PhD - Institute of Cancer Research
By funding scientists who have the potential to become leaders in their field, we are not only adding to the headcount of persons working in this underfunded area of medicine, but we are tapping into novel and innovative ideas that hopefully will lead to significant breakthroughs in diagnosis and treatment options in this field.
We want to find and contribute as much as possible to that elusive DIPG CURE!
Kathryn Taylor PhD - The Institute of Cancer Research Award £110,000
Dr Chris Jones appointed, by his peers is the Chair of the SIOPE High Grade Gliomas/DIPG Biology Group (International Society of Paediatric Oncology - Europe) and Principal Investigator (Genomics) on the North American DIPG Collaborative Grant and as such is the international lead on research into these tumours.
Following a visit of Abbie’s Army to the ICR in October 2013, we were presented the following project with the costs required to take forward this research into DIPG over the next two years:
'Translational genomics of diffuse intrinsic pontine glioma'
PhD Studentship – Kathryn Taylor
Project finishing in September 2015
Supervisor: Dr Chris Jones, Institute of Cancer Research, Sutton
The goal of Katy’s project is to identify and test novel therapeutic targets for DIPG. This comprises two main areas of work: Whole genome sequencing of a series of DIPG biopsy specimens Development of novel DIPG models
In the first two years of her project, Katy has successfully completed the biopsy sequencing study, and has a first author paper at Nature Genetics in addition to a second paper, of which she is also a contributing author (see below). Both studies have identified a gene known as ACVR1 as a major new driver in DIPG, with mutations found in approximately 25% of cases. Remarkably, these are the same mutations found in patients with the rare congenital malformation syndrome called fibrodysplasia ossificans progressiva, in which the soft tissue turns to bone. This discovery offers new insight into the links between cancer and development, and provides a new target for novel therapies in DIPG. Katy will continue to work on the functional aspects of ACVR1 in DIPG whilst funding is sought to employ a new post-doctoral fellow to take this project forward. In addition the sequencing study has identified further targets involving cell signalling pathways which also bear investigation.
In parallel, Katy has been attempting to grow numerous DIPG primary patient-derived cell cultures obtained from collaborating centres across the world. She has successfully established 8 DIPG primary cell lines as both two-dimensional stem cell cultures and three-dimensional neurospheres (clusters of cells that more closely replicate a tumour). In addition she has produced tumour models with similar cellular and invasive growth characteristics as the human disease. She is currently in the process of generating molecular profiles of these models, and they will provide the resources for assessing the potential clinical utility for the targets identified from the sequencing of the human DIPG samples.
The first step in bringing these two strands together is to carry out a functional genetic screen on the cell lines. This will include a specific ‘synthetic lethality’ experiment to identify which combination of genetic ‘hit’ selectively kills the mutant ACVR1 cells. Katy will use this information to identify alternative approaches to drugging this pathway which may be quicker to translate to the clinic given the current lack of available drugs that target ACVR1. In addition such a screen can be repurposed towards a comprehensive assessment of all candidates generated from the sequencing study to identify and prioritise the most important for preclinical study. In order to achieve this, we wish to expand the depth and breadth of our original experiment to include the entire ‘druggable genome’ across an expanded panel of DIPG cells. This will generate a unique dataset that to our knowledge is not being undertaken elsewhere.
It is anticipated that such a screen will run in the first 6 months of 2014, providing valuable functional dependency data for the ACVR1 project, and allowing for selection of novel candidates for the remainder of Katy’s PhD. The rest of her time will be spent carrying out detailed investigations for drugs targeting these most promising candidates. Owing to our leadership roles in the European DIPG working group, it is anticipated that the preclinical data generated will be used to guide the next generation of clinical trials currently being designed. Katy is an extremely talented young researcher. Supporting the remainder of her PhD made a significant contribution to the efforts at ICR to come up with better treatments for children with DIPG. Katy also received a prestigious award for her work at the SNO (Society for Neuro Oncology) conference in San Francisco in November 2013.
We were delighted to have been able to support Katy in her studies ...and even more delighted and humbled that Katy dedicated her thesis to Abbie.