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Targeting Inhibitor of Apoptosis Proteins (IAPs) to Potentiate Immunotherapy in Breast Cancer
No full textImmunotherapy has transformed cancer treatment, improving survival rates in
aggressive triple-negative breast cancer. However, most breast cancer patients do not
respond to immune checkpoint inhibitor (ICI) therapy. Thus, new strategies to enhance
immune activation are urgently needed. Effective treatment requires therapies that kill
cancer cells and mobilise the immune system. Necroptosis, unlike apoptosis, triggers
stronger immune responses by alerting the immune system. To explore immunogenic
cell death (ICD) in breast cancer, I used ASTX660 (tolinapant), a triple inhibitor of IAP
proteins, which are often overexpressed in cancer. My hypothesis was that ASTX660
could sensitise cancer cells to ICD and enhance the efficacy of ICI. The ASTEROID
phase I trial evaluated ASTX660 with pembrolizumab in therapy-resistant patients,
showing a 33% response rate, including 3 breast cancer cases. Analysis of samples
revealed ASTX660’s role in activating RIPK1-Caspase 8-mediated death, upregulating
inflammatory gene expression, and expanding TCR clonotypes. Potential biomarkers of
response included high RIPK3 expression, diverse T cell repertoires, and early increase
in circulating CD57+ effector T cells. Co-clinical studies in Brca1-/-p53-/- murine models
showed ASTX660's effectiveness under necroptotic conditions. I also developed a
method for fresh explants from patient-derived xenograft (PDX) models for ex vivo
assays. Overall, my work highlights pan-IAP inhibition as a promising strategy for improving breast cancer treatment
Pulse-by-pulse treatment planning and its application to generic observations of ultra-high dose rate (FLASH) radiotherapy with photons and protons.
No full textObjective.The exact temporal characteristics of beam delivery affect the efficacy and outcome of ultra-high dose rate (UHDR or 'FLASH') radiotherapy, mainly due to the influence of the beam pulse structure on mean dose rate. Single beams may also be delivered in separate treatment sessions to elevate mean dose rate. This paper therefore describes a model for pulse-by-pulse treatment planning and demonstrates its application by making some generic observations of the characteristics of FLASH radiotherapy with photons and protons.Approach.A beam delivery model was implemented into the AutoBeam (v6.3) inverse treatment planning system, so that the individual pulses of the delivery system could be explicitly described during optimisation. The delivery model was used to calculate distributions of time-averaged and dose-averaged mean dose rate and the dose modifying factor for FLASH was then determined and applied to dose calculated by a discrete ordinates Boltzmann solver. The method was applied to intensity-modulated radiation therapy with photons as well as to passive scattering and pencil beam scanning with protons for the case of a simple phantom geometry with a prescribed dose of 36 Gy in 3 fractions.Main results.Dose and dose rate are highest in the target region, so FLASH sparing is most pronounced around the planning target volume (PTV). When using a treatment session per beam, OAR sparing is possible more peripherally. The sparing with photons is higher than with protons because the dose to OAR is higher with photons.Significance.The framework provides an efficient method to determine the optimal technique for delivering clinical dose distributions using FLASH. The most sparing occurs close to the PTV for hypofractionated treatments
Elucidating Prostate Cancer Biology Through Integrative Computational Multi-omic Analyses
No full textin this thesis, I aimed to elucidate the microbial landscape of castration-resistant prostate cancer (CRPC), focusing on novel biomarkers of therapeutic
resistance. We employed metagenomic sequencing of over 200 CRPC patients, alongside in vitro cell Line and ex vivo patient-derived xenograft (POX), models, to investigate microbial biomarkers of progression from hormone-sensitive prostate cancer {HSPC) to CRPC.
Metagenomic sequencing effectively characterised the gut microbiome ofCRPC patients. While microbiome alpha diversity between HSPC and CRPC I remained similar, species-level changes, including an increased abundance of Adlercreutzia equolifaciens, were observed in CRPC. Further, L- 1 citrulline biosynthesis by the microbiota was linked to improved AR -negative prostate cancer cell viability, highlighting its potential role in CRPC i progression. Analysis ofCRPC biopsy samples provided inconclusive evidence for intra-tumour micro biota presence, with contamination confounding microbial classifications.
Single-nucleus sequencing revealed significant myeloid cell heterogeneity in CRPC, with varying degrees of oxidative stress-induced DNA damage I linked to myeloid-derived reactive oxygen species {ROS). This heterogeneity extended to tumour subclones, with genomic instability and replication I stress driving therapeutic sensitivity to ATR inhibition. Notably, the overexpression of the prognostic marker POLQ was associated with replication [ stress and ATR inhibition sensitivity, highlighting a potential therapeutic target for CRPC. These findings provide insights into the complex interplay: between the microbiome, inflammation, and cellular mechanisms driving CRPC progression and resistance and merit further functional validations
Addressing uncertainty in hereditary colorectal cancer: the role of a regional expert multidisciplinary team meeting.
No full textThere is frequent uncertainty in both the precise quantification of risk, and the application of clinical interventions, designed to mitigate increased heritable colorectal cancer (CRC) susceptibility. We evaluated the role of a collaborative specialist multidisciplinary team meeting (MDM) for familial and hereditary CRC, led by the St Mark's Hospital Centre for Familial Intestinal Cancer specifically in supporting the clinical management of uncertainty. A retrospective thematic analysis of meeting outcomes from inception in June 2020 until March 2023 was performed. Descriptive statistics were employed to ascertain clinicopathological data, clinical queries and whether MDM recommendations were outside the scope of current guidelines. In total 260 cases were discussed from 13 regional institutions. A prior personal history of cancer was present in 215 (82.6%), and a family history of CRC in 107(41.2%) and non-CRC 27(10.4%) cases. In thematic analysis uncertainty related to indications for genetic testing was considered in 148 (56.9%) of cases, with unexplained mismatch repair deficiency (u-dMMR) in 78 (30%) of cases, and resolution of molecular interpretation in 61 (23.5%). Surveillance related queries represented 55 (21.1%), and mainstreaming 29 (11%) of cases. Management was recommended beyond the scope of existing guidelines in 64 (24.6%) cases. This regional hereditary CRC MDM provides clinicians with support in areas of uncertainty in diagnosis and clinical management, supporting clinical decision-making where evidence and clinical guidelines may be limited. This model could be replicated to support complexity in clinical care in other geographical regions or other health conditions
Best Practice for Patient-centred Radiotherapy in Clinical Trials and Beyond-A National Multidisciplinary Consensus.
No full textAIMS: Patient-centred radiotherapy refers to an approach where patients' needs and preferences are prioritised. Guidelines for this personalised approach are lacking. We present a multidisciplinary national consensus with the aim to provide recommendations for best practice in patient-centred radiotherapy for both clinical trials and routine practice. MATERIALS AND METHODS: A multidisciplinary working group was formed, comprising of healthcare professionals and patient advocates with lived experience of radiotherapy. Three interlinking themes were identified around patient-centred radiotherapy: information, decision-making, and outcomes. Scoping reviews were carried out for each theme, considering current challenges and recommendations for best practice. Recommendations were shaped through consultation with 12 patient advocates. RESULTS: There is a pressing need to better support patients prior to, during, and following radiotherapy. Radiotherapy-related patient information is often complex and challenging to understand. Information resources should be cocreated with patient advocates and individualised wherever possible, including for patients from under-served groups. Shared decision-making (SDM) processes may enhance treatment satisfaction and reduce decision-regret, but these are not widely implemented. SDM requires prepared patients, trained teams, alongside adequate resources and should be offered as per patients' preferences. Healthcare system data offer complementary information to clinical trials, with the potential to provide additional insight into long-term benefits and risks of radiotherapy within 'real-world' conditions. Patient-reported outcome measures may provide greater insight regarding toxicity and impact on quality of life and should be used in synergy with clinician-reported outcomes. Outcome measures should be collected in the long term, and results should be widely disseminated to both the public and professional communities. Equity of access to radiotherapy, clinical trials, and survivorship services is a priority. CONCLUSION: Patients rightly expect more from healthcare professionals, and it is important that the radiotherapy community recognises this and embraces changes which will enhance patient-centred care. Our recommendations aim to guide best practice for patient-centred radiotherapy
Evaluating Molecular Characteristics of Diverse Clinical Outcomes in Clear Cell Renal Cell Carcinoma
No full textClear cell renal cell carcinoma (ccRCC) is characterised by a diversity of clinical phenotypes, yet clinically implementable biomarkers to
guide decision making are lacking. Effors to date have been limited by a reliance on single biomarkers and a failure to account for
intratumoral heterogeneity, a pervasive feature of ccRCC. Additionally, profiling efforts are often temporally disconneccted, with sampling
pre-dating systemic treatment, often by deveral years. Across three cohorts, leveraging single and multi-regional sampling approaches,
I have sought to characterise tumour molecular and immune microenvironmental features associated with differential clinico-pathological
features and survival outcomes.
Genomics biomarkers were explored across two-large scale cohorts, integrating single and multi-regional approaches with nuanced
clinical annotation. In a subset of patients undergoing deferred cytoreductive nephrectomies, dynamic changes in the tumour immune
microenvironement were identifed, which underpind durable responses to combination Ipilimumab-Nivolumab. To address the limitations
of biomarker discovery, the MANIFEST profiling platform was developed, with the aim of generating composite bimarker signatures
capable of better reconciling differential responses to immunotherapy.
Integrated genomic biomarkers have the potential to reconcile the diversity of clinical phenotypes in ccRCC, particularly when combined
with clinico-pathological features to optimise relapse prediction and when accounting for the context in which individual gene mutations
occur. Durable responses to immune checkpoint inhibitors are critically underpinned by dynamic changes in the tumour immune
microenvironement. The development of multimodal biomarkers that account for intratumoral heterogeneity, integrate dynamic features,
and incorporate both mutational and microenvironmental features is required to better predict theyrapy outcome and reconcile the
clinical diversity of ccRC
Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control.
No full textUNLABELLED: Drug resistance results in poor outcomes for patients with cancer. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. In this study, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared with standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum-resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely, fitter, sensitive cells regrew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell-free DNA obtained longitudinally from patients with ovarian cancer during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual patients with ovarian cancer. SIGNIFICANCE: Carboplatin adaptive therapy improves treatment efficacy without increasing daily dose due to reduced fitness of drug-resistant populations, which can be tracked using cfDNA and could direct adaptive therapy in future clinical trials. See related commentary by Gatenby, p. 3373
The transcriptomic architecture of common cancers reflects synthetic lethal interactions.
No full textTo maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression of BRCA1/2 synthetic lethal genes correlates with clinical outcome. Synthetic lethal genes that exhibit transcriptomic buffering also represent more robust synthetic lethal effects. These observations have implications for understanding how tumor cells tolerate TSG loss, in part explain transcriptomic architectures in cancer and provide insight into target selection
Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study.
No full textTranscriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes
Central and peripheral adiposity and premenopausal breast cancer risk: a pooled analysis of 440,179 women.
No full textBACKGROUND: Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics. METHODS: We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0-11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers. RESULTS: All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90-0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95-1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10-1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71-0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03-1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15-1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17-1.84). CONCLUSIONS: Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes