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Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy.
No full textTumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization
Incidental finding of leukaemia in circulating tumour DNA- the importance of a molecular tumour board.
No full textAs the use of liquid biopsies are increasing across multiple indications in cancer medicine, the detection of incidental findings on circulating tumour DNA is of increasing importance. We report the finding of leukaemia detected in a patient who underwent plasma-based circulating tumour DNA next generation screening as part of a screening liquid biopsy study. A BRAF V600E mutation detected was deemed pathogenic following discussion at a molecular tumour board, and recommendation of further investigations led to the diagnosis of an occult haematological malignancy. We report the importance of molecular tumour board discussion and recommendations in the identification of incidental, pathogenic findings on circulating tumour DNA
What is the carbon footprint of academic clinical trials? A study of hotspots in 10 trials.
No full textBACKGROUND: Clinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint of clinical trials, we have now applied the guidance to 10 further UK and international, academically sponsored clinical trials to continue the identification of hotspots and opportunities for lower carbon trial design. METHODS: 10 collaborating clinical trial units (CTUs) self-identified and a trial was selected from their portfolio to represent a variety of designs, health areas and interventions. Trial activity data was collated by trial teams across 10 modules spanning trial setup through to closure, then multiplied by emission factors provided in the guidance to calculate the carbon footprint. Feedback was collected from trial teams on the process, experience and ease of use of the guidance. RESULTS: We footprinted 10 trials: 6 investigational medicinal product trials, 1 nutritional, 1 surgical, 1 health surveillance and one complex intervention trial. Six of these were completed and four ongoing (two in follow-up and two recruiting). The carbon footprint of the 10 trials ranged from 16 to 765 tonnes CO2e. Common hotspots were identified as CTU emissions, trial-specific patient assessments and trial team meetings and travel. Hotspots for specific trial designs were also identified. The time taken to collate activity data and complete carbon calculations ranged from 5 to 60 hours. The draft guidance was updated to include new activities identified from the 10 trials and in response to user feedback. DISCUSSION: There are opportunities to reduce the impact of trials across all modules, particularly trial-specific meetings and travel, patient assessments and laboratory practice. A trial's carbon footprint should be considered at the design stage, but work is required to make this common place
Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
No full textPubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease
Enhancing efficiency in clinical trial toxicity data collection: Insights from bladder and prostate cancer radiotherapy studies
No full textBackground: Collection of long-term toxicity data in radiotherapy trials is important as side effects can occur years after treatment. It is however time consuming, impacting patients, healthcare staff and clinical trials units. Methods: Using trials of prostate and bladder cancer radiotherapy four approaches for improving the efficiency of toxicity data collection were explored:• Use of either patient or clinician reported outcome (PRO, CRO) collection as a single modality for accurate toxicity follow up (retrospective, exploratory analysis).• Reducing the number of CRO assessments (retrospective, exploratory analysis).• Electronic collection of PRO (prospective clinical study (SPRUCE))• Validity of using routinely collected data for long-term follow up (prospective data linkage study)Results: Patients report toxicities more frequently than clinicians with poor concordance between the two measures on an individual level. Patients report almost all severe side effects reported by clinicians. There is a correlation between acute and late genitourinary and gastrointestinal grade 2+ toxicity, but no distinct pattern to the time to appearance of toxicity when examining individual patients. It was not possible to conclude non-inferiority of response rate with electronic PRO in comparison to paper in the interim analysis of SPRUCE, but electronic PRO use had high levels of questionnaire compliance and completeness of data. Routine healthcare data picked up more late adverse events than trial case report forms and is valid when specific endpoints with accurate disease or procedure codes are used. Conclusions: It is not possible to make specific recommendations about streamlining CRO assessment points universally but the use of both PRO and CRO over the duration of follow-up is inefficient. To complete assessments, paper PRO data collection options should be maintained for patients who have reduced internet access or capabilities. Finally, routinely collected healthcare data can be used to identify late side effects for specific and carefully considered trial endpoints
Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid.
No full textLung carcinoids (L-CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L-CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L-CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole-exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L-CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L-CD-PanC and L-CD-NeU. L-CD-PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion (p < 1 × 10-6). These tumours were centrally located and showed mutational signatures of activation-induced deaminase/apolipoprotein B editing complex activity, together with genome-wide DNA methylation loss enriched in repetitive elements (p = 2.2 × 10-16). By contrast, the L-CD-NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology (p = 0.04), peripheral location (p = 0.01), high mutational load (p = 2.17 × 10-4), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L-CD-NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid (p = 0.05), suggesting a possible environmental exposure in their pathogenesis. Immunologically, myeloid and T-cell markers were enriched in L-CD-PanC and B-cell markers in L-CD-NeU tumours. The substantial epigenetic and non-coding differences between L-CD-PanC and L-CD-NeU open new possibilities for biomarker selection and targeted treatment of L-CD. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.
No full textEukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered a promising anticancer target. Here we screen a fragment library against eIF4E and identify a ligand-binding site with previously unknown function. Follow-up structure-based design yields a low nM tool compound (4, Kd = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, and demonstrates target engagement with eIF4E in intact cells (EC50 = 2 µM). By coupling targeted protein degradation with genetic rescue using eIF4E mutants, we show that disruption of both the canonical eIF4G and non-canonical binding sites is likely required to drive a strong cellular effect. This work highlights the power of fragment-based drug discovery to identify pockets in difficult-to-drug proteins and how this approach can be combined with genetic characterization and degrader technology to probe protein function in complex biological systems
Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial.
No full textMucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49)
Targeting the inflammatory response in advanced prostate cancer
No full textProstate cancer is a leading cause of male cancer mortality. Despite inflammation being implicated in prostate cancer initiation and progression, patient outcomes have been minimally impacted by immunotherapies that have imparted durable benefit in other advanced malignancies. There is an unmet need to elucidate the inflammatory response and develop novel immunotherapies for patients with prostate cancer.
In this thesis, I first investigated the expression, function, and therapeutic targeting of B7-H3, a member of the B7 family of immunomodulatory proteins, against which therapeutic antibodies, antibody-drug conjugates (ADCs), and cellular therapies are being developed. This investigation revealed that, in contrast to PD-L1 (B7-H1), which is infrequently expressed by prostate cancer cells, another member of this family B7-H3 is among the most highly expressed immunomodulatory molecules in castration-resistant prostate cancer (CRPC). B7-H3 expression was higher in tumours with pathogenic DNA damage response (DDR) gene alterations and inversely associated with the infiltration of T lymphocyte in tumour. Targeting B7-H3 in human prostate cancer cell lines, organoids, and xenografts led to B7-H3 dependent tumour cell kill. However, in vivo studies demonstrated incomplete tumour eradication, with residual B7-H3 positive cells exhibiting features of cellular senescence across all treatment-responsive models.
Tumour cell senescence, regardless of trigger, has been linked to secretory phenotypes that include chemotactic (and other) cytokines which attract pathogenic myeloid cells known to cause therapy resistance in prostate cancer mouse models. Therefore, I conducted translational and clinical studies elucidating the relationship between senescence and myeloid inflammation in patients with mCRPC. Peripheral blood and intratumour myeloid expansion correlated, with both also associating with tumour expression of senescence-associated, and negatively prognostic Glu-Leu-Arg (ELR+) CXC chemokines (named for their N-terminal glutamate, leucine, and arginine tripeptide motif preceding the C-X-C chemokine motif) that bind CXCR1 and CXCR2. CXCR2 was selectively expressed by myeloid cells in CRPC. The availability of selective and potent CXCR2 inhibitor (CXCR2i) developed to treat inflammatory non-malignant indications, allowed for further clinical investigations of this target. In an investigator-initiated, proof-of-concept, proof-of-mechanism, phase-1 trial combining a CXCR2i with enzalutamide in patients with CRPC, I showed that this combination led to dose-dependent decreases in peripheral blood neutrophils, reduced myeloid cell infiltration in some CRPC biopsies, and conferred clinical antitumour activity in some patients. Taken together, these results indicate that a senescence-associated inflammatory milieu may signal via the CXCR1/2 axis to recruit myeloid cells, with inhibition of this axis causing tumour shrinkage supporting the pathogenic role of myeloid inflammation in CRPC. A second clinical trial targeting the myeloid paracrine factor, IL-23, shown to drive AR signalling through the RORγ-JAK2-STAT3 axis was initiated but terminated by the study’s funder SUN Pharma before completion for strategic reasons after limited antitumour activity was demonstrated in a small dose escalation clinical trial.
In summary, I provided insights into the inflammatory response in CRPC and demonstrated novel immunotherapeutic approaches for its management
Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.
No full textPURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption