Trailblazers in Cancer Research : The Next Generation – The British Association of Cancer Research Early Career Conference

ACKNOWLEDGEMENTS We thank Mrs Janet Alexander and Ms Barbora Gaborova for their invaluable help with this conference's organisation, marketing, and administration.Peer reviewe

Progress towards a clinically-successful ATR inhibitor for cancer therapy

YesThe DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions

Targeted delivery of a colchicine analogue provides synergy with ATR inhibition in cancer cells

YesDespite significant preclinical promise as anticancer agents, vascular-disrupting agents have yet to fulfil their clinical potential due to systemic toxicities. ICT2588 is a tumour-selective MT1-MMP-targeted prodrug of azademethylcolchicine, ICT2552. We investigate activation of ICT2588 and subsequent release of ICT2552 in tumour cells, and examine its ability to induce G2/M cell cycle arrest. We also explore synergism between ICT2588 and ATR inhibition, since colchicine, in addition to its vascular-disrupting properties, is known to induce G2/M arrest, DNA damage, and trigger apoptosis. Several ATR inhibitors are currently undergoing clinical evaluation. The cellular activation of ICT2588 was observed to correlate with MT1-MMP expression, with selective release of ICT2552 not compromised by cellular uptake and prodrug activation mechanisms. ICT2588 induced G2/M arrest, and triggered apoptosis in MT1-MMP-expressing cells, but not in cells lacking MT1-MMP expression, while ICT2552 itself induced G2/M arrest and triggered apoptosis in both cell lines. Interestingly, we uncovered that the intracellular release and accumulation dynamics of ICT2552 subsequent to prodrug activation provided synergism with an ATR inhibitor in a way not observed with direct administration of ICT2552. These findings have important potential implications for clinical combinations of ICT2588 and DNA repair inhibitors

Trailblazers in cancer research: the next generation – the British Association of Cancer Research early-career conference

The inaugural ‘British Association of Cancer Research (BACR) Early Career Conference, Trailblazers in Cancer Research 2023’, was a 2-day meeting held in Manchester, UK. Recognising the disruption caused by the COVID-19 pandemic to early-career researchers (ECRs), the BACR executive committee organised an in-person conference to address the lack of network and training opportunities during this time. The conference brought together PhD students and post-doctoral researchers from across the UK and beyond, who shared their outstanding contributions to cancer research. The meeting incorporated several cutting-edge cancer themes, including ‘Cancer Cell Signalling and The Tumour Microenvironment’; ‘Emerging Approaches in Cancer Treatment’; ‘Cancer Omics and Lifestyle’, and ‘Nutrition and Cancer’. Alongside showcasing world-class cancer research, the meeting included a career-focused session which allowed industrial and non-academic speakers to provide vital insight into alternative career paths aside from the familiar ‘academic’ route. Importantly, the conference also introduced delegates to Patient Public Involvement in cancer research, an area of limited experience for many. Overall, the BACR Trailblazers Conference was hugely successful and presented an excellent platform for collaboration and networking among ECRs in cancer research

Using Operational Analysis to Improve Access to Pulmonary Function Testing

Background. Timely pulmonary function testing is crucial to improving diagnosis and treatment of pulmonary diseases. Perceptions of poor access at an academic pulmonary function laboratory prompted analysis of system demand and capacity to identify factors contributing to poor access. Methods. Surveys and interviews identified stakeholder perspectives on operational processes and access challenges. Retrospective data on testing demand and resource capacity was analyzed to understand utilization of testing resources. Results. Qualitative analysis demonstrated that stakeholder groups had discrepant views on access and capacity in the laboratory. Mean daily resource utilization was 0.64 (SD 0.15), with monthly average utilization consistently less than 0.75. Reserved testing slots for subspecialty clinics were poorly utilized, leaving many testing slots unfilled. When subspecialty demand exceeded number of reserved slots, there was sufficient capacity in the pulmonary function schedule to accommodate added demand. Findings were shared with stakeholders and influenced scheduling process improvements. Conclusion. This study highlights the importance of operational data to identify causes of poor access, guide system decision-making, and determine effects of improvement initiatives in a variety of healthcare settings. Importantly, simple operational analysis can help to improve efficiency of health systems with little or no added financial investment

A Systematic Review of Cost-Sharing Strategies Used within Publicly-Funded Drug Plans in Member Countries of the Organisation for Economic Co-Operation and Development

Peer reviewe

Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds

YesThe duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.The authors would like to thank Yorkshire Cancer Research (Program grant B381PA) for supporting our work focused on exploring CYPs as targets for prodrug development. The human recombinant CYP1A1 was a gift from Prof Emily E. Scott, University of Michigan; the enzyme was produced via NIH funded grant (R37 GM076343)

Lessons learned from the Alberta Border Testing Pilot Program

BackgroundDuring the Coronavirus disease (COVID-19) pandemic, countries implemented border control and quarantine measures to reduce transmission. The Alberta Border Testing Pilot Program (ABTPP) allowed international travellers entering Alberta to reduce their quarantine period following two negative COVID-19 tests. We evaluated participant experiences with the ABTPP and implementation.MethodWe used a parallel convergent mixed-methods design to explore participant experiences through electronic web-based questionnaires (n = 21,089; n = 13,839) and semi-structured telephone interviews (n = 30). We evaluated implementation through three staff focus groups (n = 11). We analysed questionnaires using descriptive statistics and analysed interviews using inductive and deductive thematic analysis. We deductively coded focus group data using the 2009 Consolidated Framework for Implementation Research (CFIR).ResultsQuestionnaires indicated minimal issues with registration forms (91.7%), symptom reports (95.5%), and COVID-19 testing (95.7%). Most respondents (95.1%) expressed willingness to participate in the ABTPP again. Interviews revealed three themes related to participant experience: program efficiency, clarity of information, and requisite effort. Focus groups identified key implementation facilitators including the single health information system, strong stakeholder partnerships, and good communication across partnerships. Barriers included program complexity, implementation timeline, and evolving external context.DiscussionParticipants reported high satisfaction with the ABTPP. Border testing programs should have high efficiency, require low effort, and use messaging that is clear and consistent. The effective implementation of border testing programs may be facilitated by strong leadership, adaptability, automated components, good communication, and simple technology. Learnings from participants and staff may help improve the implementation of border control programs for future pandemics or other emergencies.ConclusionsThe ABTTP was a novel border control measure during the COVID-19 pandemic. Our evaluation of both participant and staff experiences demonstrated high levels of traveller satisfaction and identified areas for improvement that can inform the development of future border control measures

On-going collaborative priority-setting for research activity: a method of capacity building to reduce the research-practice translational gap

Background: International policy suggests that collaborative priority setting (CPS) between researchers and end users of research should shape the research agenda, and can increase capacity to address the research-practice translational gap. There is limited research evidence to guide how this should be done to meet the needs of dynamic healthcare systems. One-off priority setting events and time-lag between decision and action prove problematic. This study illustrates the use of CPS in a UK research collaboration called Collaboration and Leadership in Applied Health Research and Care (CLAHRC). Methods: Data were collected from a north of England CLAHRC through semi-structured interviews with 28 interviewees and a workshop of key stakeholders (n = 21) including academics, NHS clinicians, and managers. Documentary analysis of internal reports and CLAHRC annual reports for the first two and half years was also undertaken. These data were thematically coded. Results: Methods of CPS linked to the developmental phase of the CLAHRC. Early methods included pre-existing historical partnerships with on-going dialogue. Later, new platforms for on-going discussions were formed. Consensus techniques with staged project development were also used. All methods demonstrated actual or potential change in practice and services. Impact was enabled through the flexibility of research and implementation work streams; ‘matched’ funding arrangements to support alignment of priorities in partner organisations; the size of the collaboration offering a resource to meet project needs; and the length of the programme providing stability and long term relationships. Difficulties included tensions between being responsive to priorities and the possibility of ‘drift’ within project work, between academics and practice, and between service providers and commissioners in the health services. Providing protected ‘matched’ time proved difficult for some NHS managers, which put increasing work pressure on them. CPS is more time consuming than traditional approaches to project development. Conclusions: CPS can produce needs-led projects that are bedded in services using a variety of methods. Contributing factors for effective CPS include flexibility in use and type of available resources, flexible work plans, and responsive leadership. The CLAHRC model provides a translational infrastructure that enables CPS that can impact on healthcare systems