from large, multi-centre BC clinical trials to develop and test a procedure to identify recurrence within RCHD. METHODS: Data from four trials of early breast cancer (TACT2, POETIC, IMPORT-HIGH and FAST-Forward) where recurrence data has been collected prospectively (gold standard) was linked with RCHD (incl. cancer registry and hospital episode statistics; HES) managed by NHS England. The procedure identified episodes of clinical activity within RCHD to classify each event type (local and distant recurrence, second cancers, death) separately, then combined to derive time-to-recurrence (TTR), disease-free survival (iDFS) and overall survival (OS) outcomes. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. Hazard ratios using Cox regression modelling, log-rank test p-values, and 3-year survival rates for the randomised treatments were reported separately for RCHD and trial data. RESULTS: The final procedure used Cancer Registry diagnoses to identify initial BCs for quality control purposes and second primary cancers. Deaths were identified via death dates and cause. Distant recurrence was identified predominantly by direct indicators of metastases (e.g. ICD10 codes C77X-79X). Local recurrence was identified via relevant surgeries' OPCS4 codes. For TTR, iDFS and OS, agreement between study and RCHD events was reasonable. Specificity was good across all endpoints (range: 97.9-99.9% for three training datasets combined), as was NPV (range: 95.2-99.6%). Sensitivity and PPV were more variable, with sensitivity ranging between 72.9 and 97.2% and PPV ranging between 82.6 and 99.5%. Values were similar when considering the test dataset. Survival estimates for TTR, iDFS and OS were similar between study and RCHD data. CONCLUSION: It is possible, with reasonable accuracy, to identify cancer recurrences using RCHD in the place of hospital-based data collection after the point of primary analysis