We are delighted to award the 2021 NCUK grant to Dr Melissa Frizziero, The Christie Hospital, Manchester.

‘Epigenetic-based biomarker discovery for Extra-Pulmonary Neuroendocrine Carcinoma’ (EP-NEC).

UPDATE

NCUK-UKINETS Grant Award 2021
Epigenetic-based biomarker discovery for Extra-Pulmonary NeuroEndocrine Carcinoma (EP-NEC)

Lay summary of the project:
NeuroEndocrine Carcinomas (NECs) are rare but aggressive, rapidly growing cancers that can originate from any organ in the body. Patients with NEC are becoming more commonly encountered in clinic. The majority of patients with NEC present with distant metastases at diagnosis meaning that they’re not amenable to curative treatment; these patients have a short life expectancy (<12 months, on average), and can only be offered chemotherapy with palliative intent or best supportive care (symptom control only). While significant research effort has been invested into NECs originating from the lung, which are the most common, NECs from outside of the lung, so-called Extra-Pulmonary (EP)-NECs, remain poorly studied. Tumour material shed into the patient bloodstream, such as tumour-derived DNA (so called ‘circulating tumour DNA’ or ctDNA) or entire tumour cells (so called ‘circulating tumour cells’ or CTCs), can provide useful information for the management of these patients. This material can be obtained through a simple blood draw and the procedure is known as ‘liquid biopsy’. Recent studies have shown that methods looking at epigenetic changes in the ctDNA (epigenetic-based ctDNA analysis) have increased ability to detect ctDNA in a variety of cancer types as compared to conventional methods looking at genetic changes in the ctDNA.

The Cancer Research UK Manchester Institute Cancer Biomarker Centre (CRUK MI CBC) is a laboratory with worldwide expertise in liquid biopsies and NEC research. Under the framework of a collaboration between CRUK MI CBC and The Manchester European Neuroendocrine Tumour Society Centre of Excellence at The Christie NHS Foundation Trust, a study has been setup to investigate whether liquid biopsies can aid in the clinical management of patients with EP-NEC. As part of this study, we have been collecting serial blood samples for ctDNA analysis from patients with an EP-NEC diagnosis undergoing palliative chemotherapy at The Christie NHS Foundation Trust in Manchester. The aim of this project is to assess whether a novel method for epigenetic-based ctDNA analysis is feasible in patients with EP-NEC and can help improve the management and treatment outcomes of these patients.

We are delighted to award the 2020 NCUK grant to Dr Marc Ooft, Consultant Histopathologist, Kings College Hospital.

His research alongside the NET GeCIP group is focusing on ‘Improving patient stratification through epigenetic and tumour microenvironmnet analysis of the 100,000 Genomes project neuroendocrine tumour cohort.’

We would also like to thank Mr P Moxham for his generous donation towards our research grant.

Prof Mark Pritchard, Professor of Gastroenterology, Institute of Translational Medicine,
University of Liverpool and Head of Liverpool ENETS Centre of Excellence at Liverpool University Hospitals NHS Foundation Trust

The aim of this project is to develop and characterise primary cultures from the tumours as well as the adjacent unaffected mucosa of patients with low grade type 1 and type 3 gastric NETs. These gastroids will then be cryopreserved in order to provide tools that can be used for future investigations about the pathogenesis and treatment of gastric NETs. We believe that we have the unique combination of a large cohort of patients with gastric NETs and the required laboratory expertise to successfully complete this project.

2019 Recipient update (2021)

Understanding how type I gastric neuroendocrine tumours develop

Prof Mark Pritchard, University of Liverpool

There are three main types of neuroendocrine tumour (NET) that develop in the stomach. The commonest type (type 1) develops in patients who have an autoimmune condition that results in destruction of the acid producing (parietal) cells in the stomach. Many type 1 gastric NET patients also have pernicious anaemia and require regular vitamin B12 injections. As a result of their stomachs producing little or no acid, these patients have very high levels of a hormone called gastrin in their bloodstream and it is this hormone that is believed to be responsible for the development of type 1 gastric NETs.

The long term outlook for most patients who have type 1 gastric NETs is very good. The majority of patients have small tumours and don’t actually need any type of active treatment. However a minority of patients have larger tumours and these may need to be removed either via an endoscope or by surgery. In 2010-4 we conducted a clinical trial involving eight patients in Liverpool and eight in Norway to test a potential new tablet treatment for type I gastric NETs (funded by Trio Medicines Ltd). If successful, this might mean that in future some type I gastric NET patients might be able to avoid surgery. The new drug (Netazepide) blocks the effects of gastrin. The trial showed promising results with a shrinkage in the size and number of the tumours in many patients and the treatment also resulted in no serious side effects ^1,2. Trio medicines Ltd are still working on the development of this drug, so at the moment it is not available for general prescription.

In 2014, we were awarded a research grant by Neuroendocrine Cancer UK to investigate how Netazepide was exerting its effects in these patients. We used stomach biopsy samples that had been taken before, during and after the patients on this trial were being treated with Netazepide. We found that only 12 genes showed significantly decreased expression when the patients were taking Netazepide. One of these genes called pappalysin or PAPP-A2 was particularly interesting. This gene encodes a protein which is an enzyme that regulates how much of a growth factor called insulin-like growth factor is present in the stomach. We performed several additional experiments which demonstrated that this signalling pathway appears to both be important during gastric NET development and in determining how these tumours respond to Netazepide treatment. As well as increasing our scientific understanding about type I gastric NETs, our research has at least partially explained how Netazepide works and it also provides opportunities to design other potential new drug treatments for type I gastric NETs in the future.

The results of our study were published in the scientific journal ‘Cellular and Molecular Gastroenterology and Hepatology’ in 2020 and are available online to read by anyone who is interested ³.

In 2019 we were awarded another grant by Neuroendocrine Cancer UK to try to grow gastric NET cells in the laboratory in order to be able to test the effects of potential new treatments before actually giving these drugs to patients within a clinical trial. This research is still ongoing and we hope to provide an update about our findings in due course.

References

1. Moore AR, Boyce M, Steele IA, Campbell F, Varro A, Pritchard DM. Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis. PLoS One. 2013;8(10):e76462.

2. Boyce M, Moore AR, Sagatun L, et al. Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis. Br J Clin Pharmacol. 2017;83(3):466-475.

3. Lloyd KA, Parsons BN, Burkitt MD, et al. Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors. Cell Mol Gastroenterol Hepatol. 2020;10(1):113-132.

The TRACERx – (TRAcking Cancer Evolution through therapy (Rx))

One of the winners of the UKINETs/NPF grants was one of the TRACERx team. We are delighted that Lung NETs will now be included in this research project. Want to know more about TRACERx? Read below….

The TRACERx (TRAcking Cancer Evolution through therapy (Rx)) lung study is a multi-million-pound research project taking place over nine years, which will transform our understanding of non-small cell lung cancer (NSCLC) and take a practical step towards an era of precision medicine. The study will uncover mechanisms of cancer evolution by analysing the intratumour heterogeneity in lung tumours from approximately 850 patients and tracking its evolutionary trajectory from diagnosis through to relapse. At £14 million, it’s the biggest single investment in lung cancer research by Cancer Research UK, and the start of a strategic UK-wide focus on the disease, aimed at making real progress for patients.

Led by Professor Charles Swanton at UCL, the study will bring together a network of experts from different disciplines to help integrate clinical and genomic data and identify patients who could benefit from trials of new, targeted treatments. In addition, it will use a whole suite of cutting edge analytical techniques on these patients’ tumour samples, giving unprecedented insight into the genomic landscape of primary and metastatic tumours and the impact of treatment upon this landscape.

In future, TRACERx will enable us to define how intratumour heterogeneity impacts upon cancer immunity throughout tumour evolution and therapy. Such studies will help define how the clinical evaluation of intratumour heterogeneity can inform patient stratification and the development of combinatorial therapies incorporating conventional, targeted and immune-based therapeutics.

Intratumour heterogeneity is increasingly recognised as a major hurdle to achieve improvements in therapeutic outcome and biomarker validation. Intratumour genetic diversity provides a substrate for tumour adaptation and evolution. However, the evolutionary genomic landscape of non-small cell lung cancer (NSCLC) and how it changes through the disease course has not been studied in detail.

The other worthy winner was Kate Lines, a PostDoctoral researcher, who works at the Radcliffe Department of Medicine in Oxford, alongside Professor Raj Thakker. She is continuing here work on molecular genetics in pancreatic neuroendocrine tumours.

“I am delighted and very grateful to have been awarded NET patient foundation award at this years UKINETs meeting. I am very much looking forward to beginning the study. As an early career scientist, this grant is especially important as the data generated from the project will help form the basis of my future NET research career”.

The aim of the project is to develop a new drug for the treatment of pancreatic neuroendocrine tumours (PNETs). We have previously shown that a drug called JQ1, which inhibits the function of a family of proteins called the BET family, could reduce the number of PNET cells in the laboratory. This family of proteins help to control the expression of genes that promote tumour cell growth and prevent tumour cell death, by binding to chemical marks in specific DNA regions, also known as epigenetic regulation. Therefore, by inhibiting the activity of the BET proteins we were able to prevent the cell growth and increase cell death.

Although JQ1 has shown promising results in PNETs, similar to a chemotherapy, it can act on any cell that expresses the BET proteins, and therefore may have side effects. The focus of this study is therefore to generate a new drug that specifically targets JQ1 only to NET cells or tissues. To do this we are using a man made version of the hormone somatostatin, called a somatostatin analogue. Receptors that somatostatin binds to are only expressed in certain endocrine tissues, and are seen in high levels in PNETs. Therefore by making a drug with a somatostatin analogue joined to JQ1, we plan to target JQ1 only to the PNET cells. We will test the ability of this new somatostatin-JQ1 drug to reduce the number of PNET cells. If successful, the ultimate aim is to use this data to plan a clinical trial of the somatostatin-JQ1 drug in PNET patients.”

2018 Recipient update (2021)

Congratulations to Christodoulos Pipinikas, the recipient of our 2016 award, which will be funding this exciting project:

Using an integrated approach combining data generated through the use of different, advanced molecular tools, we have previously demonstrated that neuroendocrine tumours of the pancreas and gastrointestinal tract are highly epigenetically dysregulated and have identified several altered biological pathways and genes that may form the basis for the development of novel therapeutic targets. In addition, our group has identified specific molecular disease subtypes associated with a significant impact on patients’ survival, indicating that these may benefit from different treatments. Using a similar approach, we would like to extend our understanding of the key molecular events involved in the development and progression of bronchopulmonary neuroendocrine tumours (BP-NETs). BP-NETs represent a significant disease burden with socioeconomic extensions due to their increased incidence and decreased 5-year survival rates. BP-NETs comprise approximately 20-25% of all lung cancers and represent a spectrum of tumours arising from neuroendocrine cells of the bronchopulmonary epithelium. Tumour classification into the correct histological sub-group is strongly predictive of patients’ prognosis but relies on few, difficult to reproduce pathological parameters which are often affected by a high inter-observer variability. Therefore, the aim of this project is to identify novel and accurate molecular tools in order to improve the classification of these tumours. This, in turn, will provide better prognostic information and help with choosing more appropriate treatments. In addition, we aim to study the underlying pathogenic mechanisms involved in disease development and progression through the use of large-scale integrated omics analyses.

Jorge Barriuso who works with Prof. Juan Valle at the Christie Hospital was awarded £30,000. The aim of the project is to identify predictive genetic markers of exceptional response to targeted therapies, therefore allowing treatment stratification. Samples from the Christie NET biobank would be used for this pilot study.

This year the £30,000 grant will be funded solely by the NET Patient Foundation, the details and timeline for applying will be posted on the UKINETs and NET Patient Foundation websites in July 2016. The successful applicant will be invited to present their project and results at the UKINETs annual meeting.

Dr Davlinder Mandair is a trainee gastroenterologist who is currently undertaking a PhD under the supervision of Prof Tim Meyer, Prof Martin Caplin and Dr Chrissie Thirlwell at the UCL Cancer Institute in London.

The project builds on previous work conducted in Prof Meyer’s Lab which demonstrated, for the first time, that circulating tumour cells (CTCs) were detectable in the blood of patients with a range of NETs, and that their presence indicated an adverse prognosis. Technology has now advanced to the extent that detailed molecular characterisation can be conducted on single cells and this project will compare the genetic changes seen in primary tumour tissue with that of CTCs and also with cfDNA (pieces of DNA that arise from the tumour and can be found circulating in the blood stream).

If we can show that CTCs and cfDNA does indeed accurately represent the tumour, then we will be able to track how the tumour evolves over time and during treatment. This may allow clinicians treating patients with NETs to select the appropriate therapy and to anticipate the emergence of resistance. As cancer therapy becomes increasingly personalised, it is important that we can undertake this type of analysis so that patients can benefit fully from the new drugs that target specific cancer pathways.

Prof Ramage is a Consultant Physician in Gastroenterology and Hepatology, and lead clinician for the Neuroendocrine Tumour Service at King’s College Hospital NHS Foundation Trust.

The project will study the NETs that were identified in the Colorectal NET and the Bowel Cancer Screening Programme (BCSP). The aim is to understand how these were identified, how they were investigated and how they were treated.

The Bowel Cancer screening programme has screened 1 million people using faecal occult blood (FOB -blood in the stool) testing and 17,500 colonoscopies have been performed. Overall, 7.8% (women) and 11.6% (men) of the colonoscopies detected a colorectal (CR) cancer. However, the data regarding the NET tumours that were identified has not been analysed.

The incidence of CR NET in the general population is thought to be 1.3 per 100,000. The incidence in patients with positive FOB is unknown but CR cancer incidence is 46 per 100,000 in England and thus NET incidence might be 46/1.3 times less likely to be found than CR cancer. This would be 35.4 times less likely which would equate to 1772/ 35.4= 50 cases. It is also possible that some ileal carcinoids will have been found during colonoscopy, and these are twice as common as CR NET.

This study will identify how many CR and ileal NET were found by screening if screening has any value for earlier diagnosis. It will also establish how many of these were seen by NET specialists.