From clonal evolution to metastasis and cachexia, Mariam Jamal-Hanjani has taken on some serious challenges during her research journey. We spoke to her and asked her to reflect on a career embedded in large-scale, collaborative and ambitious projects…
The work cancer researchers undertake has incredible ambition. Perhaps understandable then, that it’s so often described in celestial terms. Visionary projects become moonshots, new research strategies reach for the stars and biopharma spinouts explode from the launch pad.
For one emerging leader of the cancer research community this has real resonance.
“When I was a kid, I always wanted to be an astronaut,” says Mariam Jamal-Hanjani. “I remember being obsessed with stars and, you know, I’m quite tiny so at the very least I figured my center of gravity wouldn’t be an issue!”
“And then I suddenly needed spectacles – so that was the end of that.”
NASA’s loss most certainly became oncology’s gain.
Mariam is now group leader for the CRUK Lung Cancer Centre of Excellence Cancer Metastasis lab at the UCL Cancer Institute – as well as an honorary consultant in translational lung oncology for the Department of Medical Oncology at UCL Hospital. From an early academic career in physics, to a nascent clinical career she then gravitated back to research. Finding herself in the right place at just the right time, in 2012 she joined Professor Charles Swanton’s lab on a CRUK funded clinical fellowship to undertake a PhD.
Shortly after she had joined his lab, Charlie – who was to go on to be appointed CRUK chief clinician – published a paper in The New England Journal of Medicine showing how genomic heterogeneity within a tumour can essentially power tumour adaptation and therapeutic failure through Darwinian selection.
“It became clear that actually, to study this properly, we needed more than a single biopsy,” Mariam says. “We needed multiple biopsies to understand the evolutionary history.” It was this thinking which led on to become TRACERx. At over £10million, it was the biggest single investment in lung cancer research CRUK had ever made, and the start of a strategic focus on the disease.
“My immediate thought was that this was highly controversial and something patients would not be in favour of – I was very wrong.”
Hot on the heels of this auspicious start, a late-night discussion with Charlie sowed a seed which was to bloom into another world first. “It really was a random thought that Charlie had one winter night,” explains Mariam. “He said ‘you know, we should set up autopsy studies.’ My immediate thought was that this was highly controversial and something patients would not be in favour of – I was very wrong.”
Several years – and much sweat and tears – later, Mariam became the lead for the PEACE (Posthumous Evaluation of Advanced Cancer Environment) study. It involves people living with incurable cancer donating their bodies for research after they die, so that Mariam and her team, as well many other cancer researchers, can better understand how cancer develops and spreads, why treatments stop working, and how the body reacts in the final stages of cancer.
Her career, then, has been forged within very ambitious projects – but, for Mariam, to get here wasn’t necessarily a straightforward journey.
A numbers game
It was a love of numbers which first sparked a young Mariam’s imagination.
“Maths was a real strong point in the family,” she says. “Both my parents are mathematicians and I have two brothers who are also mathematicians. But I studied theoretical physics, because I was a bit obsessed with Einstein when I was a child.”
On a whim, she had a conversation with the medical school at UCL, applied and got in to study medicine as a graduate student. After a stint in renal medicine, a colleague pointed her in the direction of oncology. And, as a junior doctor, it was a challenge she certainly found compelling. “It’s pathology at its most advanced,” she says. “The minute you’ve got metastatic disease, and there’s organ failure, it could be all the medicine disciplines rolled into one, whether it’s bleeding in the brain, whether it’s heart failure – it was really hardcore clinical medicine.”
It was this tough clinical work, combined with her own personal experience of cancer, which got Mariam thinking about improvements in cancer care. Back in the 1970s one of her brothers was diagnosed with leukaemia, and whilst the resultant chemo- and radiotherapy did prove to be successful, it put real strain on the family. “My parents struggled a lot, but he was one of the very few that was cured during that period of time,” she says. “Treatments have of course changed and improved now, but when I was surrounded by it as a clinician, you still question what else could be done.”
And so, the call of research became loud and clear for Mariam. After being connected to Charlie via one of her clinical consultants, she was awarded a CRUK clinical fellowship to do a PhD.
The dawn of TRACERx
Many a research career is rooted in at least a little serendipity. And Mariam was perfectly placed to make the most of hers. Shortly after she joined Charlie’s lab, he published a paper which really became a cornerstone of tumour heterogeneity. It was instrumental in forming the lab’s ideas on how to tackle some of the therapeutic barriers which could emerge as a tumour develops.
And from one of those ideas TRACERx was born. “It was clear that we needed multiple biopsies, to understand the evolutionary history of a patient’s tumour,” explains Mariam. “But at this point, it was just a thought in Charlie’s head, it wasn’t even called TRACERx. He wanted to do something ambitious and large scale that tried to understand how tumours evolve in lung cancer, because that’s an unmet need. And it’s hard not to be driven and motivated by that kind of enthusiasm.”
CRUK bought into the idea and a collaborative project between the Francis Crick Institute, UCL and the University of Manchester was born.
“In the very early days, when we first started with the pilot study, we were studying multi-region tumour samples from lung cancers, and we were getting a lot of data. We didn’t have fancy genetic sequencing pipelines, or a massive team of bioinformaticians,” says Mariam. “We would sit and look at every single mutation on the computer using genomic sequencing, looking at the genome browsers trying to make sure if it’s real or not, and we would manually make the evolutionary trees for each tumour.”
But the project grew, and the nine-year programme would go on to study the evolution of lung cancer in unprecedented detail, from diagnosis through to disease relapse, with the aim of learning how to treat people based on the individual characteristics of their cancer. The findings continue to give vital insight into the disease, and what’s more, the data set collected has taken on a gravity of its own having attracted researchers from across multiple disciplines – and Mariam is at the heart of it all.
“I learned from Charlie. It was his vision, and he brought all these different investigators across the country with him. It was truly team science before the term even existed, and there were aspects he was happy for me to lead on because I felt passionate about them. Together, we felt that the patient was always at the heart of our research” she says.
One ambitious, collaborative and logistically ground-breaking study is often all you might get to work in a career as a researcher. And you’d be lucky at that. But Mariam soon found herself at the cusp of another.
Legacy of the patients
Close to a decade ago, Mariam began exploring the idea of setting up an autopsy study to examine how patients’ cancer evolves and spreads. From the get-go, she says, it was always going to be a challenge.
“There were several small cohort autopsy studies already set up in the US, often involving ‘warm autopsies’, whereby samples are collected within six to eight hours after death. This isn’t something we can achieve given that we work within the constraints of the NHS and its infrastructure.”
And then was the non-trivial problem of communicating this to potential donors. Would patients even want to have that discussion? “Actually, it was mostly the doctors treating these patients that were worried about having these discussions given the stigma of death,” she says. “But then the patient advocates we worked with closely were very encouraging and open minded about the idea of autopsies to support cancer research.”
So, after a few years of getting into the detail of the logistics, the ethics and the patient advocacy, in 2016 Charlie and Mariam established the PEACE research autopsy programme for which she is also the chief investigator. As a clinician, of course, she wasn’t a complete stranger to the mortuary. “You become familiar with it when you’re a medical student and a doctor because sometimes you have to view a body in order to complete the death certificate paperwork,” she says. “But this was a whole different thing. This involved performing an autopsy for research purposes and collecting tissue samples from different parts of the body where the cancer had spread.”
“PEACE is something I have never stopped wanting to make a success… it’s the legacy of our patients.”
The project has now performed over 230 autopsies and has recruited over 390 patients. It gives Mariam and the team – and many other researchers in the PEACE Consortium – unique access to tissue that simply couldn’t be studied while patients are alive. Like TRACERx, it’s giving real insights, but the most striking thing for Mariam is the staggering altruism on display from her donors.
“This has been a really tough study to set up logistically, and the fact that patients are willing to donate their bodies knowing they gain nothing from it directly is truly humbling,” she says. “Instead, they hope that future generations of patients with cancer and researchers will benefit and because of that, PEACE is something I have never stopped wanting to make a success… it’s the legacy of our patients.”
“There’s so much you can learn given the opportunity to study these precious samples, and we’ve already begun to study the patterns in which cancer cells migrate from one site of the body to the next,” she adds.
New and continuing challenges
Despite being firmly rooted in the lab for the inception of two innovative team-science programmes, the pull of the clinic hadn’t entirely left Mariam.
“After my PhD, I was ready to go back to clinical training. That’s, after all, why I had gone to medical school,” she says. “And then I realised I couldn’t leave studies like TRACERx and PEACE and that I wanted to continue to be part of the research we had always hoped would make a difference for patients.”
Then, a few years ago, she capitulated to the lure of research. “I just thought there’s so much I want to do. I need a lab of my own and the ability to continue working with colleagues and collaborators, and to bring other early career researchers into the fold,” she says.
Now a group leader at the UCL Cancer Institute, the future looks bright as ever for Mariam. And, having blossomed as a researcher in the crucible of two highly collaborative projects, it’s perhaps natural that many of her current endeavours fit firmly into a thoroughly modern vision of team science.
As a member of the Cancer Grand Challenge CANCAN team, she is part of an international effort to understand the biology behind cancer cachexia. It’s an involvement that has stemmed from the spectacularly well curated TRACERx longitudinal data set.
“By analysing scans performed longitudinally in patients during follow up using semi-automated pipelines to examine body composition, we’re beginning to develop more efficient ways of looking at muscle and fat in the body,” she explains. “And we can use this to identify patients who develop the cachexia-like phenotype of muscle and or fat wasting during the course of their disease.”
Despite major clinical applications, there is still relatively little known about the condition. And that must change, says Mariam. “I’ve seen it many times in the patients I care for – the muscle and fat loss are a very real thing, and we have no idea how to manage it. We know it means they die sooner. We know it means they don’t tolerate treatment, and we’re helpless.”
There has been research – almost 30 years of mouse and in vitro work in fact, but real breakthroughs in understanding are yet to emerge. The frontier of this understanding of a complex set of interactions between tumours and patients, through metabolism and the immune, endocrine and central nervous systems is now of real interest to Mariam.
And as for Cancer Grand Challenges, she is also a member of the eDyNAmiC team. In this, she is interested in understanding the role of extrachromosomal DNA (ecDNA) in cancer evolution, its interaction with the tumour microenvironment and how it leads to drug resistance. Both TRACERx and PEACE play a crucial role in the study of ecDNA from early to late-stage disease. In particular has the potential to shed light on how ecDNA drives cancer progression.
Then there is the next iteration of TRACERx. Patient recruitment is coming to a close soon, and despite the continuing value of the data generated, it’s time to look to the future. The TRACERx EVO programme has been awarded £14.9 million in funding by Cancer Research UK and the UCL Biomedical Research Centre to drive another step change in the way we understand and treat lung cancer.
And it’s this, the treatment of the disease, which has always been key for Mariam. “We had to look forward and think, how can we further advance what we had learnt from TRACERx and what are the questions we can address in light of new technologies?” She says. “We knew that we always wished we could do more with the entire genome, rather than just the exome, but, really, the key factor is asking ‘how do you translate this to patient benefit?’ One of the things that EVO will allow us to do is investigate whether some of our previous findings in TRACERx can be validated in an entirely different patient cohort, and that’s vital for patient impact.”
But that’s the future. For now, TRACERx has generated data from blood and tumour samples from over 800 patients with non-small cell lung cancer. The PEACE team have performed over 230 autopsies. Both studies continue to forward our knowledge of cancer in unique ways, but there is also incredible power in the overlap says Mariam.
“We have a cohort of patients who were recruited into both the TRACERx and PEACE studies,” she says. “When you combine a study, like TRACERx, which studies cancer from diagnosis through to relapse, with a study like PEACE, you have the ability to study the full spectrum of the disease.”
Tracing and genomically mapping individual tumours over the course of their development and metastasis, in situ, to explore how Darwinian evolution can render therapy impotent… this is, most certainly, ambitious stuff. Moonshots, reaching for the stars; perhaps those lofty idioms really do apply after all.
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Phil Prime
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