Research Updates – 2022
Chris Steele
Since starting my PhD in the Suzanne’s lab I have been working on two questions:
First, what are the mechanisms that allow relapsed B cell lymphoma cells to become resistant to therapy, and secondly, why do some patients go on to relapse while others don’t.
These are both big questions to answer but we have already made some inroads in the lab through Sorcha and Jamie’s work which puts me in a great position to start from. In particular, my efforts are focused on developing genetic engineering strategies using the patient derived xenografts (PDX) established by Sorcha and Jamie. This work has only recently been made possible by a technological advancement in culturing the human tumour cells in flasks in the lab.
To shed some light on the first question I am planning to deactivate specific genes that have previously been highlighted in the lab as potential culprits. I want to do this for over twenty thousand genes (affecting just one gene per cell) whilst simultaneously treating the cells with different experimental drugs. At the end of the drug treatment, DNA will be isolated from the cells, particularly cells from patients that have relapsed, and the sequence determined to find out which genes affect cell survival and activity of the drugs. This approach has never been tried before and is therefore a really exciting opportunity to potentially point us towards new therapeutic designs for children with B-NHL who go on to relapse.
The second arm of my work aims to determine if there are any cells in the tumours which are resistant to therapy from the beginning, i.e. before the child has had any treatment – this is called intrinsic resistance (as opposed to resistance that develops as an adaption to therapy), building on the ‘Queen Bee’ hypothesis. To do this I will put a tag on individual cells in the tumour allowing us to track them over time under different conditions such as in the presence of drugs.
These technologies are complicated and will initially take some time to optimise and prepare before I get to the really exciting analysis of the tumour cells. I am extremely thankful to the Alex Hulme Foundation for the opportunity to be able work on these important projects in the name of Alex. It fills me with joy and fulfilment to dedicate my PhD research to what is clearly an understudied and underfunded area. I look forward to updating you all next year once this work has progressed.
Kind regards
Chris Steele
Jamie Matthews
During my Alex Hulme Foundation-funded PhD, I’ve been analysing the genetic code of B cell Non-Hodgkin Lymphoma (B-NHL) tumours from patients who relapsed, and comparing findings to those patients who had good outcomes. We are starting to build a picture of what kinds of genetic alterations are associated with treatment failure, and by tracking the cancer genetics over time, I have found that we can detect rare mutations which may lead to drug resistance in the future, before relapse has occurred. As tumour DNA sequencing is becoming a routine procedure in the NHS for childhood cancer patients, I believe we will have the opportunity to use these data to better predict the risk of treatment failure in individual children. This information will enable doctors to intensify treatment for high-risk patients and bring the NHL survival rate closer to 100%, but also to choose gentler treatments for lower-risk patients who would benefit from reduced toxic side-effects of chemotherapy.
I have also been building on the fantastic patient-derived xenograft (PDX) resource that Sorcha established, which now represents a wider range of patients, including some from children who sadly relapsed. My PhD work on B-NHL genetics shows that identifying the differences between individual cancer cells in one patient is as crucial as determining differences between patients for predicting future resistance to treatment. To ensure that our PDX models are capable of capturing this heterogeneity (i.e., the genetic differences that exist between individual tumour cells in one patient), I compared the genetics of the established PDX with the original patient cells (direct from the patient without growth in mice) to show that the PDX faithfully maintains the complex genetic structure of the patient’s tumour, including rare mutations in the DNA that are present in less than 1% of the cancer cells. This means that these PDX models can be used to study how the tumours evolve over time and when exposed to treatment, to identify why they become resistant to drugs.
In addition, I have now tested close to two thousand individual drugs for their ability to kill B-NHL cells in a petri dish. Several promising drugs have been identified and the next step will be to evaluate them in our full cohort of patient PDX, to identify drugs with strong efficacy across the spectrum of B-NHL, both primary tumours and those that have relapsed and become resistant to other treatments.
As scientific meetings are now going ahead after the pandemic, I am particularly looking forward to the 7th International Symposium for Childhood and Young Adult NHL, where we are going to share our findings and ideas as well as Alex’s story with the worldwide paediatric NHL community. I will be presenting our work by giving an oral presentation and am looking forward to receiving peer review from the audience. Having passed my PhD viva last month, I am very pleased that Suzanne and I were able to secure external funding for me to continue on this project as a postdoctoral researcher. It’s very exciting to be part of a passionate and growing team focused on paediatric B-NHL!
Kind Regards
Jamie Matthews
Alex Hulme Foundation PhD Student – 2017 to 2022