Silent theatre 1 – Tuesday 5 November

10:30 am-11:00 am

Room: Hall 4


Programme session type(s): Silent theatre

Evaluation of older patients in early phase clinical trials
Speaker: Jessica Lowe
Affiliation: The Christie NHS Foundation Trust, Manchester, UK

Abstract:

Older patients (pts) make up two thirds of cancer pts but only one third of the cancer trial population. It is unknown whether older pts have poorer outcomes in early phase clinical trials (EPCTs). The aim of this research was to understand if EPCTs at a large specialist cancer centre represented older pts (aged ≥65 years (yrs)) and to understand their clinical outcomes compared to younger (<65yrs) pts.

Method

Retrospective data analysis was undertaken for new EPCT pts seen at the Christie NHS Foundation Trust (period covered 1st January 2018 to 31st December 2018). Demographic data was collected, including toxicity and response data from those that received an investigational medicinal product (IMP). Statistical analysis was conducted using cross-tabulation and Fisher Exact Test.

Results

A total of 436 pts were seen, including 130 pts ≥65yrs (30%). A random selection of 131 pts <65yrs were assessed as controls. In the older pt group, 101/130 (78%) were deemed to be eligible for a phase 1 clinical trial and 29/101 (29%) were subsequently enrolled on to a trial with an IMP. In the <65yr group 97/131 (74%) of pts were deemed suitable and 21/97 (22%) subsequently went on to an IMP trial. There were no significant differences between these groups (p-value 0.663). Despite older pts having significantly more co-morbidity than younger pts (p-value = 0.0127), they were no more likely to suffer ≥ Grade 3 toxicity (p-value = 0.170), require dose reduction ((p-value = 0.671) or drop out of study than the control group (p-value = 0.982). There was no difference in response to treatment between the two groups (p-value 0.762).

Conclusion

Despite there being a significant difference in comorbidities between older and younger pts, we did not find any significant differences between pt outcomes or bias of pt selection within our EPCTs.

Next generation Cytogenetics: Comprehensive Structural Analysis of Cancer Genomes by Optical Genome Mapping
Speaker: Yannick Delpu
Affiliation: Bionano Genomics

Abstract:

Tumors are often comprised of heterogeneous populations of cells, with certain cancer-driving mutations at low allele fractions in early stages of cancer development. Effective detection of such variants is critical for diagnosis and targeted treatment. Conventional karyotype and cytogenetics approaches are manually intensive. Microarrays cannot detect calls in segmental duplications and repeats, often miss balanced variants, and have trouble finding low-frequency mutations. Typical short sequence reads are limited in their ability to span across repetitive regions of the genome and to facilitate structural variant (SV) analysis.

Method

Based on specific labeling and mapping of ultra-high molecular weight (UHMW) DNA, we developed a single-molecule platform that has the potential to detect disease-relevant SVs and give a high-resolution view of tumor heterogeneity. We developed a DNA isolation and sample preparation workflow that preserves the DNA integrity and conserves structural variation information from blood, cells, and preserved tissue. Single molecules are labeled at specific motifs and analyzed in massively parallel nanochannels. The single-molecule maps are used in a bioinformatics pipeline that effectively detects structural variants at low allele fractions. It includes rare variant analysis and fractional copy number analysis.

Results

Preliminary analyses using simulated and well-characterized cancer samples showed high sensitivity for variants of different types at as low as 5% allele fractions. The candidate variants are then annotated and further prioritized based on control data and publically available annotations. The data are imported into a graphical user interface tool that includes new visualization tools (such as Circos diagrams) for real-time interactive visualization and curation.

Conclusion

Bionano offers sample preparation, DNA imaging and genomic data analysis technologies combined into one streamlined workflow that enables high-throughput genome mapping on the Bionano Saphyr system. Together, these components allows for efficient analysis of any genome of interest from heterogenous samples.

Genetically raised serum bilirubin levels and respiratory cancer: a cohort study using UK Biobank
Speaker: Laura Horsfall
Affiliation: University College London, London, UK

Abstract:

Moderately raised serum bilirubin levels are associated with lower rates of respiratory cancer in large observational studies. It is unclear whether these relationships reflect antioxidant properties of bilirubin protecting against the carcinogenic effect of smoke oxidants or are due to confounding by lifestyle factors. We report the results of the first large-scale analysis of the causal relationship between bilirubin levels and respiratory cancer using a Mendelian randomisation approach.

Method

This research included unrelated participants of white British ancestry participating in the UK Biobank Resource. Average bilirubin levels in people homozygous for the minor T allele of rs887829 in the UDP-glucuronosyltransferase 1-1 gene are 8-10 µmol/l (80-100%) higher than those without this genotype. Using multivariable Poisson regression, we analysed the relationship between rs887829 T homozygosity and the incidence of respiratory cancers derived from national registers. The results were stratified by smoking behaviour with never smokers used as a negative control group.

Results

The analysis included 363,059 people, 1,962,584 person-years (PYs) at risk and 1188 respiratory cancer events. One in ten participants were homozygous for the T allele of rs887829 (n=35,881). There was no relationship between the genotype and respiratory cancer in never smokers or people smoking less than 20 cigarettes per day. The incidence rate in people homozygous for rs887829 T allele smoking 20 or more cigarettes per day was 10 per 10,000 PYs versus 17 per 10,000 PYs for the other genotypes. The adjusted incidence rate was 43% lower in rs887829 TT homozygotes relative to the other genotypes (incidence rate ratio: 0.57; 95%CI: 0.38 to 0.86; p=0.0065). 

Conclusion

Moderately raised bilirubin may help protect people exposed to high levels of smoke oxidants against respiratory cancers. The role as a therapeutic target and a low-cost causal biomarker for disease risk stratification requires further research. Wellcome Trust funded:209207/Z/17/Z

Inhibition of prostate cancer cell growth, motility and ability to alter monocyte/macrophage lineage commitment by a novel TRAF6 inhibitor
Speaker: Denise Giovana Carrasco Gonzalez
Affiliation: University of Sheffield

Abstract:

The pro-inflammatory TRAF6 signalling pathway plays a key role in prostate cancer, immunity and bone remodelling. However, the role of TRAF6 in the ability of prostate cancer cells to grow, metastasise and influence the differentiation of uncommitted monocyte/macrophage into tumour-associated macrophage (M2) and bone-specific macrophages (osteoclasts) remains unknown.

Method

Results

Here, we show that TRAF6 is highly expressed in a panel of human and mouse prostate cancer cells including the osteotropic human PC3 and C42-B4 and mouse RM1-BM, and pharmacological inhibition of TRAF6 using the verified TRAF6 inhibitor 6877002 and its novel congeners FSAS1 – FSAS8 suppressed cell growth in a dose and time-dependent manner (IC50<2μM). The most potent congener FSAS3 enhanced the ability of uncommitted monocyte/macrophages (M0) to differentiate into classically-activated macrophages (M1) rather than tumour-associated M2, as assessed by flow cytometry. Additionally, FSAS3 reduced the ability of the uncommitted M0 macrophage to form bone-resorbing TRAP-positive osteoclasts in the presence and absence of tumour-derived factors from human PC3 prostate cancer cells (30% reduction, p<0.05). FSAS3 treatment had no effects on the ability of M1 to reduce the viability of human PC3 prostate cancer cells or the viability of the uncommitted M0 – thus excluding cytotoxic effects of this compound on macrophages. Additionally, conditioned medium from M2 macrophage – but not M0 and M1 phenotype – enhanced PC3 proliferation, wound-healing cell migration and transwell invasion and these effects were significantly inhibited by FSAS3 (20% reduction, p<0.05). Mechanistically, FSAS3 reduced IκB phosphorylation induced by RANKL and macrophage-derived factors in PC3 cells, indicative of NFκB inhibition.

Conclusion

These findings identify FSAS3 and its derivatives as a novel class of anti-cancer and antiresorptive agents which may be of value in the treatment of prostate cancer. In vivo studies to test the effects of FSAS3, alone and in combination with chemotherapeutic agents, on the initiation and progression of prostate cancer-associated bone disease are ongoing.