5728 research outputs found
Sort by
Patient experience preparing for prostate cancer radiotherapy.
No full textINTRODUCTION: Bladder and rectal preparation regimes for prostate cancer (PCa) radiotherapy (RT) can heighten anxiety before and during RT. Patient's perception of RT preparation is under-represented in the literature. To address this gap, patient's experience of preparation with respect to understanding, comfort, anxiety, effectiveness and impact on daily life was examined. MATERIALS AND METHODS: A novel patient preparation survey was created and validated, it contained 12 original questions related to general, bladder and rectal preparation. Plus, the Patient Health Questionnaire 4 (PHQ4) and question 15 of the Expanded Prostate Cancer Index Composite (EPIC).Eligible patients were individuals referred for prostate or prostate bed +/- pelvic lymph node RT from March-May 2024. Surveys were issued immediately after the patient's planning scan, those completing the survey at this timepoint were asked to repeat it in their first and final weeks of RT. RESULTS: The survey was completed by 103/125 eligible patients at their planning scan, 47/103 in the first and 52/103 in the final week of RT. Perception of preparation was largely positive. For general and bladder preparation positive question response rate ranged from 55 to 98 % and negative from 0 to 26 %. Rectal preparation response rate was 59-100 % positive and 0-35 % negative. Difficulty maintaining a full bladder and using enemas was greatest at the end of RT.No significant difference in experience was found for participants using or not using enemas for preparation. Anxiety and depression (PHQ4) affected 12-13 % of respondents, and significantly more patients reported bowel toxicity (EPIC), in the last week of RT compared to earlier timepoints. CONCLUSION: The authors conclude that the preparation needs of their patients are well met. However, a considerable number did find preparation difficult, disruptive and ineffective, more so at the end of treatment. Further qualitative analysis of patient's experience is needed to better understand why individuals experience varies
WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.
No full textThe lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression
Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial.
No full textUse of signal transduction inhibitors as single agents to treat cancer leads to resistance because of the plasticity of intracellular signaling, and combination therapy can overcome this. We describe the first-in-human trial of avutometinib (RAF-MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose and schedule. The recommended phase 2 dose and schedule for a 28-day cycle was determined to be avutometinib 3.2 mg once a day, twice weekly (Monday and Thursday or Tuesday and Friday), and defactinib 200 mg twice a day, seven days a week. Both drugs were administered orally on a 3 weeks 'on' and 1 week 'off' basis. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4-63.1) and a median progression-free survival of 20.1 months (95% confidence interval 11.2-43.9) in patients with low-grade serous ovarian cancer. This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820
Addition of oncolytic virotherapy to clinical isolated limb perfusion for melanoma and sarcoma activates antitumor immunity.
No full textBACKGROUND: We previously showed that oncolytic virotherapy delivered by isolated limb perfusion (ILP), combined with immune checkpoint inhibition, prevents both local tumor progression and systemic metastases in an animal sarcoma model. METHODS: We describe a first-in-human phase I/II trial combining oncolytic herpes simplex virus, talimogene laherparepvec (T-VEC), with melphalan and tumor necrosis factor-alpha delivered by ILP, in patients with locally advanced sarcoma or melanoma. RESULTS: T-VEC/ILP is well tolerated, with an overall response rate of 53% in all patients and 44% in sarcoma. Importantly, we report durable complete responses in sarcoma subtypes usually unresponsive to ILP. Translational analysis of longitudinal tumor and blood samples showed that T-VEC induced an inflammatory gene expression profile within injected tumors, which was more sustained in sarcoma than in melanoma. In relation to clinical outcome, responding patients with sarcoma showed a greater increase in gene expression for interferon response after virus treatment than non-responding patients. Analysis of the T-cell repertoire (TCR) in tumor and blood showed that clonality was higher in the tumor, but lower in the blood, in responders following virotherapy, suggesting that virus treatment may expand intratumoral T-cell clones that recognize tumor and/or viral antigens. Increased TCR diversity in the blood was suggestive of a systemic immune response. CONCLUSIONS: These clinical and translational findings support the further development of oncolytic virotherapy/ILP combinations to activate both systemic and local antitumor immunity, including in tumor types such as sarcoma, which are largely refractory to current treatment with immunotherapy
A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
No full textReactive oxygen species (ROS) influence cell proliferation and fate decisions by oxidizing cysteine residues (S-sulfenylation) of proteins, but specific targets and underlying regulatory mechanisms remain poorly defined. Here, we employ redox proteomics to identify cell-cycle-coordinated S-sulfenylation events and investigate their functional role in proliferation control. Although ROS levels rise during cell cycle progression, the overall oxidation of the proteome remains constant, with dynamic S-sulfenylation restricted to a subset of cysteines. Among these, we identify a critical redox-sensitive cysteine residue (C41) in the cyclin-dependent kinase (CDK) inhibitor p21. C41 oxidation regulates the interaction of p21 with CDK2 and CDK4, controlling a double-negative feedback loop that determines p21 stability. When C41 remains reduced, p21's half-life increases in the G2 phase, resulting in more p21 inheritance to daughter cells, suppressing proliferation and promoting senescence after irradiation. Notably, we identify dynamic S-sulfenylation on further cell cycle regulators, implying coordination of cell cycle and redox control
Response of GEM models of neuroblastoma to cabozantinib assessed by multiparametric magnetic resonance imaging.
No full textBACKGROUND: In neuroblastoma MYCN amplification is associated with enhanced angiogenesis and poor survival. Mutations in the anaplastic lymphoma kinase (ALK) gene can occur with MYCN amplification, conferring a very poor prognosis. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF)/c-MET signalling are implicated in neuroblastoma progression. Cabozantinib has potent activity against VEGFR2 and MET. METHODS: The efficacy of cabozantinib against tumours arising in GEM models of high-risk neuroblastoma was assessed using multiparametric MRI. Tumour-bearing Th-MYCN and Th-ALKF1174L/Th-MYCN mice were imaged prior to, 24 and 48 hrs after treatment with either 30mg/kg/day cabozantinib or vehicle. Treatment-induced changes in tumour volume, native T1, R2* and ADC were evaluated, and histological correlates sought. Additional Th-MYCN mice were treated daily for up to 28 days. RESULTS: Cabozantinib elicited significant 24 and 60 % growth delay 24 and 48 hrs after treatment in tumours in Th-MYCN mice, and a significant 6-8 % reduction in native T1. Tumour R2* was significantly reduced 48 hrs post-treatment. Significantly higher tumour necrosis and apoptosis, and significantly lower Ki67, CD34 and VEGFR2 staining, was determined from the cabozantinib-treated mice. Treatment of Th-ALKF1174L/Th-MYCN mice caused significant 4 % and 21 % tumour growth delay, and a significant 5 % reduction in native T1 at 48 hrs. Daily cabozantinib treatment of Th-MYCN mice elicited significant tumour growth delay over 7 days which translated into significant survival benefit. CONCLUSION: Cabozantinib exhibits activity against neuroblastomas arising in both Th-MYCN and Th-MYCN/ALKF1174L mice, revealed in situ using MRI. Native T1 is an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma
Precision Oncology: A Global Perspective on Implementation and Policy Development.
No full textDespite the acknowledged merits of precision oncology (PO) and its increasing global implementation, its full potential for advancing care and prevention remains unrealized. The benefits are currently accessible to only limited patient segments because of multifaceted barriers. Successful implementation hinges on various factors-scientific complexities not limited to technical, clinical, regulatory, economic, administrative, and health care policy-related challenges. From building infrastructure to the associated costs, including research and development, testing, processing, and trained personnel, a lack of alignment persists. Administrative alignment with regulatory and payor acceptance is crucial. Health care policy must adapt to the ongoing shift from a one-size-fits-all treatment to a personalized approach. Without official endorsement of long-term gains over short-term costs and the health establishment's readiness for innovation, PO prospects, even in prosperous economies, may stagnate. Lower-income countries face exacerbated challenges, intensifying barriers to adoption. Nevertheless, growing awareness and utilization, driven by recognized potential for patients and public health, along with successful examples and advocacy, are progressively influencing policy for a more inclusive and beneficial approach to PO adoption
Summary from the NCI clinical trials planning meeting on next generation of clinical trials in non-muscle invasive bladder cancer.
No full textThe National Cancer Institute organized a virtual Clinical Trials Planning Meeting (CTPM) on 'Defining the next generation of clinical trials with combination therapies in non-muscle invasive bladder cancer (NMIBC)' led by the Bladder Cancer Task Force of the NCI Genitourinary Cancers Steering Committee. The purpose of this meeting was to accelerate advances in clinical trials for patients with high-risk NMIBC. The meeting delivered a multidisciplinary expert consensus on optimal strategies for next-generation clinical trial designs in NMIBC with prioritization of combination therapies. Two clinical trial concepts were developed for potential implementation within the National Clinical Trials Network
The Impact of Collagen Heterogeneity on the Immune Landscape of Pancreatic Ductal Adenocarcinoma and Its Role in Personalising IL-12- Based Immunotherapy
No full textThe aggressive cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by an immunosuppressive tumour microenvironment (TME) and collagen-rich desmoplastic stroma. This TME leads to tumour heterogeneity and resistance to therapies, including immunotherapy and patients often rely on toxic chemotherapy. Moreover, second-generation cytokine-based immunotherapy has limited clinical success in pan-cancers. Therefore, I hypothesised that classifying PDACs into immunologically relevant subgroups will improve our understanding of immune heterogeneity and enhance the personalisation of second-generation cytokine-based immunotherapy. To test this hypothesis, a novel 27-exclusive immune gene signature (PDACi) was developed using a unique virtual microdissection analysis of Nanostring gene expression from 22 matched PDAC and patient-derived xenograft (PDX) tumours. The PDACi signature classified PDACs (n=664) into four subtypes: two (immune-depleted/dormant and collagen-enriched) associated with worse survival and two with better prognoses and higher immune cell infiltration. Using cross-species analysis, I identified subtype-specific mouse models (n=12) and tested different immunotherapy modalities, including collagen-bound pro-inflammatory cytokine (CBD-IL-12) therapy, CBD-IL-12 to reduce systemic toxicity compared to wildtype-IL-12. This bioengineered-CBD-IL-12 combined with anti-PD-1 significantly extended survival in mice (p=0.002) with collagen-rich subtype tumours while reducing liver metastasis and cachexia-like features. Spatial and gene expression (Phenocycler, flowcytometry and bulk-deconvolution) analysis showed that CBD-IL-12 treatment increased unusually Th1-polarised cytotoxic CD4+ T-cells and immune-active myeloid cells and reduced Th17-cells and immunosuppressive myeloid cells compared to the control treatment. Mechanistically, CBD-IL-12 combined with anti-PD-1 treatment remodelled the collagen composition in the TME and induced cancer cell dormancy by enhancing the epithelial-like phenotype via IL-7 signalling, thereby reducing metastasis. Intriguingly, CBD-IL-12 treatment had a preventative effect in a liver metastases model. Overall, the immune signature PDACi captures immune heterogeneity, enabling tailored immunotherapy for PDAC subtypes in mouse models, particularly with CBD-IL-12 and PD-1 treatment, with a potential to advance personalised PDAC treatment in patients with further validation
Engineering MRI-detectable extracellular vesicles to study breast cancer metastatic organotropism in vivo
No full textMetastatic breast cancer exhibits a non-random distribution of metastases in a distinct pattern of organs, a process referred to as metastatic organotropism. Tumour-derived extracellular vesicles (EVs) are an emerging mediator in the metastatic cascade. EVs are nano-sized, cell-derived vesicles that contain a range of bioactive molecules. Evidence from in vitro and ex vivo studies implicate EVs in metastatic organotropism. However, definitive in vivo evidence of EV localisation to metastatic sites is weaker. This research aimed to engineer MRI-detectable EVs as a tool to image the in vivo localisation of breast cancer-derived EVs in tumour models.
A workflow to isolate EVs from adherent cell lines was validated and further optimised by the adoption of an alternative size exclusion chromatography resin that increased EV yield. To facilitate in vivo study design, two human breast cancer cell lines were then characterised. These cells lines induced different patterns of metastasis in vivo when propagated as orthotopic tumours. Furthermore, the in vitro EVs isolated from these cell lines were enriched for different adhesion proteins. Together, the in vivo characterisation and proteomic results suggested that the EVs derived from these two sub-type cell lines may show different localisation in vivo and are valuable models for downstream studies.
Electroporation was used to load EVs with MRI-detectable ultrasmall superparamagnetic iron oxide (USPIO) particles. USPIO-loaded EVs (USPIO-EVs) were characterised with a range of techniques to optimise loading and purification. Preliminary experiments suggested these USPIO-EVs produce MRI contrast in vitro. An in vivo study was performed, which indicated that any excess free USPIO particles in the final sample would not generate sufficient contrast to interfere with a downstream biodistribution study. Once validated in vivo, the imaging platform developed in this research could be used to investigate the role of EVs in the metastatic organotropism of breast cancer