Silent theatre 2 – Tuesday 5 November

12:40 pm-2:00 pm

Room: Hall 4


Programme session type(s): Silent theatre

The gut microbiome and response to neoadjuvant chemotherapy in breast cancer
Speaker: Kirsty Ross
Affiliation: Beatson West of Scotland Cancer Centre, Glasgow, UK

Abstract:

Pre-clinical data suggest that the activity of cytotoxic chemotherapy may be dictated by the gut microbiome. Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) predicts improved event-free and overall survival in patients with all breast cancer subtypes. This prospective study investigates the compositional and functional changes in the gut microbiome during NACT and explores correlations with pathological response.

Method

Female patients receiving NACT for breast cancer at the BWoSCC were enrolled from Aug2017-Mar2019. Stool samples were collected at 3 timepoints: 1) before 1st cycle NACT, 2) during NACT, 3) after final cycle of NACT. DNA was extracted and the V4 region of the 16S rRNA gene was amplified for 2×250 bp next-generation sequencing. After surgery each patient’s response was categorised as pCR (ypT0/is ypN0) or non-pCR.

Results

To date 21 patients have been recruited (18 currently evaluable.) Median age and BMI were 56 (range 33-72) and 28.6 kg/m2(range 19.6-55.6) respectively. Most (n=9, 42.9%) had HER2+ cancers whilst 8 (38.1%) had TNBC and 4 (19%) had (ER+HER2-). NACT included FEC-T in 9 (42.9%), FEC-TH in 6 (28.6%) and other regimes in 6 (28.6%). pCR was observed in 4 of 18 evaluable patients (22.2%.) Taxonomic richness was non-significantly higher in responders vs. non-responders at timepoints; 1) mean 515 vs. 367; p = 0.059, 2) mean 496 vs. 330; p = 0.061 and 3) mean 548 vs. 293; p = 0.069. In patients with 3 timepoint samples available (n=5), lack of response was associated with an increasing proportional abundance of Bacteroides, after completion of NACT (mean 0.57 vs. 0.13; p=0.038.)

Conclusion

Early data demonstrate non-significant trends in compositional differences in the gut microbiome structure of patients with pCR versus non-pCR. These include lower richness and higher proportional abundance of Bacteroides in the non-pCR group.

Exploring metastatic dormancy to tackle breast cancer metastasis
Speaker: Stefania Di Blasio
Affiliation: The Francis Crick Institute

Abstract:

Over ninety percent of breast cancer-related death are caused by metastasis. Disseminated tumour cells (DTCs), that have reached distant organs via circulation, can remain within the host tissue without outgrowing. This phenomenon is known as metastatic dormancy. Albeit non proliferative, DTCs retain their capacity to originate metastasis several years after cancer is first diagnosed. The cause of their reactivation is largely unknown. Recent studies have suggested that an unhealthy lifestyle, such as tobacco smoking or high-fat diet, has a dramatic effect on the homeostasis of healthy tissues. Indeed, high-fat diet was shown to induce important systemic perturbations in the inflammatory compartment. These effect, associated to poor lifestyle factors, may induce dormant DTCs to awaken and outgrow. Here, we focus on the potential effects of obesity and inflammation to perturb the bone microenvironment, causing metastatic reactivation.

Method

We employ a novel experimental approach where metastatic competent cells are pushed into dormancy by an in vivo engineered dormant-permissible tissue. Of note, our strategy does not require the use of cancer cells intrinsically unable to grow in vivo, thereby recapitulating clinical features of breast cancer metastasis to the bone.

Results

We aim at dissecting the interaction between cancer cells and the components responsible for the switch of a dormant niche supporting quiescence, to a pro-metastatic niche supporting cancer growth.

Conclusion

The outcome of this study will provide insights into molecular drug targets on DTCs, that can be combined with factors specifically triggering pro-metastatic niche components activity, for tackling breast cancer metastasis.

Proteomic Profiling on apoptotic effect of keto-boswellic acid
Speaker: Fahad AL Zadjali
Affiliation: Sultan Qaboos University

Abstract:

Acetyl 11-keto-b-boswellic acid (AKBA) is a natural-triterpene that has anti-inflammatory effect via targeting 5-lipoxygenase. At higher dose it selectively exerts selective toxicity toward multiple tumor cell lines and spares normal epithelial cells. Multiple cellular targets of AKBA were proposed and usually major key players in cancer cell apoptotis. Yet, specific apoptotic mechanism of AKBA is not yet known. We aimed to identify apoptotic mechanism of AKBA via proteomic profiling on breast cancer MCF-7 cells.  

Method

MCF-7 cells were treated with 50 μM AKBA for 24 hr before lysis. Proteins were extracted and were subjected to isolectrical focusing into 7 fractions. Each fraction was run into nano-HPLC inline with Orbitrap Q Exactive instrument. Proteomic profile of more than 4000 proteins were detected. Variance stablizing normalization was used to normalize the signal ratio. Difference in the protein abundance between control and AKBA treatment groups was analyzed using  t-test. Statistical significances were adjusted for multiple comparison using False Detection Rate (FDR) at 5%.  Fold change was calculated from the ratio between treated/control. We used the fold 1.6 as cut-off value used generally in proteomic. 

Results

Proteomic profiling revealed majority of downregulate dproteins were mitochondrial proteins. Down regulated proteins (NDUFV1, NDUFA2, MRPL45, MRPL14, MRPL21, MRPL37) are cellular component of mitochondrial envelope, mitochondrial membrane and mitochondrial inner membrane. They linked to mitochondrial pathway translational initiation, translational elongation, translational termination, mitochondrion organization and mitochondrial translation. Up regulated protein are involved in autophagy and mitophagy pathway (FUNDC1, SQSTM1, ULK1).

Conclusion

Porteomic data show that AKBA upregulates autophagy pathway along with downregulation of mitochondria. This suggest that cellular mechanism of tumor cell toxicity driven by AKBA is mediated via mitophagy-induced apoptosis.  

NCRI Consumer Forum: Patients as Partners in Cancer Research
Speaker: Richard Stephens
Affiliation: NCRI

Abstract:

The NCRI Consumer Forum is a professional, focussed and committed group of 92 consumer research partners who help NCRI achieve its aims by working in collaboration. NCRI Consumers have developed Value and Impact Measures (‘VIM’), a suite of metrics capturing the range of individual activities and the collective contribution of NCRI Consumers to research. 

Method

VIM data is collected via an annual survey of the 92 members of the NCRI Consumer Forum. 60 of the 92 NCRI Consumers have returned their 2019 VIM submission. Additional data is collected via ad hoc reports, meeting attendee lists etc.

Results

60 Consumers work with research funders or other organisations beyond the NCRI.

47 Consumers work with charities, NHS Trusts, online communities, local patient groups et al.

27 Consumers are NIHR LCRN Patient Research Ambassadors.

 

20 Consumers work/have worked with strategic bodies e.g. NICE, MHRA, HRA, BBMRI-ERIC, EORTC.

22 Consumers work/have worked with industry including Big Pharma, biotech companies and medical device manufacturers.

 

40 Consumers serve on Trial Management Groups and/or Trial Steering Committees.

20 Consumers sit/have sat on research funding committees, national and local, specific and generic.

14 Consumers hold governance/accountability posts, e.g. Board members, Charity Trustees, NHS Commissioners.

 

25 Consumers have been published in peer-reviewed journals.

46 Consumers have presented at conferences or events throughout UK and internationally.

 

15 of the 16 NCRI Partners have NCRI Consumers involved in their work.

 

NCRI Consumers are preparing examples and case studies to illustrate these numbers and to show linkages between them.

Conclusion

The NCRI Consumer Forum has 92 motivated, educated, patient and carer volunteers, working extensively and collaboratively to improve the quality of cancer research in the UK and beyond.  

Do Neutrophil Counts Pre-chemotherapy Treatment provide Clinical Value.
Speaker: Pinkie Chambers
Affiliation: UCLH NHS Foundation Trust

Abstract:

As chemotherapy patient numbers have increased, treatment pathways in the UK have adapted to maximise capacity. A strategy commonly adopted is one whereby a patient will have blood tests on a separate day to chemotherapy to ensure neutrophil count recovery has been achieved. In many cases this is duplicated again on the day of treatment. We aimed to understand the proportion of patients that had received these duplicate tests and the value this provided to care.

Method

We extracted a dataset from the chemotherapy electronic prescribing system at one tertiary referral cancer hospital from January 2016-January 2018. We included patients aged 18 and over, receiving first line therapy for diffuse large B-cell lymphoma, colorectal cancer (adjuvant) and early breast cancer. Data were extracted for age, treatment and neutrophil counts with corresponding dates.  Descriptive statistics were used to analyse the difference between duplicate blood results and those taken pre-cycle 2 chemotherapy using STATA version 15.1.

Results

300 patients were included. 212/300 patients were female and the median age of the whole sample was 55 (range 21-83).  The mean baseline neutrophil count was 4.7 (SD 2.748123).  We found that 147/300 (49%) patients had received two blood tests within 6 days of chemotherapy administration; of these 37 (25%) were repeated as the neutrophil count taken was below the required threshold value to allow treatment. Of those with neutrophils above the threshold, 71% (79/110) were found to have a lower count value on the day of treatment than that taken 5/6 days prior.  In 7 cases the neutrophil value was below 1.2×109 /L .  In all cases cycle 2 was safely administered.

Conclusion

We have demonstrated that duplication of blood tests does occur, however the value is unclear.  We have showed evidence of potential delayed nadir occurring in patients but this may not be of clinical significance. 

Treatment and survival in non-metastatic muscle invasive bladder cancer: analysis of a national patient cohort.
Speaker: Joseph John
Affiliation: Taunton and Somerset NHS Foundation Trust, Taunton, UK

Abstract:

One third of patients have non-metastatic muscle invasive bladder cancer at diagnosis – an aggressive but potentially curable disease.

Objectives

– To assess the one-year survival of all patients with non-metastatic muscle invasive bladder cancer (T2-4N0M0) in England in 2016, according to treatment modality, disease stage and sex.

– To assess for an association between patient comorbidities and treatment modality for non-metastatic muscle invasive bladder cancer (MIBC).

Method

National cancer registration and analysis service (NCRAS), radiotherapy data sets (RTDS), systemic anti-cancer treatment (SACT) and hospital episode statistics (HES) databases were searched for all patients diagnosed with non-metastatic MIBC in England in 2016. Age and Charlson comorbidity index (CCI) were determined. Treatment modality was ascertained, including radical cystectomy or radiotherapy, the use of neoadjuvant chemotherapy (NAC), and palliative treatment. One-year overall survival was calculated according to treatment group, disease stage and sex.

Results

Non-metastatic MIBC was registered as being diagnosed in 2519 patients. The median age was 76, and the overall one-year net survival was 66% (64 – 68%, 95% confidence interval). Radical treatment was performed in 53% (24% cystectomy, 29% radical radiotherapy). Cystectomy patients received NAC in 37% of cases, compared with 48% of radical radiotherapy patients. Palliative or no active treatment occurred in 47%. Radically treated patients receiving NAC had 8% higher one-year survival compared with radically treated patients not receiving NAC; 91% (88 – 93%) and 83% (80 – 85%) respectively, p = 0.05. Statistically better survival for patients receiving NAC was observed with radical radiotherapy but not with radical cystectomy (p = 0.05). One-year survival was lower for patients receiving palliative intent or no active treatment and was lower in females compared with males, independent of MIBC stage. CCI was recorded as being lower in a higher proportion of patients receiving radical treatment.

Conclusion

One-year survival in non-metastatic MIBC remains low. The superior survival in radically treated patients receiving NAC reflects trial data, and the low penetrance of NAC warrants closer investigation. There is a need to design studies aimed towards improving outcomes for the large patient group who currently receive palliative or no treatment, and for the significantly aged population described.

“I thought there would have been pain” A qualitative investigation of patients’ experiences of the route to, and diagnosis of, head and neck cancer.
Speaker: Jennifer Deane
Affiliation: Newcastle University

Abstract:

Patients with head and neck cancer (HNC) often present late, negatively impacting survival and patient-reported outcomes. HNC can present in seemingly benign ways and there is difficulty in knowing where to seek help. This study aimed to explore the patient experience of the route to diagnosis, using qualitative methods, as an important step to inform future work on reducing delays.

Method

19 patients with a diagnosis of head and neck cancer were recruited through 3 NHS Trusts. Semi-structured face to face interviews were undertaken, guided by a topic guide which covered; experiencing a health problem, engaging with the healthcare system, communication of a diagnosis and knowledge and understanding of cancer. Participants were recruited until data saturation was reached and a thematic analysis conducted on the data.

Results

Seven themes were identified: The C Word (Communication and Cancer); Control; The 2 Week Wilderness; Negotiation and Navigation; Symptoms and Emotional Labour; and Knowledge which underpinned all of the other themes. Patients expected that cancer symptoms would be painful therefore non-painful symptoms were often ignored. They reported that healthcare professionals (HCPs) rarely used the word “cancer” causing confusion around their diagnosis. They described difficulty negotiating and navigating the healthcare system, and often wanted to hand over control to HCPs. Most spoke about the time between biopsies and the confirmed diagnosis as a particularly difficult time where they had minimal access to support. The whole route required patients to manage not only their own emotional response but also the responses of HCPs, their family and friends.

Conclusion

These findings give a deeper understanding of the experience of initially registering a potential symptom to the point of diagnosis in HNC. The results advance knowledge around the needs of patients at different points during the route to diagnosis.

PLGA-Disulfiram microparticles inhibit NF-κB and PD-L1 pathway and reverse chemoresistance induced by mesothelioma stem cells.
Speaker: Garima Tyagi
Affiliation: Wolverhampton university

Abstract:

Mesothelioma (MM) is a malignancy with < 12-month overall survival. Only one drug (Pemetrexed) is available for MM treatment. MM recurrence is very common due to chemoresistance caused by cancer stem cells (CSCs). Our previous publications demonstrate that hypoxia-induced NF-κB pathway activation plays a pivotal role in the maintenance of CSCs, chemo-radio-resistance and cancer metastasis. Hypoxia and NF-κB also induce PD-L1 expression in cancer allowing them to evade the host immune system. Development of a drug simultaneously targeting hypoxia-NF-κB-CSCs axis and PD-L1 is of clinical significance.

Our previous studies have shown that Disulfiram (DS) a clinically used anti-alcoholism drug, in combination with copper (Cu) has strong toxicity in CSCs from a wide range of cancer types. The clinical application of DS in cancer has been limited by its very short half-life (4 minutes) in the bloodstream. MM mainly infiltrates local organs and tissues with rare distant metastasis. Considering this growing feature of MM, we developed a biodegradable and controlled released poly (lactic-co-glycolic acid) microparticle-encapsulated Disulfiram (PLGA-DS) for local treatment of MM.

Method

MTT cytotoxicity assay, flow cytometry analysis of CSC markers, hypoxic cell cultures, western blot, stable over-expression and knock out of NF-κBp65, CSC sphere reformation, invasion/migration assay.

Results

Hypoxic culture significantly induces Pemetrexed and Cisplatin resistance in MM cell lines. Hypoxia-cultured cells showed high NF-κB expression, CSC markers and manifested strong migration/invasion ability. PLGA-DS showed strong toxicity to MM cell lines and reversed hypoxia-induced chemoresistance. PLGA-DS/Cu completely reversed hypoxia and CSC induced chemoresistance and abolished CSC population in culture. PLGA-DS inhibited the hypoxia-induced NF-κB and PD-L1 expression and blocked the migration/invasion ability. PLGA-DS/Cu also potentiates the cytotoxic effect of cisplatin/pemetrexed synergistically. The in vivo studies are ongoing.

Conclusion

DS is an FDA approved a drug with all safety data available. It can be quickly translated for the treatment of MM in clinics.

Waiting for a miracle or best medical practice? End-of-life medical ethical dilemmas in Bahrain
Speaker: Barrak Almoosawi
Affiliation: University of Edinburgh

Abstract:

In Bahrain, maintaining life support at all costs is a cultural value considered to be embedded in the Islamic religion. We explore end-of-life decision making for brain dead patients in an Arab country where medical cultures are dominated by Western ideas and the lay culture is Eastern.

Method

In-depth interviews were conducted from February to April 2018 with 12 Western-educated Bahraini doctors whose medical practice often included end-of-life decision making. Discussions were about who should make withdrawal of life support decisions, how decisions are made and the context for decision making. To develop results, we used the inductive method of thematic analysis.

Results

Informants considered it difficult to engage non-medical people in end-of-life decisions because of people’s reluctance to talk about death and no legal clarity about medical responsibilities. There was disagreement about doctors’ roles with some saying that end-of-life decisions were purely medical or purely religious but most maintaining that such decisions need to be collectively owned by medicine, patients, families, religious advisors and society. Informants practised in a legal vacuum that made their ethics interpretations and clinical decision making idiosyncratic regarding end-of-life care for brain dead patients. Participants referred to contrasts between their current practice and previous work in other countries, recognising the influences of religious and cultural dimensions on their practice in Bahrain.

Conclusion

End-of-life decisions challenge Western-trained doctors in Bahrain as they grapple with aligning respect for local culture with their training in the ethical practice of Western medicine.

Oncogenic Ras/ERK signalling alters cell shape and mechanics to facilitate cell division under confinement
Speaker: Helen Matthews
Affiliation: University College London

Abstract:

Tumours are stiffer than healthy tissue, due to high cell density and extra-cellular matrix deposition. Cancer cells, unlike normal cells, continue to divide in this mechanically-altered micro-environment. We asked how the genetic changes in cancer cells alter the cell division process to allow cells to respond to mechanical constraints.

Method

To study the effect of oncogene activation on cell division, we used an inducible system to activate RasV12 in normal epithelial cells. We imaged dividing cells using time-lapse microscopy and quantified mitotic cell shape. We also measured cell mechanics in interphase and mitosis using atomic force microscopy. We then challenged cells with and without RasV12 to divide in conditions of physical confinement under stiff hydrogels.

Results

We found that activation of RasV12, for as little as five hours, dramatically altered mitotic cell shape by increasing acto-myosin contractility, in a manner dependent on the downstream MEK/ERK signalling cascade. The same effect was observed following long term RasV12 activation.The Ras/ERK pathway also altered cell mechanical properties, so that Ras-activated cells were softer in interphase but stiffened more in mitosis. These mechanical changes allowed cells to exert more force to round up and divide when confined underneath stiff hydrogels. Conversely, inhibition of the Ras/ERK pathway prevented mitotic rounding in confinement, resulting in multiple mitotic defects including spindle fracturing and chromosome loss.

Conclusion

Activation of the oncogenic Ras/ERK signalling pathway promotes cell rounding and stiffening in mitosis, enabling cells to divide in confined conditions where normal cells fail. This could provide an advantage for cell division in mechanically stiff environments like tumours.

Project Swallow: Living with oesophageal cancer
Speaker: Henry Goodfellow
Affiliation: university college London

Abstract:

Centralisation of oesophageal cancer care improves outcomes and reduces healthcare costs but it can also affect the patient experience and increase the administrative burden on healthcare staff. Under a centralised care pathway, patients lose the continuity of care as they are transferred between different hospital trusts, travelling further whilst unwell.

Aim:

To create two digital health interventions (DHI), delivered through a computer software, to be used by healthcare staff, and a mobile phone app for patients and their carers.

Objectives:

  • Improve patient experience
    • Provide one source of reliable health and support information individualised to patients
    • Improve communication with their care team.
  • Improve health service efficiency.
    • Reduce the administrative burden on HCPs
    • Improve auditing across sites for adherence to pathway and cancer wait times
    • Reduce DNA rates and A+E attendances
  • Improve health outcomes
    • More patient centred care decisions (quality vs quantity)
    • Standardise care across hospital trusts.

Method

Multi-disciplinary approach consisting of PPI, academics, clinicians, Commercial “Living with” who have expertise apps for the NHS and cancer charity Macmillan. The project is divided into 4 main work packages.

  • Summarising the evidence base with a literature review
  • Determining using needs using qualitative methodology.
  • Designing the Digital health interventions using the principles of agile participatory design.
  • Refining the prototype with a small non clinical pilot.

Results

Poster outlining the protocol and logic model of the project

Conclusion

Our vision is that every patient with cancer will have personalised digital support throughout their cancer journey.

Engineered 3D-microtumours for personalized cancer therapy
Speaker: Nobina Mukherjee
Affiliation: University of Oxford

Abstract:

Lack of patient’s response to cancer treatment is one of healthcare’s biggest challenges. A fundamental reason for this is the cellular heterogeneity that exists within and between cancer patients. Tissue engineering can address this by forming physiologically relevant, 3D-tumour models for drug evaluation. The development of personalized therapies specifically tailored to tumour models derived from patient biopsies will revolutionize cancer treatment. 3D human tumour models will have greater predictive capability over animal models that often exhibit species-dependent drug responses. They will therefore reduce the economic and ethical costs of drug discovery.

The objective of our research is to engineer 3D-microtumours from patient biopsy-derived cells and use them as a platform to predict the treatment of individual cancer patient. 

Method

We have developed a droplet microfluidic based technique for the highly-scalable and reproducible production of microtumours from the cells of individual patients. In our most recent work, we have fabricated monodisperse, matrix protein (ECM) containing 3D-microtumours (diameter: 150 μm to 1000 μm) with high throughput (thousands of highly reproducible microtumours can be produced in 2 hours). This novel microfluidic will significantly advance the application of personalized cancer therapies.

Results

As a proof-of-principle we have engineered co-culture microtumours of human ovarian cancer cells and fibroblasts in Matrigel. In our system, structures are tailorable in size. Large microtumours are spontaneously produced by templating on the diameter of the PTFE tube. Previously, the production of large spheroids (diameter >500 μm), which are essential to study hypoxia in tumour, was only possible from small cell aggregates and took 1–2 weeks. In a first of its kind demonstration we have engineered Matrigel-containing microtumours at the production rate of 10 per second.  Cells in the 3D-microtumours show approximately 90% viability after production and can proliferate, migrate, and assume expected morphologies.

Conclusion

Our approach demonstrates the power of tissue engineering and microfluidics on being able to construct microtumour mimics from the patient biopsy and test chemotherapeutics based on individual’s drug response. This time- and cost-effective, high-throughput approach will make personalized therapy part of the mainstream healthcare. This will enable a significant step towards making personalised cancer therapy accessible to all.