Silent theatre 1 – Sunday 3 November

6:50 pm-8:30 pm

Room: Hall 4


Programme session type(s): Silent theatre

Assessment of the effect of oncolytic virotherapy in combination with cavitational ultrasound in the treatment of colorectal liver metastases using a precision cut tumour slice model
Speaker: Marcos Kostalas
Affiliation: Royal Surrey County Hospital, Guildford, UK

Abstract:

Oncolytic virotherapy is a powerful emerging tool in the treatment of cancer. Clinical trials have confirmed the therapeutic effects of oncolytic virotherapy in the treatment of multiple solid tumours. A limitation of this novel treatment is the restricted ability of oncolytic viruses to reach and to penetrate target tumours following intravenous administration. One proposed method of overcoming this is through the concurrent application of ultrasound and specialised cavitational nuclei that expand and violently collapse at specific frequencies enabling greater tissue penetration of anti-cancer agents.

Method

Tissue cores, up to 8mm in diameter were obtained from patients with colorectal liver metastases. Cores were sliced using a vibrating microtome to 300µm thickness. These were then treated with oncolytic vaccinia virus. Ultrasonic exposures were carried out using the System for Acoustic Transfection (SAT) chamber. This system was based on prior design but modified to allow a decrease in the exposure area for the prepared tumour slices.

Results

Initial experiments found that vaccinia virus in combination with cavitational ultrasound and sulphur hexafluoride microbubbles significantly increased staining for cleaved caspase 3 in treated organotypic cultures of colorectal liver meatsatases compared with vaccinia virus alone. The study also found that the combination of oncolytic virus treatment and cavitational ultrasound enabled the utilisation of lower viral concentrations whilst maintaining similar levels of staining for cleaved caspase 3 and therefore virus activity compared with higher concentrations of virus.

Conclusion

Overall, we found that the combined treatment of colorectal liver metastases with vaccinia virus and exposure to cavitational ultrasound and sulphur hexafluoride microbubbles improved the anti-cancer effects of oncolytic vaccinia virus. Combining this treatment with oncolytic virotherapy is a promising technique to improve the anti-cancer effect following the systemic administration of oncolytic vaccinia virus.

Patients’ experience of nutritional care during cancer treatment
Speaker: Lesley Turner
Affiliation: NIHR Cancer and Nutrition Collaboration, London, UK

Abstract:

Good nutrition is integral to the prevention of cancer, as well as to the treatment of the disease and end of life care. The NIHR Cancer & Nutrition Collaboration was set up in 2014 to build and maintain a community of practice of researchers, clinicians and patients. The group presented to the Consumer Forum Dragon’s Den at the 2014 NCRI Conference, who suggested conducting a patient survey to gain insight into nutritional care during cancer treatment.

Method

A survey was conducted between January-February 2015 comprising 43 questions, to find out: 1) whether patients receive consistent, evidence-based advice; 2) what other nutritional support, advice and care patients would like to receive; and 3) the major gaps in service provision at diagnosis, during and after treatment. The survey was circulated via the Independent Cancer Patients’ Voice and the NCRI Consumer Forum. Results were analysed by the NIHR Cancer and Nutrition Collaboration.

Results

Of 96 responses, 72% were female and most participants were aged between 60-69 years (33%) and 50-59 years (29%). Most patients (n=69, 72%) reported receiving no nutritional advice from their healthcare team, either because they were not offered it (76%) or the patients did not know nutritional advice existed (10%). The most commonly reported problems were changes in taste and smell (70%), appetite loss (69%), nausea and vomiting (56%), being unsure of what to eat (56%) and the inability to be physically active (56%).

Conclusion

Many patients reported unsatisfactory experiences of nutritional care in relation to cancer. Gaps identified by patients include how to deal with side-effects of chemotherapy, weight changes and specific foods and diets that patients should or should not consume. There is a need for better evidence to allow more reliable and consistent nutritional and dietetic information for those living with and beyond cancer.

Bioelectical impedance changes during chemotherapy for early breast cancer: The Cando-2 study
Speaker: Stephen Wootton
Affiliation: University of Southampton, Southampton, UK

Abstract:

Excess adiposity and/or lack of lean tissue may be important determinants of chemotherapy outcomes. Bioelectrical Impedance Analysis (BIA) appears readily accessible in clinical settings but changes in hydration during treatment may violate the core assumptions that predict body composition. The measured values of resistance, reactance and phase angle remain secure and may in themselves differentiate between patients in terms of their resilience or response to treatment. The aim of this study was to better characterise the changes in impedance measures in women with early breast cancer during six cycles of standard neo/adjuvant chemotherapy (CANDO-2).

Method

Female patients with stage 1-3 invasive breast cancer were recruited from the breast oncology clinic at University Hospital Southampton between September 2014 and September 2015 and received standard-of-care neo/adjuvant chemotherapy (6 x 3 weekly cycles FEC100-T100).  Segmental BIA (Seca mBCA515) was measured in 29 women prior to each cycle and after the 6th cycle; impedance measurements were expressed as standard deviation scores (SDS) against device-specific healthy reference population values.

Results

The mean SD scores for resistance at 50 kHz (R5), reactance at 50kHz (Xc50), impedance ratio (R200:R5) and phase angle (PhA) at baseline were all within one SD of the median for the reference population. With each cycle of chemotherapy the mean R50 Z score rose progressively, especially from cycle 4 when docetaxel was commenced (P<0.01) with a corresponding fall in IR reflecting an increase in ECW and oedema. Mean Xc50 and PhA SD scores fell markedly with successive cycles reflecting loss of cellular integrity (P<0.01) with more than half of the patients with SD values greater than -2SD by the end of treatment.

Conclusion

Impedance measures offer the opportunity to objectively characterise systemic changes in physiological and metabolic state during treatment and may mark important differences between patients in their resilience to chemotherapy.

Molecular and functional studies on a sub-population of T cells resistant to Galectin-9
Speaker: Thi Bao Tram Tran
Affiliation: Gustave Roussy Institute, Villejuif, France

Abstract:

Galectin-9 (Gal-9) is a member of the galectin family, which recognizes glycans containing β-galactoside bonds. Although lacking a secretion signal, Gal-9 is detected in the extracellular environment. It can be released by malignant cells and exhibit immunosuppressive effects, especially in nasopharyngeal carcinoma (Klibi et al., 2009, Blood), and melanoma (Enninga et al., 2016, Melanoma Res.).  One aspect of gal-9 immunosuppressive effects is the induction of T-cell apoptosis. However, a fraction of T-cells from PBMCs appears to be consistently resistant to gal-9. Our aim is to investigate the phenotype and functional properties of this T-cell sub-population.

Method

In the current study, we applied a 7-day selection by Gal-9 treatment at 45 nM on PBMCs activated by anti-CD3/CD28 antibodies. The surviving T cell subsets were then stimulated by Gal-9, but at a lower concentration, followed by CyTOF and metabolomic analyses.

Results

Selected T cells were not only less prone to apoptosis but also retain a higher rate of cell proliferation and DNA synthesis. By using mass cytometry and meta-clustering algorithm, we observed an enrichment of CD4+ T cells co-expressing ICOS, CTLA-4, and PD-1, beside a regression of CD8+ T cells. We also found a subgroup of CD4+ T cells expressing CCR4 in the absence of FoxP3 suggesting a selective advantage for an atypical population of T-regs. The metabolomic profile of the selected subsets, on the other hand, showed significant increases in proline metabolism, putting forward a potential mechanism to explain their proliferative feature. Intriguingly, we also found an increased ratio of S‑adenosylmethionine/methionine in selected cells, suggesting possible modifications in DNA methylation.

Conclusion

Overall, the profile of the surviving T cell subset gradually takes shape, suggesting a predominant suppressive activity. With a better understanding of how Gal-9 reshapes T cell population, we hope to elucidate how it contributes to immune evasion in tumour microenvironment.

Hormone-related diseases and prostate cancer: an English national record linkage study
Speaker: Eleanor Watts
Affiliation: University of Oxford, Oxford, UK

Abstract:

There is evidence that circulating insulin-like growth factor (IGF-I) and testosterone concentrations are related to prostate cancer risk. Acromegaly is associated with clinically high IGF-I concentrations, while Klinefelter’s syndrome, testicular hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnoses with these conditions are associated with subsequent prostate cancer diagnosis and mortality.

Method

Linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 were used to construct and follow-up cohorts of men aged ≥35 years diagnosed with i) acromegaly (n=2,495) and ii) hypogonadal-associated diseases (n=18,763): Klinefelter’s syndrome (n=1,992), testicular hypofunction (n=8,086) and hypopituitarism (n=10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for subsequent prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a wide range of relatively minor surgeries and conditions, among whom there were nearly 130,000 observed prostate cancer diagnoses and 30,000 prostate cancer deaths.

Results

For men diagnosed with acromegaly, the subsequent HR for prostate cancer was 1.33 (95% CI 1.09-1.63; P=0.005; n observed cases=96) and the HR for prostate cancer death was 1.44 (95% CI 0.92-2.26; P=0.11; n deaths=19). Diagnosis with Klinefelter’s syndrome was associated with a lower prostate cancer risk (HR=0.58, 95% CI 0.37-0.91; P=0.02; n observed cases=19) and hypopituitarism was associated with a reduced risk of prostate cancer death (HR=0.57, 95% CI 0.42-0.79; P=0.001; n deaths=23).

Conclusion

Our results support the hypothesised role of IGF-I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer etiology.

Smoking cessation for cancer prevention: Can incentives play a role? Evidence from a Cochrane review
Speaker: Caitlin Notley
Affiliation: Norwich Medical School, Norwich, UK

Abstract:

Smoking remains the leading preventable cause of cancer globally. Financial incentives are effective for smoking cessation, but long-term cessation is necessary for cancer prevention.

Method

Systematic review of randomised controlled trials, allocating individuals, workplaces, groups or communities to incentives or control. Including mixed populations and pregnant women. The outcome was abstinence from smoking at longest follow-up (at least six months from intervention start or to the end of pregnancy).

Results

33 mixed-population studies met inclusion criteria, including 21,600 participants in community settings, clinics, workplaces, and drug clinics. The relative risk (RR) for quitting with incentives at longest follow-up compared with controls was 1.49 (95% confidence interval (CI) 1.28 to 1.73; 31 RCTs, adjusted N = 20,097; I2 = 33%). We conducted a sensitivity analysis to explore the effect of incentives offered up until long term follow-up compared to those where longest follow-up occurred after the incentive schedule had ended. Results were not sensitive to the exclusion of six studies where incentives were offered at long term follow-up (RR 1.40 95% CI 1.16 to 1.69; 25 RCTs; adjusted N = 17,058; I2 = 36%). We included 10 studies of 2,571 pregnant smokers. Together, nine of ten trials with usable data delivered a RR at longest follow-up (up to 24 weeks post-partum) of 2.38 (95% CI 1.54 to 3.69; 9 RCTs; N = 2273 participants; I2 = 41%), favouring incentives.

Conclusion

Overall there is high quality evidence that incentives improve smoking cessation at long term follow-up in mixed population studies and thus may have a role to play in cancer prevention. The effect of incentives appears to be sustained over time (both while in place and following discontinuation). There is moderate quality evidence that incentives for pregnant women improve smoking cessation rates, both at the end of pregnancy and post-partum.

Reduction of full-length transglutaminase 2 (TG2-L) expression decreases cisplatin chemoresistance in an MCF-7 model of hormone-positive breast cancer
Speaker: Peter Coussons
Affiliation: Anglia Ruskin University

Abstract:

Cisplatin is a highly effective chemotherapeutic drug that has the unfortunate downside of rapidly inducing chemotherapeutic resistance. Although it can be effective in the treatment of hormone-negative breast cancer, cisplatin has been less effective in the treatment of hormone-positive breast cancer. The highly pleiotropic enzyme, tissue transglutaminase 2 (TG2), is overexpressed in many cancers, where it is involved in diverse cellular functions including cell proliferation, cell cycle control, endocytosis, apoptosis and chemoresistance. TG2 exists mainly as a full-length “long” form (TG2-L), and a truncated “short” (TG2-S) form, which can modulate opposing functions. For example, while TG2-L subdues cell differentiation and supports cell survival, TG2-S promotes cell death. Here, we investigate whether modulation of TG2 expression might be a route to reducing cisplatin chemoresistance in hormone-positive breast cancer cells.

Method

In order to raise or lower TG2 expression, cisplatin-sensitive and cisplatin-resistant MCF-7 breast cancer cells were treated for up to 72 hours with non-toxic doses of either retinoic acid (+), or the TG2 inhibitor, cystamine (-), or anti-TG2 siRNA (-), respectively. Cells were then exposed to clinically relevant doses of cisplatin for a further 24 hours. MTT assay measured cellular viability, flow cytometry measured levels of apoptosis and necrosis, and Western blot analysis measured TG2 expression.

Results

Retinoic acid treatment of cells induced overexpression of TG2-L, promoting cell survival and increased cisplatin chemoresistance in all cases. Conversely, both cystamine and anti-TG2 siRNA treatment selectively suppressed TG2-L expression (with little effect on TG2-S expression), reducing cisplatin chemoresistance to basal control levels, without affecting cell viability.

Conclusion

The model suggests that limiting levels of TG2 expression, either by restricting retinoid availability, or through pharmacological intervention with TG2 inhibitors could improve cisplatin effectiveness in the treatment of hormone-positive breast cancer.

Assessment of CCR5/Maraviroc immunotherapy in combination with PD1 and MR-Guided radiotherapy for treatment of pancreatic cancer
Speaker: Simone Lanfredini
Affiliation: Oxford University

Abstract:

Pancreatic ductal adenocarcinoma (PDAC), is the most prevalent form of pancreatic cancers with poor survival outcomes. Results from the clinic have demonstrated the lack of efficacy when either radiotherapy (RT) or immunotherapy are used as a monotherapy. Recent publications revealed a synergistic effect on RT-induced immune-modulation and reduced immune-suppression when the immunotherapy was administrated concurrently with RT in mouse models. Other publications demonstrate that immune-evasion in PDAC depends on the CCL5/CCR5 axis to recruit immunosuppressive T-regulatory cells (Tregs) into the tumour microenvironment. Therefore, targeting the migration of Tregs through modulation of CCL5/CCR5 axis can potentially inhibit tumour growth in pancreatic cancer.

Aim:Working within the Precision Panc platform, this pre-clinical study is evaluating the impact of fractionated MR-guided radiotherapy in combination CCR5 inhibitor and simultaneous inhibition of the immune checkpoint axis PD1/PD-L1.

Method

For the purpose of this study we generated a syngeneic orthotopic pancreatic mouse model. Tumour cells derived from the Lox-Stop-Lox (LSL)-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC) mouse model, are injected in the tail of the pancreas. We are able to monitor tumour growth using a respiratory motion desensitised T2-weighted MRI imager. Taking advantage of in-house developed technology, we use the SARRP in combination with MRI imaging to deliver MR-guided fractionated radiotherapy in combination with CCR5 inhibitor (Maraviroc) and PD1 inhibitor. To investigate the immunological microenvironment, we developed a 17-colour flow cytometry (FC) panel to immune-phenotype cytotoxic T, T regulatory, NK, NK/T and B cells, M-MDSC, PMN-MDSC, M1 and M2 macrophages in the peripheral blood and tumour infiltrate

Results

Outcome data will be presented at the meeting.

Conclusion

Using the established orthotopic mouse model our aim is to investigate how the combination of MRI-guided radiotherapy and immune therapies can modulate the tumour microenvironment and the immune response in pancreatic cancer. 

The antitumoral activity of the tomatine againts human hepatocellular carcinoma
Speaker: César Echeverría
Affiliation: UNIVERSIDAD DE ATACAMA

Abstract:

Hepatocellular carcinoma (HCC) is a highly lethal tumor that commonly occurs in patients with chronic liver disease and cirrhosis. HCC has a poor prognosis due to its high recurrence rate and resistance to chemotherapy. To date, liver transplantation is the best form of treatment because it removes the tumor as well as damaged hepatic tissues that may provoke chronic liver disorders. Several experimental and clinical investigations have occurred, with the goal of preventing recurrence and secondary tumors and improve the clinical outcome of HCC patients. Tomatine is a glycoalkaloid that has shown antiproliferative and apoptotic activities in cell lines such a liver, colon, leukemic and lung cancer cells. However, the mechanism in HCC remains unknown. The aim of this study was to evaluate the anticancer effect of tomatine either HCC in a mouse tumour model.

Method

We studied the effect of tomatine in vitro (HepG2). Cytotoxicity of tomatine on HepG2 was assessed using a MTT assay and cytometry flow. HepG2 cells were treated (between 30 minutes and 8 hours) with Tomatine (10 uM), the Bcl-2 protein family, Cytochrome-c, P53 and caspase-3/7, were examined by immunocytochemistry, western blot and luminescence analysis, and on the other hand DCFH-DA and Fura-2AM were used to detect the level of intracellular Reactive oxygen species (ROS) and calcium respectively. We also evaluated the antitumor activity of tomatine against HepG2 cell tumors grown subcutaneously in mice.

Results

Cell viability experiments showed that tomatine had significant cytotoxic effects on the HCC cell lines HepG2, and the cells were found to be in the Annexin V positive/ propidium iodide-negative phase of cell death. Additionally, the Bcl-2 protein family, Cytochrome-c, P53 and Caspase-3 and -7 were activated by tomatine in HepG2 cells. On the other hand, tomatine induced ROS and calcium accumulation after of treatment on HepG2 cells. In animal experiments, our data indicate that intraperitoneal administration of tomatine significantly attenuates the growth of HepG2 cell tumors grown.

Conclusion

Our study provides first evidence for in vivo antitumor efficacy of a-tomatine against the HCC. The potential usefulness of tomatine in HCC prevention and therapy requires further investigation.

Flavonoids potentiated anticancer activity of cisplatin in lung cancer by inhibiting histone deacetylases
Speaker: Vivi, Wei Yan
Affiliation: School of Pharmacy, The Chinese University of Hong Kong

Abstract:

Cisplatin is used in first-line chemotherapy of non-small cell lung cancer (NSCLC). However, its effectiveness is hindered by drug resistance, which is mediated by DNA repair, reduced apoptosis and insensitivity to cell cycle arrest. Combination of histone deacetylase inhibitors (HDACIs) and other anticancer drugs has emerged as a promising strategy to circumvent drug resistance. By facilitating histone acetylation, HDACIs upregulate tumour suppressor genes and downregulate drug resistance genes to kill cancer cells. Dietary flavonoids have been proposed to possess HDAC inhibitory effect.

Method

NSCLC cell lines (A549, H1650 and H1975) harbouring different oncogenic abnormalities were employed in the study. Western blot analysis was used to screen selected flavonoids for potential HDAC inhibition. Cell cycle arrest and apoptosis mediated by the HDAC-inhibiting flavonoids were evaluated by cell cycle analysis and Annexin-V apoptosis assay, respectively. Quantitative real-time PCR was employed to examine the expression of selected cell cycle-regulatory and apoptotic genes by the HDACIs. Regulation of transcriptional machinery by HDACIs was investigated by chromatin immunoprecipitation (ChIP) assay.

Results

Apigenin, a flavone-class flavonoid, was found to exhibit the strongest HDAC inhibitory effect. Therefore, combination of apigenin and cisplatin was investigated. Cisplatin-apigenin combination was found to produce significantly more S phase prolongation and G2/M cell cycle arrest, and apoptosis by inducing p21 and PUMA, respectively. Results from ChIP assay illustrated that apigenin reduced the binding of HDAC1 and increased histone acetylation at the gene promoter of p21 and PUMA, thus driving the observed transcription activation.

Conclusion

Apigenin was identified as a novel HDAC inhibitor. It was shown to potentiate the anticancer effect of cisplatin by inducing cell cycle arrest and apoptosis. In-depth investigation about the underlying mechanisms and optimum dosing sequence both in vitro and in vivo will be warranted to establish the usefulness of the new drug combination to circumvent drug resistance.

SWATH mass spectrometry: Quantitative mapping of soft tissue sarcomas by digital proteome profiling
Speaker: Lukas Krasny
Affiliation: The Institute of Cancer Research, London, UK

Abstract:

Soft tissue sarcomas (STS) are a rare and heterogeneous group of cancers. Our knowledge of STS biology is limited and although progress has been made in the genetic characterization of these diseases, comprehensive molecular profiling at the protein level has not been undertaken. One of the challenges associated with tumour proteomics is the presence of formalin-induced protein crosslinks in formalin-fixed paraffin-embedded (FFPE) tissue which complicates conventional proteomic workflows.

Method

In this study, we used digital proteome profiling by sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry (MS) to characterise a discovery cohort of STS cases (n=39) across 4 histological subtypes. Validation of findings was performed in an independent cohort of STS specimens (n=64) using a conventional proteomic approach that involves TMT labelling and off-line fractionation.

Results

Using SWATH-MS, we quantified 2865 proteins in the discovery cohort from starting material equivalent to a 5μm FFPE tissue section. Significantly altered expression levels of 884 proteins were found by ANOVA (FDR<0.05) in at least one of the four STS subtypes. Further analysis of these proteins by principal component analysis (PCA) and hierarchical clustering (HC) revealed distinct separation of samples into three subgroups corresponding to STS histological subtypes. Gene set enrichment analysis (GSEA) was employed to identify underlying biological processes and candidate therapeutics that are enriched in individual subgroups. In the validation cohort, 5642 proteins were quantified with 2114 proteins showing significantly altered expression levels in at least one of the STS subtypes (ANOVA, FDR<0.05) and analysis by PCA and HC showed similar histological subtype separation and biological pathways as the discovery cohort.

Conclusion

We demonstrate the potential of SWATH-MS for the molecular characterization of STS with minimal consumption of readily available FFPE tissue material. To our knowledge, this study is the most comprehensive analysis of the STS proteome to date.

Can we cure oligometastatic rectal adenocarcinoma with synchronous liver metastasis: a pre-operative short-course radiotherapy and induction chemotherapy regimen.
Speaker: Shagufta Mirza
Affiliation: Leeds Teaching Hospital,Leeds, UK

Abstract:

The treatment dilemma of rectal cancers with synchronous liver oligometastases (SLOM) is whether to prioritize the primary tumour or systemic disease. There is potential risk for local or systemic progression during prolonged induction chemotherapy (ICT) or long course concurrent chemo-radiotherapy respectively. Since 2012, the Leeds Cancer Centre and surrounding cancer units have offered short course radiotherapy (SCRT) 25Gy in 5 fractions, followed by 12 weeks (6 cycles) of oxaliplatin-fluoropyrimidine ICT prior to surgery.

Method

Between January 2012 and March 2017, 41 rectal cancer patients with synchronous liver oligometastases (SLOM) were planned for SCRT and ICT. Intention-to-treat analysis was performed. Pelvic failure was defined as distant or pelvic progression during neoadjuvant treatment precluding surgery, or pelvic recurrence following curative surgery. Distant failure was defined as distant or pelvic progression during neoadjuvant treatment precluding metastatectomy, or distant recurrence following curative surgery.

Results

At diagnosis, 41/41 patients had threatened mesorectal fascia. 14/41 patients had borderline resectable or unresectable SLOM. All patients completed SCRT and 39/41 had ICT (median 6 cycles). Post treatment pelvic restaging: 33/41 patients had partial or complete responses of the primary tumour and 3/41 stable disease. 5/41 had no pelvic restaging due to systemic progression. Post-treatment liver restaging: 18/41 patients had partial or complete responses. 10/41 stable disease, and 10/41 progressive disease.3/41 had no liver restaging due to pelvic or systemic progression. 29/41 patients had primary tumour resections of which 16/41 then had liver metastatectomies.

Median follow-up was 37.2 months.  8/41 patients had no progression or recurrence. 3/41 pelvic failure only, 19/41 distant failure only and 11/41 both distant and pelvic failure. Seven patients with relapsed disease had salvage surgery. Median and 3-year overall survival were 27.4 months and 43.4 % respectively.

Conclusion

SCRT followed by ICT is a feasible strategy achieving reasonable cure rates for oligometastatic rectal adenocarcinoma.

Investigate a potential link between sensitivity of basal subtype of Breast Cancer BCa to RNAP1 inhibitors and the levels of activated rRNA synthesis.
Speaker: Sameerh Alsahafi
Affiliation: Queens University Belfast

Abstract:

Cancer has been identified as a group of diseases characterized by abnormal cell growth and uncontrollably by up-regulation of the normal cell. The most frequently diagnosed cancer in women is breast cancer. BCa is characterised high heterogeneity and based on gene expression profiles, its classified into 5 subgroups: luminal A, Luminal B, basal-like, Her2/Neu amplified, and normal-like. Basal-like tumours are usually aggressive, with strong tendency to metastasis and hence poor prognosis. In eukaryotic cells, the nucleolus is the region of the nucleus that constructs ribosomal subunits. The nucleolar size correlates with the level of rRNA synthesis, which is transcribed by RNA polymerase 1 (RNAP1) during the initial stage of ribosome biogenesis. A characteristic feature of uncontrolled cancer cell proliferation is associated with the increased transcription of rRNAs. In recent years the rRNA transcription has emerged as a novel target for anticancer therapy, and specific RNAP1 transcription inhibitors are currently undergoing clinical trials for patients with advanced haematological malignancies the consequence of the rupture of the nucleus and activation of p53, depending on apoptosis. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity.four drugs:CX-5461, BMH-21, PMR-116 and 9HE are small molecules and selective inhibitors of RNAP1 transcription which have moderate effect on transcription by other nucleolar polymerases and protein translation and which are at different stages of clinical development. CX-5461 inhibits transcription by displacing essential promoter recognition factor SL1 thus preventing an initiation of transcription. BMH-21 inhibits elongation and induces rapid degradation of RNAP1. 9-Hydroxyellipticine (9HE) Selecting ellipticine derivatives that were capable of intercalating into DNA with a high affinity. PMR-116 demonstrated a great potential as RNAP1 inhibitor, and characterized by low cytotoxity and very high anti-cancer effect. However, the exact molecular mechanisms of RNAP1 inhibition is unknown. Therefore, here we aim to investigate the mechanism PMR116 action in breast cancer cells.

Method

Results

Conclusion

Resveratrol's effects on a BRAF mutant mouse model of colorectal carcinogenesis
Speaker: Grandezza Aburido
Affiliation: University of Leicester

Abstract:

Prevention of colorectal cancer (CRC), the second most common cause of cancer death in the UK, is feasible. However, safer therapeutic options are needed to improve preventive efficacy across various CRC subtypes. Moreover, few studies have attempted to identify/develop therapies to prevent the BRAFV600E mutant (BRAF+) subtype which leads to a poor prognosis. Interestingly we have found that resveratrol, a natural compound with anti-cancer properties, significantly prolongs the survival of BRAF+ mice. This increased survival, however, is observed only when the mice are given a high-fat diet (HFD) and not a normal-fat diet (NFD) (unpublished). The aim of this study was to investigate, at protein level, the effects of resveratrol in this HFD-fed mouse model and potential reasons for the survival increase.

Method

Mouse intestine sections and plasma from 3-day and 6-week resveratrol intervention studies were analysed via proteomic techniques, and protein expression differences established bioinformatically. Two resveratrol doses were studied, 0.7ppm and 143ppm – 143ppm being equivalent to 1g in humans.

Results

Protein changes differ at 3 days and at 6 weeks but generally, a BRAF+ along with a HFD led to expression changes of proteins with potentially pro-cancer activities. Many of these changes were ‘reversed’ by both doses of resveratrol, but the higher dose of resveratrol was shown to be more effective. Bioinformatics disclosed the pro-cancer protein functions/processes reversed by resveratrol to include processes such as cell division/differentiation, neural development, and calcium signalling. Potential biomarkers of resveratrol’s efficacy were also identified from the plasma, such as SPTLC2 and ATP2B2.

Conclusion

From this study, insight on the largely pleiotropic effects of resveratrol in this BRAF mutant model along with a HFD was identified at protein level, and evidence of how resveratrol prolongs survival of these mice has also been obtained. Thus, resveratrol’s potential chemopreventive properties in this particular CRC subtype has been elucidated.

Atezolizumab for locally advanced or metastatic urothelial carcinoma of the urinary tract: Analysis of UK patients treated in the international SAUL study
Speaker: Robert Huddart
Affiliation: Institute of Cancer Research

Abstract:

Atezolizumab, which targets PD-L1, is approved as treatment for locally advanced/metastatic urothelial carcinoma based on results from the IMvigor210 (NCT02108652) and IMvigor211 (NCT02302807) phase II/III trials. The single-arm international SAUL study (NCT02928406; n=1004) in a broader population demonstrated median overall survival (OS) of 8.7 months and a safety profile consistent with previous atezolizumab trials. We analysed outcomes in 38 patients with urothelial carcinoma treated in UK centres in SAUL.

Method

Patients with pretreated locally advanced/metastatic urothelial carcinoma, including those with renal impairment, ECOG performance status 2 (PS2), stable controlled autoimmune disease or corticosteroid treatment, received atezolizumab 1200mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included OS, progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR).

Results

Median age was 70 years, 11% had ECOG PS2, 45% had never smoked, 92% were platinum pretreated, 47% had received no chemotherapy for metastatic disease and 39% would have been ineligible for the pivotal IMvigor211 trial. At the data cut-off (16-Sep-2018, 16 months’ median follow-up), treatment was ongoing in 8 patients (21%). Median treatment duration was 2.9 (range 0–18) months. The most common adverse events (AEs) were fatigue (21%), urinary tract infection (18%) and nausea (18%). Grade ≥3 AEs occurred in 55%, considered treatment related in 8 patients (21%; 6 grade 3, 1 grade 4, 1 grade 5). AEs led to treatment discontinuation in only 2 patients (5%). Median OS was 7.5 (95% CI 2.6–14.2) months, 1-year OS rate was 34% (18–50%), median PFS was 2.1 (2.1–4.4) months, ORR was 11% (3–25%) and DCR was 40% (24–57%).

Conclusion

Atezolizumab demonstrated good tolerability in 38 UK patients with urothelial carcinoma treated in SAUL. Efficacy results are consistent with previous atezolizumab results in this setting.

Delivery of radiotherapy clinical trials: Recommendations for best practice across Clinical Trial Units (CTU) and the National Radiotherapy Trials Quality Assurance Group (RTTQA)
Speaker: Lisette Nixon
Affiliation: Cardiff University, Cardiff, UK

Abstract:

Radiotherapy delivery within multicentre clinical trials should be consistent and in accordance with the protocol.   Evidence shows poor protocol adherence affects outcomes and therefore the interpretation, credibility and impact of trial results. The NIHR funded National Radiotherapy Trials Quality Assurance (RTTQA) group monitors radiotherapy quality in NIHR CRN portfolio trials. A standardised approach to partnership working between NCRI Cancer Clinical Trials Units (CTUs) and the RTTQA group supports efficient development and delivery of radiotherapy trials. The NCRI Clinical and Translational Radiotherapy Research Working Group (CTRad) recognised that a consistent approach to CTU-RTTQA collaboration is needed and tasked a working group to develop comprehensive guidance.

Method

A working group was convened from CTRad members to promote closer working relationships between RTTQA and CTUs through shared working practices and experience. Using the Clinical Trials ToolKit as a prompt, key tasks were identified and roles and responsibilities for both stakeholder groups proposed.

Results

Recommendations for best working practice were developed for dissemination to all CTUs managing radiotherapy trials. Areas for collaborative working during study development (pre-funding award), protocol development (post-funding award), pre-accrual trial set up and during- and post-accrual were identified.  

On confirmation of study funding RTTQA will work with the protocol development group/trial management group to agree the RTQA programme. RTTQA will lead the radiotherapy guidelines development (to supplement the trial protocol) and support radiotherapy focussed training/education. CTUs will ensure the guidelines and protocol are consistent and oversee document version control/amendments during the trial.

Proactive engagement between CTUs and RTTQA was highlighted as a key component of this partnership ensuring efficient and effective delivery of clinical trials.

Conclusion

The RTTQA group and CTUs are key partners in radiotherapy clinical trials. Common working practices underpinned by good communication and an understanding of roles and responsibilities facilitate efficient trial set up and delivery.