Study into treatments for high grade neuroendocrine tumours and neoplasms, supported by the Miranda Filmer Fund

 

A research project made possible by the Miranda Filmer Fund, and led by leading neuroendocrine specialist Professor Martyn Caplin, is advancing the use of genomic profiling to treat neuroendocrine tumours (NETs).

This study explores why some cells within a patient are more aggressive, why their change their structure, and how they respond to treatment.

The aim is to increase understanding of which treatments work better on which patients.

There are different types of neuroendocrine tumours, NETs and NENs. This research is focussed on the most aggressive form which sadly affected Miranda Filmer, one of our amazing, courageous and inspirational patients. Miranda, a gifted equestrienne and sportswoman, was diagnosed in 2017 and died on 10 June 2022, aged 30. The zebra motif below both captures Miranda’s passion for horse-riding and alludes to the universal international symbol for rare diseases. Clinicians are often told, “when you hear the sound of hooves, think horses, not zebras.” They are urged to assume that the simplest explanation of a patient’s symptoms is correct to avoid misdiagnosing them with rare conditions. However, medical ‘zebras’ do exist, and it is important that clinicians equipped to diagnose and treat them when they occur.  

“When you hear the sound of hoof beats, sometimes it is a zebra”

High grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes, unlike lower grade neuroendocrine tumours (NETs) which have a median overall survival of between 8-16 years, high grade (grade 3, G3) NENs have an overall survival of only about 7 months. Current treatment options for high grade NENs are limited and confer small survival benefit to patients.

Little is known regarding the underlying genetic make-up of these rare tumours, and we lack an understanding of the genetic differences between G3 NEN and G3 NET and how these differences may be utilised to better understand how these tumours develop and direct therapies to improve treatment options for patients, like Miranda, with these tumours.

The scientific programme aims to undertake:

 

1. Genetic profiling (looking at changes to in the DNA of genes) and

2. epigenetic profiling (looking at changes that control gene expression)

on tissue samples from patients with high grade neuroendocrine neoplasms, both well differentiated G3 Neuroendocrine tumours and poorly differentiated neuroendocrine carcinomas.

• Examination of tissue samples currently in the UCL/Royal Free biobank.
• Analysing formalin-fixed paraffin-embedded tissues by DNA extracted for genomic profiling through next generation sequencing (NGS) and for epigenetic analysis using techniques such as immunohistochemistry.

3. Immune assessment

• Investigation into immune related characteristics of these tumours with techniques to establish tumour mutational burden, mis match repair status and PDL1 expression with the aim to establish if these tumours would be sensitive to immunotherapy treatments.

4. Correlation with functional PET imaging

• Correlation of these molecular genetic findings with the radiological characteristics of the patient’s cancers based on the FDG PET and Gallium 68 Dotatate PET activity, to ascertain if there is a relationship between the genetic and epigenetic characteristics of these tumours and their functional imaging behaviour.

This research is to be carried out in the UCL laboratories at the Royal Free Hospital and the clinical oncology department at The Royal Free Hospital. A clinical fellow will be responsible for performing the above analysis in the laboratory, supervised by two clinical supervisors and a laboratory supervisor, working closely with our NET pathologist on sample acquisition and analyses. The aim is to recruit a second clinical fellow as the research progresses.

Functional PET imaging will be performed at Royal Free Hospital Nuclear Medicine Department.

The team hope to publish preliminary data at an international conference at least in abstract form by March 2024.

The second stage of this research will be to utilise the laboratory findings acquired and translate these findings into clinical practice within the Neuroendocrine Unit at The Royal Free Hospital. The experts at the hospital will construct predictive testing models to identify novel therapies to be used in the treatment of neuroendocrine tumours (both targeted therapies and immunotherapies) using the molecular profiling data acquired in the first stage of the research. They wish to achieve this by:

1. Developing novel neuroendocrine carcinoma cells lines (which would be the first such cell line developed) with the aim of testing novel therapies on these cell lines.

2. Utilizing existing models such as those developed by CURESPONSE and VIVAN, in which we would mimic the molecular profile of the tumours that we had identified to be common in NENs and test the effectiveness of novel therapies directly in these models.

Using this data, they would then set up clinical trials through our NETs clinic with the aim of delivering novel therapies directly to patients to acquire toxicity and quality of life data and to establish the progression free survival and overall survival benefit of these novel therapies.

 

We are so proud of our amazing and courageous daughter and she will be forever remembered. The idea behind this research is to identify NETS and NENs sooner and to target effective therapies and prolong the life of those diagnosed with complex disease.”
Antonia and Charles Filmer

We are proud to be facilitating the Miranda Filmer Fund by working with Charles and Antonia Filmer, following the loss of their daughter, Miranda. The exceptional fundraising could be genuinely transformational for the world-renowned work of the Royal Free London in the field of neuroendocrine cancer research. We are immensely grateful to the wide network of generous donors to the Miranda Filmer Fund.”
Jon Spiers, Chief Executive of the Royal Free Charity