Proffered papers session


Programme session type(s): Proffered papers session

Chair: Fiona Walter, University of Cambridge, UK
Presenter: Chit Fang Cheok, Institute of Molecular and Cell Biology (IMCB), Singapore
Presenter: Jo Brett, Oxford Brookes University, UK
Presenter: Richard Shaw, University of Liverpool, UK
Presenter: Samantha Quaife, University College London, UK

08:15-09:00

Room: Dochart

Proffered paper sessions are dedicated to the highest scoring abstracts chosen by the scientific committee. They are grouped by type of science presented (following the main Conference streams) and in broad terms cover basic, translational and clinical research.

The abstracts being presented in this session are:
1. Precision therapy in the p53 pathway – Chit Fang Cheok

2. HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): a randomised controlled trial of hyperbaric oxygen to prevent osteoradionecrosis of the irradiated mandible. – Richard Shaw

3. The Lung Screen Uptake Trial (LSUT): Applying behavioural science to optimise informed participation among high-risk and socioeconomically deprived groups – Samantha Quaife

4. E-cigarettes as a Smoking Cessation aid in Cancer Patients: Health Professionals knowledge, attitude and current practice – Jo Brett

Precision therapy in the p53 pathway
Speaker: Chit Fang Cheok
Affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR

Abstract:

Mutation in the Tp53 gene frequently occurs in various human cancers; yet, therapies against this large cohort of cancers are lacking. Targeting p53 deficiency, in particular, through exploiting the altered fitness of tumor cells harboring p53 mutations presents unique opportunities to target a broad spectrum of p53 mutations that are clinically prevalent, including hotspot missense and nonsense mutations. Despite the discoveries of various roles of p53 in diverse cellular functions, pharmacologic manipulation of these complex pathways for therapeutic benefit still remains challenging. We have taken a synthetic lethal approach to screen for selective sensitizers of tumor cells harboring p53 deficiency.


Method

We developed a robust and sensitive fluorescence-based imaging assay to screen for new synthetic lethal interactions in the p53 pathway. Differentially labeled isogenic cells containing wildtype or p53 deletion were co-cultured and subjected to a Pharmakon library of 1600 FDA-approved compounds.

Results

Through a HTS screen, we identified an FDA-approved anthelmintic that preferentially impaired the growth of p53-mutant cells, of both human and mouse origins. In addition to an extensive validation performed using cell line panels, we established cancer cell line and patient-derived xenografts (PDX), and demonstrated that loss or mutation of p53 led to increased tumor growth reduction following monotherapy with the anthelmintic. Metabolome profiling reveals unexpectedly that deficiency in p53 led to a preferential accumulation of a fatty acid that underlies a catastrophic mitochondrial-dependent cell death induced by the anthelmintic niclosamide. Deconvolution of the mechanism of drug action led us to uncover new roles of p53 in promoting cell survival by efficiently coupling the transcriptional activation of lipid oxygenation genes to counteract metabolic crisis induced by niclosamide.

Conclusion

We proposed a new paradigm for targeting p53 mutation/loss by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling (accepted in Nature Communications). Further implications of new findings will be discussed.

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): a randomised controlled trial of hyperbaric oxygen to prevent osteoradionecrosis of the irradiated mandible.
Speaker: Richard Shaw
Affiliation: University of Liverpool

Abstract:

Hyperbaric oxygen (HBO) has been advocated in the prevention and treatment of osteoradionecrosis of the jaws following head and neck radiotherapy, but supporting evidence is weak. The aim of this randomized trial was to establish the benefit of HBO in prevention of osteoradionecrosis following high risk surgical procedures to the irradiated mandible.

Method

HOPON was a randomized controlled phase 3 trial.  Participants were recruited who required dental extractions or implant placement in the mandible with prior radiotherapy of at least 50Gy.  Eligible patients were randomly assigned (1:1) to receive, or not receive HBO. All patients received chlorhexidine mouthwash and antibiotics. For patients in the HBO arm, oxygen was administered in 30 daily dives at 100% oxygen to a pressure of 2.4 ATA for 80-90 minutes.  The primary outcome measure was the diagnosis of osteoradionecrosis six months following surgery as determined by a blinded central review of clinical photographs and radiographs.  Secondary endpoints included grade of osteoradionecrosis, osteoradionecrosis at other time-points, acute symptoms, pain and quality of life. Trial registration: European Clinical Trials Database, ID: EudraCT200700622527

Results

144 patients were randomised, and 100 were analysed for the primary endpoint.  The incidence of osteoradionecrosis at the primary endpoint was 6%, OR 1.13, two-sided Fishers Exact P = 1 (95% CI: 0.14 to 8.92). Patients in the hyperbaric arm had less acute symptoms or late pain but no significant differences in quality of life. Drop-out was higher in the HBO arm, but baseline characteristics of groups completing the trial were comparable between the two arms.

Conclusion

The low incidence of osteoradionecrosis seen in the HOPON trial makes it unnecessary to recommend HBO for dental extractions or implant placement in the irradiated mandible.  These findings are in contrast to a recently published Cochrane review, and challenge a long-established standard of care.

The Lung Screen Uptake Trial (LSUT): Applying behavioural science to optimise informed participation among high-risk and socioeconomically deprived groups
Speaker: Samantha Quaife
Affiliation: University College London

Abstract:

Low uptake of lung cancer screening by high-risk and ‘hard-to-reach’ groups threatens its effectiveness and equity.  Research implicates psychological barriers including fear, fatalism and stigma.  This trial tested a ‘targeted, stepped and low-burden’ invitation strategy. 

Method

A randomised controlled trial tested the invitation strategy.  Individuals (n=2012) aged 60-75 with a recent (<7 years) smoking history were identified from primary care and randomised (1:1) to the intervention or control group.  Both groups received a stepped sequence of GP letters: pre-invitation, invitation with scheduled appointment, and reminder re-invitation with scheduled appointment.  The intervention group also received a targeted and low-burden leaflet, while the control group received a screening information booklet similar to existing programmes.  The primary outcome was uptake of a nurse-led Lung Health Check hospital appointment at which low dose CT (LDCT) screening was offered.  Data on demographics, smoking, screening knowledge and decisional satisfaction were collected.

Results

75% of invitees were current smokers and 96% lived within the two most deprived national quintiles.  Half (53%) attended and 91% of those eligible decided to have the LDCT scan.  Multivariate logistic regression showed no effect of the intervention on uptake (aOR:1.02, 0.86-1.22).  Fewer current smokers attended compared with former smokers across invitation groups (aOR:0.70, 0.56-0.86).  Socioeconomic deprivation was associated with lower uptake across continuous scores (p<.01), although this trend was only statistically significant in the control group (p<.01; e.g., 43% uptake in most deprived study-specific quintile vs. 60% in least deprived study-specific quintile), not in the intervention group (p=.189; e.g., 48% vs. 56%).  Invitation groups did not differ on screening knowledge or decisional satisfaction.

Conclusion

Uptake may be higher than previously observed if offered as an organised screening programme.  A targeted, stepped and low-burden invitation approach shows promise for better engaging lower socioeconomic status individuals without compromising informed decision-making.  Further research is critical for engaging smokers.