2019 RESEARCH DONATION
Funding in-depth genomic molecular characterisation of two paediatric chordoma cell lines and PDX models. One confirmed INI1 deleted and one not deleted.
In 2017, thanks to the investment of a family affected by paediatric chordoma, the Chordoma Foundation (USA) was able to offer the research community a $25,000 prize for developing a paediatric chordoma cell line. The prize announcement was successful, and they now have a validated paediatric chordoma cell line available for distribution to researchers across the globe.
Additionally, they also have a corresponding patient-derived xenograft (PDX) model that was developed from the same initial tumor as the cell line. These resources are a valuable asset as they enable researchers to test the effects of drugs in the paediatric cell line and then advance promising drugs into the corresponding PDX model to look at the effects on tumor growth in the mouse model. To make these tools even more beneficial to the research community it will be important to perform in-depth genomic characterization of the two models. Performing this characterization could provide researchers with clues as to what drugs and combinations to test in the models and enable them to identify drugs that may work in patients with similar genomic alterations. Additionally, the genomic data for these paediatric chordoma models will be entered in a public data repository available to all researchers worldwide.
Therefore, researchers who are currently unaware of paediatric chordoma could become interested in studying the disease if they discover genetic alterations similar to ones they are studying in other cancers. We have approximately four additional paediatric chordoma cell lines that have been submitted for validation to confirm that they are truly chordoma.
Funding the testing of five drugs in paediatric chordoma PDX models
The purpose of developing validated and molecularly characterised paediatric chordoma cell lines and animal models is ultimately to identify new and/or better treatment options for children affected by paediatric chordoma. The Chordoma Foundation’s Drug Screening Program (DSP) enables researchers to quickly test drugs in animal models and determine if there is enough activity to warrant initiation of a chordoma-specific clinical trial or expansion of an existing trial in another cancer to include a chordoma-specific cohort. Given that we now have three validated paediatric chordoma PDX models – one confirmed to be INI1 deleted, one not deleted, and the third pending characterisation of INI1 loss they positioned to test drugs that have demonstrated promising results in adult chordoma cell lines to determine if they can affect tumor growth in the xenograft models. Additionally, if they reserve testing to drugs that are in clinical development or approved for other cancer indications, they can rapidly advance promising drugs that show activity in these preclinical models to the clinic so that the youngest members of the community can benefit from this research as soon as possible.
Continuing to fund the National UK Chordoma Cohort Study
A lot of progress has been made over the last year. In January 2018, Understanding Chordoma: A National Cohort Study opened at centers across England. More than 50 participants with a diagnosis of chordoma have joined the study since then. Participants are being followed for up to eight years after enrolment, during which time clinical data is collected alongside tissue samples and blood samples. These samples are/ will be genetically analysed to provide more information about what we know about what causes and drives chordoma, and why is it resistant to many therapies. The aim of the study is to understand the molecular basis of the disease so that we can develop new tests for early diagnosis, treatment and surveillance.
Since the study opened, over 25 tumor samples have been submitted for whole genome sequencing, RNA sequencing and methylation analysis. A manuscript has also submitted which goes some way to explain regulation of brachyury (TBXT) in chordoma; the study has also identified a ‘tool’ compound which appears to silence brachyury (TBXT) in the laboratory. Work is now needed with Pharmaceutical companies to see if such tool compounds can be transformed into therapies for the clinic – this is not an easy task – but progress has been made. This manuscript is: “Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival” (bioRxiv 432005; doi: https://doi.org/10.1101/432005.)
The National Cohort Study has initiated the formation of a UK network comprising of patients, their families and medical health care workers, through which it aims to deliver a better and a more standardised management of patients with chordoma, in both children and adults. The hope is that this chordoma network will be the legacy of the study, facilitating the sharing of expertise in this rare disease for years to come. At present, a Clinical Research Fellow, funded by Chordoma UK, travels to centers to meet teams and help to establish the network. The Chordoma Foundation along with The Drew Barker-Wright Charity supports the basic research associated with the National UK Cohort Chordoma Study. The Drew Barker-Wright Charity has a specific focus on Paediatric Chordoma.
The research program involves the recruitment of patients with chordoma of all ages. There is a focus on undertaking research on chordoma from paediatric patients. However, the rare occurrence of chordoma in children makes this challenging but, it is believed that understanding chordoma occurring in any age group would be beneficial to the chordoma patient and health care community at large.
This year will see more centers opening in the National Cohort Study, with further recruitment; working hard to strengthen and expand the clinical network with a focus on centers that see paediatric patients with chordoma. Finally, the project looks forward to analysing the results generated during the past twelve months and sharing these findings.