The path to least resistance: How our researchers are outsmarting cancer’s survival skills

Breast cancer cells

“To be told after treatment that there seemed to be residual disease due to chemo resistance was very hard to hear” – Tina, breast cancer patient

Despite the huge progress we’ve made in breast cancer survival – which has doubled in the UK over the past 40 years – Tina’s is a reality for many women with triple negative breast cancer, a subtype that can be harder to treat. “For these women, when cancer does recur it’s more difficult to get on top of,” explains Cancer Research UK clinician scientist Dr Sheeba Irshad. Dr Irshad is part of a growing cohort across our institutes and centres who are working to expose and exploit the mechanisms that allow some cancer cells to resist treatment (from chemotherapy to targeted treatments and even immunotherapies), lay dormant and then re-emerge later, when they’re harder to eradicate.

Cause and effect

“Drug resistance is a major reason why cancer regrows after treatment, so it’s also a significant contributor to people not surviving their disease,” confirms Professor Dan Tennant, a Cancer Research UK biochemist at the University of Birmingham. He’s setting his sights on hypoxia – a low-oxygen state in cells that occurs in most solid cancers and is a leading cause of drug resistance. Like all cells, cancer cells need oxygen to survive and multiply. When oxygen is scarce, they’re forced to adapt, finding compensatory ways to complete fundamental processes. What’s left is a cancer cell with a markedly different metabolism than a cancer cell with a normal oxygen supply. And one that stands out to someone like Professor Tennant, who’s investigating how cancer cells survive such hostile conditions.

“I don’t think it’s a coincidence that, for example, glioblastoma – an aggressive brain tumour – is one of the most hypoxic tumour types and also incredibly resistant to treatments,” he reasons. “Given that hypoxic cells are some of the most drug-resistant cells within a tumour, by targeting them, we can directly alleviate resistance.” And because the rest of the body has a normal oxygen supply, going after just the hypoxic cancer cells means patients should experience fewer negative side effects. “Thinking about long-term therapy and a person’s quality of life, that’s a huge bonus,” he adds.

Earlier this year, Professor Tennant’s team landed on a promising drug target. By feeding hypoxic cells nutrients such as sugars and watching how they use them compared to cancer cells with normal oxygen levels, they identified an enzyme that plays a critical role in hypoxic cells. When they removed the enzyme from cancer cells in mice, it caused the hypoxic tumour cells to die.

Despite this focus on the most fundamental elements of biology, Professor Tennant and his team are making steady progress toward the clinic – not least because just 50 metres away, Cancer Research UK neurosurgeon Professor Colin Watts is collecting tissue samples from volunteer patients and passing them to the team so they can check their lab-based models against the real thing. The data generated on each side quickens the pace of progress. As Professor Tennant explains, “Now, when we take our discovery science and try to translate it into new therapies, it has a better chance of working.”

Unintended consequences

It’s an attitude shared by Professor Stephen Tait at the Cancer Research UK Beatson Institute in Glasgow, who’s also eager to use our vast clinical network to translate lab discoveries swiftly. He and his team are examining what happens when treatments do their job well but cause harmful unintended consequences. They found that when chemotherapy successfully kills a cancer cell, the dying cell can emit a protein that acts as a protector to neighbouring cancer cells, shrouding them from chemotherapy and allowing them to emerge unscathed. Professor Tait now hopes to test this by combining chemotherapy with a drug to inhibit this protein.

It’s promising work, but perhaps more exciting is some of the team’s earlier research, which is now flying towards the clinic thanks to an alliance set up by Cancer Research UK. It’s based on their discovery that by blocking a class of proteins called caspases before a cancer cell is killed, the dying cell releases signals to the immune system. In normal circumstances, the immune system ignores cell death – if it didn’t, it would constantly be responding to the billions of cells that die within us each day. But with the immune system alerted, any leftover cancer cells can be ambushed and killed. Professor Tait is modest about the discovery: “Like a lot of things in research, if you just stay alert, you see exciting stuff going on,” he says. But their findings could lead to a new class of treatments that combine the strength of chemotherapy with the body’s perceptive immune response.

Over the edge

Back in Birmingham, Cancer Research UK cell biologist Dr Clare Davies is also making clinically relevant fundamental discoveries. She’s studying breast cancer stem cells, which initiate breast tumours. “These cells are inherently chemo-resistant because they can repair the DNA damage that chemotherapy induces,” she explains. They manage to do this because they have enhanced genes and mechanisms that control DNA repair pathways. These cells also multiply slower than other cancer cells, and because chemotherapy actively targets rapidly dividing cells, they face less bombardment.

“We often think that science is a slow burn, but this shows it can really fly when people invest the time and money” – Dr Clare Davies

Developing drugs that specifically target the pathways enhanced in cancer stem cells would provide a new way to tackle chemo-resistant breast cancer. And Dr Davies and her team have identified an enzyme that they believe helps keep cancer stem cells alive by increasing these pathways. “If we can inhibit this enzyme while also delivering chemotherapy, we can block the repair mechanisms and push the cancer stem cell over the edge,” she explains, suggesting that we could cut cancer recurrence off at the source. “Cancer is clever. It evolves,” she says. “We must understand the mechanisms underlying this evolution by studying cancer stem cells.”

Dr Davies is now working with a pharmaceutical company to progress this work to patients through a clinical trial. “We often think that science is a slow burn, but this shows it can really fly when people invest the time and money.”

One step aheadFour researcher images: Dr Sheeba Irshad, Professor Dan Tennant, Professor Stephen Tait, Dr Clare Davies

While these steps forward are cause for enthusiasm, they must also be met by innovation and resource in the clinic. That’s why Dr Irshad is leading a clinical trial platform named PHOENIX, which aims to accelerate the drug development pipeline for hard-to-treat breast cancers. Biopsies taken before and after treatment help the team understand the chemo-resistant disease in each individual patient and monitor the efficacy of specific drugs. “These short-term efficacy trials allow us to design better trials with a higher likelihood of success,” Dr Irshad explains.

It’s then that the progress made in breast cancer survival really begins to count. “We’re lucky in breast cancer care that if secondary cancer is likely, we do have options for our patients,” she adds. “We can be proactive – and that really matters.”

With so many advances in drug discovery over the past few decades – from improving chemotherapy and radiotherapy, to delivering targeted treatments and immunotherapies – drug resistance deals a cruel blow. Only by bridging the biomedical and clinical worlds, and working in partnership with health systems and philanthropic partners, can we create the infrastructure and funding required to support our researchers and clinicians as they strive to remain one step ahead – and ensure people like Tina aren’t left in limbo, waiting to be told whether their cancer has returned.

Researcher images from top to bottom: Dr Sheeba Irshad, Professor Dan Tennant, Professor Stephen Tait, Dr Clare Davies

Tina’s story

I found out I had breast cancer on Wednesday 13 January, 2021. I remember the day well.

When I was told that my treatment hadn’t been entirely successful, I initially felt very upset. I’d had a difficult time through chemo, needing multiple blood transfusions and experiencing multiple delays in treatment due to low blood counts. To then be told that there seemed to be residual disease due to chemo resistance was very hard to hear.

From the outset, my hospital team have been fantastic. The oncologists always had a positive approach. As a mother of young children, I felt that this was essential. And when Dr Irshad told me that I would be entered into the trial, I felt hopeful and grateful that it was possible.

It’s incredibly important that researchers like Dr Irshad continue vital research in this area. I never thought I would get breast cancer. I have become friends with a lot of women with breast cancer since my diagnosis. We’re all so different. I would give anything to know what caused it. I’m hoping that, with research, not only will we find treatments but also causes. I have a daughter and would not want her to go through what I have been through. Currently, I’m doing really well. I have returned to work fully and lead a normal life. Lots of good things have happened as a result of my diagnosis. I’ve realised how many people care for me and my family and I now lead a healthier lifestyle.

*Name has been changed at the request of the contributor.

We’re tremendously grateful for funding we’ve received from supporters including Gonzalo and Maria García, Garfield Weston Foundation, Denise Leffman Trust and Mike Jackson, which has helped facilitate the work featured in this article.

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