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'It's Skin Cancer'… a Rollercoaster of a Journey for Teenagers, Young People and Their Significant Other.
No full textAIM: To explore the lived experience of young people aged 16-24 years diagnosed with melanoma and that of their significant other in England. DESIGN: Interpretive phenomenological analysis. METHODS: Data were collected between August 2023 and January 2024 from one specialist cancer centre in England. Thirteen young people were approached, and 10 took part. Each young person was asked to nominate a significant other. Five nominated a significant other, and five nominated no one. Although interviews were offered face-to-face, virtual was the preferred method. In-depth semi-structured interviews were audio-recorded with the participant's consent. Interview data were transcribed verbatim and analysed. FINDINGS: The core conceptual thread woven throughout the findings was 'It's like being on a rollercoaster,' which is representative of the ups and downs of the treatment trajectory, often without the support of age-appropriate specialist care. Four superordinate themes were identified: 'Is something wrong?', 'Suddenly it's serious', 'Out on a limb' and 'Finding our place'. CONCLUSION: Although most young people were treated in a primary treatment centre for adults with cancer, their experience was challenging from route to diagnosis through their treatment and beyond. Few received age-appropriate care to support their physical, emotional, and social wellbeing to help them navigate the experience. IMPACT: There is limited evidence exploring the experiences of teenagers and young adults living with melanoma or that of their significant other. This enriched understanding supports improvement of the care pathway and service delivery for these young people and their families. PATIENT AND PUBLIC INVOLVEMENT: One young person with lived experience was paid as a consultant to be part of the research team. He helped develop the grant application and research questions, data analysis, and writing this paper
Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening.
No full textTRF1 is a subunit of the shelterin complex that binds to and protects the linear ends of chromosomes known as telomeres. Both genetic deletion and chemical inhibition of TRF1 have been shown to block the growth of lung carcinoma, glioblastoma, and renal cell carcinoma in mice without affecting mouse survival or tissue function, making TRF1 a potential therapeutic target in cancer1-3. Here, we report the discovery of a series of fragment hits that bind at the interface between the TRFH domain of TRF1 (TRF1TRFH) and a peptide of TIN2 (TIN2TBM), an interaction essential for the recruitment of TRF1 to shelterin, using X-ray crystallography (XChem) and ligand-observed NMR (LO-NMR) fragment screening. We discovered a first-in-class inhibitor of the TRF1:TIN2 interaction (compound 40) that binds to TRF1TRFH with a KD of 29 µM (95% CI: 20-41 µM), displaces a TIN2 probe with an IC50 of 67 µM (95% CI: 10-120 µM), and expels TRF1 from purified shelterin. Aided by a novel crystal system of TRF1TRFH, we characterised fragments binding in a hotspot at the TRF1:TIN2 interface; these will serve as a starting point for the structure-guided development of potent inhibitors of TRF1 protein:protein interactions to disrupt shelterin complex assembly
Stereotactic Body Radiation Therapy for Oligoprogressive Disease in Androgen-Suppressed Prostate Cancer: Primary Endpoint Analysis of the TRAP Trial.
No full textPURPOSE: Optimal management of oligoprogressive prostate cancer while on androgen receptor pathway inhibitors (ARPIs) is not known. The TRAP trial tests the role of stereotactic body radiation therapy (SBRT) in this setting. The objective of this phase 2 prospective, nonrandomized, single-arm trial was to determine if local control of oligoprogressive disease with SBRT can delay further progression by >4 months, postponing time to next therapy. METHODS AND MATERIALS: Men with castration-resistant prostate cancer with ≤2 oligoprogressive sites developing on treatment with an ARPI, after initial response to therapy, were recruited. All patients were treated to a dose of 30 Gy in 5 fractions (alternate days) or 36 Gy in 6 fractions weekly (prostate only). RESULTS: Eighty-six men were recruited between October 2018 and February 2023. SBRT was delivered to 81 men. Mean age was 74 years. Most patients (67%) had 1 oligoprogressive disease lesion. Sites irradiated were bone (59%), lung (1%), lymph node (32%), and prostate (7%). Median follow-up was 22.9 months at the time of analysis. Fifty-five (68%) patients had progressed, 33 (41%) of patients progressed within 6 months of radiation therapy. Median progression-free survival (PFS) was 6.4 months (95% CI, 5.9-11.4). An estimated 39% (95% CI, 29-49) of patients have a prolonged PFS of > 12 months. Thirty-three (41%) of patients had started new treatment or died. Median time to either next treatment or death was 27.0 months (95% CI, 14.9-29.6). Median overall survival was 27.2 months (95% CI, 24.7-36.6). Four deaths occurred within 6 months of SBRT; none were related to radiation therapy treatment. CONCLUSIONS: The TRAP trial has demonstrated a median PFS of 6.4 months after SBRT for oligoprogression of prostate cancer, meeting the primary endpoint. Further analysis of biomarker panel including circulating DNA and whole-body magnetic resonance imaging will promote better patient selection
Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition.
No full textTumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutic opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils and synergize with endocrine therapy
Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer.
No full textPURPOSE: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. METHODS: We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of "very-rare" variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework. RESULTS: For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 "hotspot" regions wherein the DS-VRMV-LR increased to 1226.9. CONCLUSION: These data provide quantitative measures for very rare missense and truncating variants in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification
Mediator Kinase Inhibitor Selectivity and Activity in Colorectal Cancer.
No full textThe Mediator complex is a regulator of gene expression, influencing chromatin structure and RNA polymerase II-mediated transcription. Its activity is controlled by a protein kinase module, which includes cyclin-dependent kinases 8 and 19, that phosphorylates RNA polymerase II and transcription factors to regulate gene expression. Using orthogonal approaches combining chemical and genetic tools, we demonstrated the selectivity of our small-molecule inhibitors derived from 3,4,5-trisubstituted pyridine and 3-methyl-1H-pyrazolo[3,4-b]pyridine chemical series in human colorectal cell culture and tumor xenograft models. The lack of activity of our inhibitors in CDK8/19 double knockout models, with respect to molecular, proliferative, and antitumor end points, revealed their specificity and dependence on these kinases. Using our chemical probes and knockout models, we explored Mediator kinase function in human colorectal cancer cells. Phospho-proteome profiling revealed substrates enriched with transcription and chromatin regulators, while promoter reporter experiments identified transcription factor binding sites, including TCF/LEF and AP1, regulated by Mediator kinases. Additionally, altered phosphorylation of several Mediator subunits suggests a mechanism for the rapid regulation of the Mediator complex. Overall, our results demonstrate that CDK8 and CDK19 play pivotal roles in regulating gene expression associated with oncogene activation and signaling pathways. Further studies are warranted to elucidate their broader cellular roles and regulatory mechanisms. The selective inhibitors validated in this study will provide valuable tools for such mechanistic investigations into Mediator kinase functions and their potential therapeutic exploitation
The Integration of Germline Genetic Variations to Precision Medicine in Healthcare as applied to Screening and Treatment Paradigms
No full textIn recent years, the ability to use an individual’s genetic information to predict, prevent, diagnose, and treat a wide range of conditions had grown substantially. Advances in genomic research, personalised medicine, and bioinformatics have enabled healthcare providers to give more accurate risk prediction, improve earlier detection, and customise targeted treatment strategies based on an individual’s genetic profile.
Applications of genomic medicine already span multiple healthcare domains, such as cancer diagnosis and management, cardiovascular disease, rare inherited disorders, and pharmacogenomics. Recent advances in genomics offer new opportunities to enhance traditional screening models through integration of genetic risk information , including both high-penetrance single gene variants and polygenic risk scores (PRS).
My MD(Res) investigates the use of germline genetic testing in two distinct settings: a feasibility study exploring the use of whole genome sequencing (WGS) in primary care among asymptomatic individuals, and the use of germline testing to guide treatment in men with metastatic castration resistant prostate cancer (mCRPC).
The 90S Study recruited individuals from a private general practice for germline genetic testing as an adjunct to medical screening. Results show that 22% (23/104) of participants had actionable germline genetics variants altering medical management or screening pathways. Ten of these (43%) had pathogenic variants in cancer predisposition genes, 60 (58%) participants harboured recessive alleles and 43 (41%) had pharmacogenetic variants. Participants who had a PRS above the 80th percentile may have a significantly increased risk of the associated cancer. This study shows how embedding germline WGS testing in a medical screening pathway is feasible in a community-based healthcare setting.
The BARCODE2 study is part of a clinical trial examining the use of a panel of DNA repair genes (DRG) to target therapy among men with mCRPC. This work includes analysis of 220 study
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participants. The pathogenic/likely pathogenic (P/LP) detection rate was 15.5%. Overall, carriers had higher Gleason scores (8-10) and higher PSA at diagnosis compared with non-carriers. Sub-analyses showed that BRCA2/ATM carriers had more aggressive disease at diagnosis compared with non-carriers. Time to onset of castration resistant disease was significantly shorter among BRCA2/ATM carriers (p=0.04).
These studies provide evidence to support broader use of genomically informed screening and treatment pathways
Quantitative image quality metrics enable resource-efficient quality control of clinically applied AI-based reconstructions in MRI.
No full textOBJECTIVE: AI-based MRI reconstruction techniques improve efficiency by reducing acquisition times whilst maintaining or improving image quality. Recent recommendations from professional bodies suggest centres should perform quality assessments on AI tools. However, monitoring long-term performance presents challenges, due to model drift or system updates. Radiologist-based assessments are resource-intensive and may be subjective, highlighting the need for efficient quality control (QC) measures. This study explores using image quality metrics (IQMs) to assess AI-based reconstructions. MATERIALS AND METHODS: 58 patients undergoing standard-of-care rectal MRI were imaged using AI-based and conventional T2-weighted sequences. Paired and unpaired IQMs were calculated. Sensitivity of IQMs to detect retrospective perturbations in AI-based reconstructions was assessed using control charts, and statistical comparisons between the four MR systems in the evaluation were performed. Two radiologists evaluated the image quality of the perturbed images, giving an indication of their clinical relevance. RESULTS: Paired IQMs demonstrated sensitivity to changes in AI-reconstruction settings, identifying deviations outside ± 2 standard deviations of the reference dataset. Unpaired metrics showed less sensitivity. Paired IQMs showed no difference in performance between 1.5 T and 3 T systems (p > 0.99), whilst minor but significant (p < 0.0379) differences were noted for unpaired IQMs. DISCUSSION: IQMs are effective for QC of AI-based MR reconstructions, offering resource-efficient alternatives to repeated radiologist evaluations. Future work should expand this to other imaging applications and assess additional measures
Optimising image-guided radiotherapy in extracranial renal cell carcinoma
No full textCurative-intent stereotactic body radiotherapy (SBRT) for primary inoperable renal cell carcinoma (RCC) has world-wide recognition following a proliferation of clinical studies demonstrating excellent clinical outcomes. Patients are often older, frail or have comorbidities precluding them from gold-standard invasive intervention. Although severe toxicity rates from SBRT are low, moderate toxicity is common. Cancer-specific survival decreases with increasing tumour size. Immunotherapy and targeted treatments have transformed the treatment landscape of metastatic RCC (mRCC). Patterns of failure are changing with often one or a few problematic areas requiring local control.
This thesis evaluates SBRT dosimetry with Volume-Modulated Arc Therapy, CyberKnife and Proton Beam Therapy. In smaller tumours, dosimetric feasibility is demonstrated using all 3 techniques, however protons significantly reduced organ at risk (OAR) doses. In larger tumours, protons maintained prescription dose in more cases and resulted in a significant reduction in OAR doses compared to photons. Real-time tracking using CyberKnife may be beneficial in very mobile tumours. This work aims to lead to a clinical feasibility study of stereotactic protons in primary RCC. For large cases with significant bowel overlap, no techniques met bowel constraints. Carbon-ion therapy is thought to be more radiobiologically effective than photons. Through international collaboration, a radical hypofractionated approach is investigated in such cases and shows dosimetric feasibility.
A systematic review is undertaken to evaluate metastasis-directed ablative therapies in mRCC. This leads to the development of a single-centre randomised feasibility study of high-dose hypofractionated radiotherapy versus palliative radiotherapy for local control. Interim results meet feasibility criteria.
This work aims to lead to a collaborative programme of clinical research, incorporating both translationally-rich studies and real-world data. My hope is that future work will aid development of patient-selection tools, to encourage equity of access and prioritisation of advanced technology when it is most likely to lead to improved patient outcomes
Enhancing small molecule binding through computational analysis of water networks
No full textWater molecules in protein binding sites can play a critical role in small
molecule binding and are an important consideration in structure-based drug
design. Water networks add complexity as displacing one water molecule has
subsequent effects on the surrounding network. When modifying the structure
of a lead compound, the disruption of a water network can have beneficial or
detrimental effect on potency, but the outcome is difficult to predict experimentally.
Computational methods can be used to study these water networks and provide
insights to guide synthesis.
Three computational methods for solvent analysis, including Grand Canonical
Monte Carlo (GCMC) simulations, Molecular Dynamics (MD) simulations with
GCMC sampling and 3D Reference Interaction Site Model (3D-RISM), were
evaluated using a protein-bound water molecule known to be displaceable in
KRASG12C but not KRASG12D. GCMC simulations proved the most effective,
particularly for targets with complex water networks.
GCMC was then combined with alchemical free energy calculations to
retrospectively study a series of BCL6 inhibitors that sequentially displaced water
molecules from a network. The methods helped rationalise the structure-activity
relationship of the compounds by quantifying individual contributions to the
binding affinity from the changes in the water network and new interactions with
the protein.
GCMC was also applied prospectively to design BRD9 inhibitors that
perturb a conserved water network. Using a known scaffold, a generative AI
model proposed substituents that pointed towards a water network in the Kac
binding site, which is an approach previously used to gain selectivity in other bromodomains but unprecedented for BRD9. The GCMC predictions of the
binding free energy of the water network were used to shortlist compounds for
synthesis and testing.
Together, these case studies demonstrate the practical value of GCMC in drug
design, highlighting its potential to enhance small molecule binding by analysing
water networks in the binding site