{"id":28081,"date":"2022-05-25T08:00:29","date_gmt":"2022-05-25T08:00:29","guid":{"rendered":"https:\/\/news.cancerresearchuk.org\/?p=24321"},"modified":"2024-11-03T15:13:38","modified_gmt":"2024-11-03T15:13:38","slug":"the-path-to-least-resistance-how-our-researchers-are-outsmarting-cancers-survival-skills","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/the-path-to-least-resistance-how-our-researchers-are-outsmarting-cancers-survival-skills\/","title":{"rendered":"The path to least resistance: How our researchers are outsmarting cancer\u2019s survival skills"},"content":{"rendered":"
\"BreastBreast cancer cells Credit: NCI<\/p>

” data-medium-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/05\/Untitled-620-x-348-px-300×168.jpg” data-large-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/05\/Untitled-620-x-348-px.jpg”><\/p>

Breast cancer cells Credit: NCI<\/p><\/div>

Drug resistance is one of biomedicine\u2019s biggest threats, standing in the way of cures for all manner of viruses, infections and diseases, including cancer. But our scientists across the country are working hard to tackle it.<\/em><\/strong><\/p>

After a shock breast cancer diagnosis in January 2021 at the age of 48, doctor and mother Tina* underwent six months of chemotherapy, which for many people with early-diagnosed breast cancer can be curative. But a test following treatment confirmed the presence of residual cancer cells. Cells that had somehow survived the treatment onslaught. Cells that indicate the cancer could return. \u201cWhen I was told that my treatment hadn\u2019t been entirely successful, I initially felt very upset,\u201d Tina recalls. \u201cI\u2019d 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.\u201d<\/p>

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\u201cTo be told after treatment that there seemed to be residual disease due to chemo resistance was very hard to hear\u201d \u2013 Tina, breast cancer patient<\/strong><\/cite><\/p>\n<\/blockquote>\n

Despite the huge progress we\u2019ve made in breast cancer survival \u2013 which has doubled in the UK over the past 40 years \u2013 Tina\u2019s is a reality for many women with triple negative breast cancer, a subtype that can be harder to treat. \u201cFor these women, when cancer does recur it\u2019s more difficult to get on top of,\u201d 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\u2019re harder to eradicate.<\/p>\n

Cause and effect<\/h2>\n

\u201cDrug resistance is a major reason why cancer regrows after treatment, so it\u2019s also a significant contributor to people not surviving their disease,\u201d confirms Professor Dan Tennant, a Cancer Research UK biochemist at the University of Birmingham. He\u2019s setting his sights on hypoxia \u2013 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\u2019re forced to adapt, finding compensatory ways to complete fundamental processes. What\u2019s 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\u2019s investigating how cancer cells survive such hostile conditions.<\/p>\n

\u201cI don\u2019t think it\u2019s a coincidence that, for example, glioblastoma \u2013 an aggressive brain tumour \u2013 is one of the most hypoxic tumour types and also incredibly resistant to treatments,\u201d he reasons. \u201cGiven that hypoxic cells are some of the most drug-resistant cells within a tumour, by targeting them, we can directly alleviate resistance.\u201d 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. \u201cThinking about long-term therapy and a person\u2019s quality of life, that\u2019s a huge bonus,\u201d he adds.<\/p>\n

Earlier this year, Professor Tennant\u2019s 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.<\/p>\n

Despite this focus on the most fundamental elements of biology, Professor Tennant and his team are making steady progress toward the clinic \u2013 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, \u201cNow, when we take our discovery science and try to translate it into new therapies, it has a better chance of working.\u201d<\/p>\n

Unintended consequences<\/h2>\n

It\u2019s an attitude shared by Professor Stephen Tait at the Cancer Research UK Beatson Institute in Glasgow, who\u2019s 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.<\/p>\n

It\u2019s promising work, but perhaps more exciting is some of the team\u2019s earlier research, which is now flying towards the clinic thanks to an alliance set up by Cancer Research UK. It\u2019s 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 \u2013 if it didn\u2019t, 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: \u201cLike a lot of things in research, if you just stay alert, you see exciting stuff going on,\u201d he says. But their findings could lead to a new class of treatments that combine the strength of chemotherapy with the body\u2019s perceptive immune response.<\/p>\n

Over the edge<\/h2>\n

Back in Birmingham, Cancer Research UK cell biologist Dr Clare Davies is also making clinically relevant fundamental discoveries. She\u2019s studying breast cancer stem cells, which initiate breast tumours. \u201cThese cells are inherently chemo-resistant because they can repair the DNA damage that chemotherapy induces,\u201d 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.<\/p>\n

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\u201cWe often think that science is a slow burn, but this shows it can really fly when people invest the time and money\u201d \u2013 Dr Clare Davies<\/strong><\/cite><\/p>\n<\/blockquote>\n

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. \u201cIf we can inhibit this enzyme while also delivering chemotherapy, we can block the repair mechanisms and push the cancer stem cell over the edge,\u201d she explains, suggesting that we could cut cancer recurrence off at the source. \u201cCancer is clever. It evolves,\u201d she says. \u201cWe must understand the mechanisms underlying this evolution by studying cancer stem cells.\u201d<\/p>\n

Dr Davies is now working with a pharmaceutical company to progress this work to patients through a clinical trial. \u201cWe often think that science is a slow burn, but this shows it can really fly when people invest the time and money.\u201d<\/p>\n

One step ahead\"Four<\/h2>\n

While these steps forward are cause for enthusiasm, they must also be met by innovation and resource in the clinic. That\u2019s 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. \u201cThese short-term efficacy trials allow us to design better trials with a higher likelihood of success,\u201d Dr Irshad explains.<\/p>\n

It\u2019s then that the progress made in breast cancer survival really begins to count. \u201cWe\u2019re lucky in breast cancer care that if secondary cancer is likely, we do have options for our patients,\u201d she adds. \u201cWe can be proactive \u2013 and that really matters.\u201d<\/p>\n

With so many advances in drug discovery over the past few decades \u2013 from improving chemotherapy and radiotherapy, to delivering targeted treatments and immunotherapies \u2013 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 \u2013 and ensure people like Tina aren\u2019t left in limbo, waiting to be told whether their cancer has returned.<\/p>\n

Researcher images from top to bottom: Dr Sheeba Irshad, Professor Dan Tennant, Professor Stephen Tait, Dr Clare Davies<\/em><\/p>\n

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Tina\u2019s story<\/strong><\/h2>\n

I found out I had breast cancer on Wednesday 13 January, 2021. I remember the day well.<\/p>\n

When I was told that my treatment hadn\u2019t been entirely successful, I initially felt very upset. I\u2019d 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.<\/p>\n

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.<\/p>\n

It\u2019s 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\u2019re all so different. I would give anything to know what caused it. I\u2019m 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\u2019m 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\u2019ve realised how many people care for me and my family and I now lead a healthier lifestyle.<\/p>\n

*Name has been changed at the request of the contributor.<\/em><\/p>\n<\/div>\n

We\u2019re tremendously grateful for funding we\u2019ve received from supporters including Gonzalo and Maria Garc\u00eda, Garfield Weston Foundation, Denise Leffman Trust and Mike Jackson, which has helped facilitate the work featured in this article.<\/strong><\/p>\n

More on this topic<\/h3>\n<\/p>\n

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