A recent population-based study indicates that among children with cancer, those with obesity at the time of diagnosis may face an elevated risk of dying. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
The retrospective study was based on information from the Cancer in Young People in Canada (CYP-C) database, including all children with newly diagnosed cancer aged 2 to 18 years across Canada from 2001 to 2020. Obesity was defined as age and sex-adjusted body mass index at or above the 95th percentile.
Among 11 291 children with cancer, 10.5% were obese at the time of diagnosis. Investigators assessed 5-year event-free survival (survival free of cancer relapse), as well as overall survival.
Compared with patients without obesity at the time of initial cancer diagnosis, those with obesity had lower rates of 5-year event-free survival (77.5% versus 79.6%) and overall survival (83.0% versus 85.9%).
After adjusting for factors including age, sex, ethnicity, neighbourhood income quintile, treatment era, and cancer categories, obesity at diagnosis was linked with a 16% increase in the risk of relapse and a 29% increase in the risk of death. The negative impact of obesity on prognosis was especially pronounced in patients with acute lymphoblastic leukaemia and brain tumours.
“Our study highlights the negative impact of obesity among all types of childhood cancers. It provides the rationale to evaluate different strategies to mitigate the adverse risk of obesity on cancer outcomes in future trials,” said co–senior author Thai Hoa Tran, MD, of the Centre Hospitalier Universitaire Sainte-Justine, in Montreal. “It also reinforces the urgent need to reduce the epidemic of childhood obesity as it can result in significant health consequences.”
Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0
A recent double-blinded, peer-reviewed analysis published in Cancer Letters revealed that an experimental test for pancreatic cancer correctly identified 71% of lab samples compared to only 44% correctly identified by the current gold-standard test.
An experimental blood test for pancreatic cancer that was developed by teams led by VAI Professor Brian Haab, PhD, and Randall E. Brand, MD, a physician-scientist and professor of medicine at the University of Pittsburgh, created the test. This evaluation by a commercial laboratory is an important milestone toward making the test available for patients.
Before the new test can be used by doctors to diagnose cancer, it must undergo clinical validation. During this process, a CLIA-accredited diagnostics laboratory adapts the experimental test into a version that reliably works under the strict conditions in a clinical lab. CLIA is a rigorous federal standard that ensures lab quality.
“Validation studies are essential for transforming a test developed in an academic lab into one that is used to diagnose real people,” Haab said. “For a person being evaluated for pancreatic cancer, the stakes are high. Validation studies ensure that new tests work as intended.”
The new test works by detecting two sugars — CA199.STRA and CA19-9 — that are produced by pancreatic cancer cells and escape into the bloodstream. CA19-9 is the current gold-standard biomarker for pancreatic cancer. Haab’s lab identified CA199.STRA as a cancer biomarker and developed the technology to detect it.
The new test also greatly reduced the number of false negatives while maintaining a low false positive rate, according to the recent analysis. Low rates of false positives and false negatives are important because they reflect the test’s ability to correctly identify the presence or absence of cancer.
Clinical validation of the test will be conducted by ReligenDx, a CLIA-accredited diagnostics lab based in Pennsylvania. The process is expected to take two years.
If successful in clinical validation, Haab envisions the test being used in two main ways: 1. Catching pancreatic cancer more quickly in people at high risk of the disease, which would enable earlier treatment and 2. Monitoring progression and treatment response in people diagnosed with pancreatic cancer.
These images show slices of mouse liver under the microscope, with tumours outlined in yellow and green indicating the expression of different proteins within cells. The left column is a control group. In the centre column, the protein detected (TBG-Cre) is expressed in all liver cells, so the entire image appears green. In the right column, the protein detected (p21-Cre) is only expressed in senescent liver cells. Because green is only visible within the tumour area, the results show that liver tumours originate from previously senescent liver cells. Photo credit: UC San Diego Health Sciences
A new study on the development of liver cancer reveals a complex interplay between cellular metabolism and DNA damage that drives the progression of fatty liver disease to cancer. The findings, published in Nature, suggest new paths forward for preventing and treating liver cancer and have significant implications on our understanding of cancer’s origin and the effects of diet on our DNA.
The incidence of the most common form of liver cancer, hepatocellular carcinoma (HCC), has grown by 25-30% in the past two decades, with much of the growth attributed to the dramatic rise in fatty liver disease. About 20% of individuals with fatty liver disease have a severe form of the disease, called metabolic dysfunction-associated steatohepatitis (MASH), that greatly increases the risk of HCC. However, how MASH transitions to liver cancer is not well understood.
“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” said Michael Karin, PhD, Distinguished Professor in the Department of Pharmacology at UC San Diego School of Medicine. MASH ends up destroying the liver, or leading to often-fatal liver cancer, but little is know of the process at the subcellular level.
The researchers used a combination of mouse models and human tissue specimens and databases to demonstrate that MASH-inducing diets, which are rich in fat and sugar, cause DNA damage in liver cells that causes them to go into senescence, a state in which cells are still alive and metabolically active but can no longer divide. Senescence is a normal response to a variety of cellular stressors. In a perfect world, senescence gives the body time to repair damage or eliminate the damaged cells before they’re allowed to proliferate more widely and become cancerous.
“A poor, fast-food diet can be as dangerous as cigarette smoking in the long run. People need to understand that bad diets do far more than just alter a person’s cosmetic appearance. They can fundamentally change how our cells function, right down to their DNA.”
Michael Karin, PhD
However, as the researchers discovered, this isn’t what happens in liver cells, also known as hepatocytes. In hepatocytes, some damaged cells survive this process.
These cells are, according to Karin, “like ticking time bombs that could start proliferating again at any point and ultimately become cancerous.”
“Comprehensive genomic analyses of tumour DNA indicate that they originate from liver cells damaged by MASH, emphasising a direct link between diet-induced DNA damage and the development of cancer,” added study co-author Ludmil Alexandrov, PhD, associate professor of cellular and molecular medicine and bioengineering at UC San Diego and member of UC San Diego Moores Cancer Center.
The findings suggest that developing new drugs to prevent or reverse DNA damage could be a promising therapeutic approach for preventing liver cancer, particularly in people with MASH.
“There are a few possibilities for how this could be leveraged into a future treatment, but it will take more time and research to explore these ideas,” said Karin. “One hypothesis is that a high-fat diet could lead to an imbalance in the raw materials our cells use to build and repair DNA, and that we could use drugs or nutri-chemicals to correct these imbalances. Another idea is developing new antioxidants, much more efficient and specific than the ones we have now, and using those could help block or reverse the cellular stress that causes DNA damage in the first place.”
In addition to opening these new avenues of treatment for liver cancer, the study also offers new insight into the relationship between aging and cancer.
“We know that aging increases the risk of virtually all cancers and that aging is associated with cellular senescence, but this introduces a paradox since senescence is supposed to guard against cancer,” said Karin. “This study helps reveal the underlying molecular biology that allows cells to re-enter the cell cycle after undergoing senescence, and we believe that similar mechanisms could be acting in a wide range of cancers.”
The findings also help directly quantify the detrimental effects of poor diet on cellular metabolism which, according to Karin, could be used to help guide public health messaging related to fatty liver disease.
“A poor, fast-food diet can be as dangerous as cigarette smoking in the long run,” said Karin. “People need to understand that bad diets do far more than just alter a person’s cosmetic appearance. They can fundamentally change how our cells function, right down to their DNA.”
Cancer immunotherapy is known to also make patients more vulnerable to heart attack and stroke. A new study led by researchers at NYU Langone Health points to a possible explanation for this side effect: the treatment interferes with immune regulation in the heart’s largest blood vessels.
This new work focused on immune checkpoint inhibitors, which work by blocking molecules embedded on the surface of cells – immune checkpoints – which normally serve as “brakes” that prevent excess immune activity, or inflammation. Some tumours are known to hijack these checkpoints to weaken the body’s defences, so by blocking the checkpoints, the treatments enable the immune system to kill tumour cells.
Unfortunately, this treatment type may also trigger damaging levels of inflammation in the heart, brain, stomach, and other organs, the researchers say. For example, past studies have shown that about 10% of those with atherosclerosis have a heart attack or stroke following cancer treatment. Until now, the specific mechanisms behind this issue had remained unclear.
To address this question, the research team explored at a cellular level how immune checkpoint inhibitors interact with immune cells within arterial plaques. A genetic analysis by the study authors showed that the same type of immune checkpoints targeted by cancer therapies also appear in arterial immune cells, establishing a link between checkpoint inhibitors and cardiovascular events.
“Our findings provide new insight into how a drug intended to target tumours can also prompt a heightened immune response in arteries and increase risk of heart disease,” said study co-senior author Chiara Giannarelli, MD, PhD. “Cancer patients and their physicians should be aware that they may need to monitor for new heart concerns following cancer treatment,” added Dr Giannarelli.
For the current study, published in Nature Cardiovascular Research, the researchers analysed the genetic activity of thousands of immune cells collected from the plaques of 50 men and women undergoing a surgical procedure to address atherosclerosis.
The investigators also explored how type 2 diabetes, a known risk factor for both cancer and heart disease, may make those with atherosclerosis even more vulnerable to the ill effects of checkpoint inhibitors, adds Dr Giannarelli, also an associate professor in the Department of Pathology at NYU Grossman School of Medicine. As part of the study, the team assessed immune checkpoint activity in arterial tissue collected from eight patients with diabetes and four healthy volunteers. Notably, none had a history of atherosclerosis. The results showed that the diabetes patients had less measurable communication between checkpoints, which in turn can prompt increased inflammation.
Other experiments further revealed that taking immune checkpoint inhibitors might make it harder to combat atherosclerosis. Under normal circumstances, physicians typically prescribe low-fat diets to reduce plaque buildup and inflammation. Indeed, the researchers’ experiments in rodents confirmed that such diets boost communication between immune checkpoints within arteries. However, cancer patients may be at a disadvantage because their therapy, by blocking these same checkpoints, may counteract the anti-inflammatory benefits of fat reduction.
“Our findings highlight how cancer, diabetes, and heart disease do not exist in a vacuum, and that it is critical to consider how targeting one of these conditions can affect the others,” said study co-senior author Kathryn J. Moore, PhD. “Now that experts have a better understanding of the interplay between these diseases, they can begin to explore new strategies to lower the risk of unintended health concerns caused by their treatment,” added Dr Moore. She cautions that the study did not directly assess immune checkpoint behaviour in cancer patients. The team plans to do so in future investigations, she adds.
Researchers from POSTECH and Kyungpook National University have developed a novel inhalable therapeutic delivery system for lung cancer, making use of mucoadhesive protein nanoparticles inspired the adhesive properties of marine mussels.
Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancer cases and treatment is particularly challenging due to difficulties in early detection. Current anticancer treatments are predominantly administered intravenously, impacting both malignant and healthy tissues, often leading to severe adverse effects. As a result, inhalable therapeutics have emerged as a promising alternative, enabling localised drug delivery directly to the lungs. A major obstacle to this approach is the lung’s mucosal barriers and immune cells. Building on this context, collaborative research has culminated in the development of a mucoadhesive protein nanoparticle designed for lung cancer treatment.
This approach leverages the remarkable adhesive properties of marine mussel proteins, renowned for their underwater adhesion. Drawing inspiration from the oxidation-reduction mechanisms of foot protein type 6 (fp-6), the researchers engineered foot protein type 1 (fp-1) by integrating cysteine, creating a biomaterial with enhanced adhesive strength and precise drug delivery capabilities within the lung cancer microenvironment. These nanoparticles exhibit exceptional therapeutic efficacy by enabling selective payload release while effectively inhibiting release in healthy tissues to minimise adverse effects. Moreover, the intrinsic biocompatibility, biodegradability, and immunocompatibility of marine mussel proteins ensure superior biological safety and substantially prolong the retention of anticancer drugs, thereby amplifying their therapeutic impact.
In animal models of lung cancer, the nanoparticles developed by the research team and their contained anti-cancer drugs showed effectiveness in inhibiting cancer cell metastasis and invasion after being delivered to the lungs through a nebuliser and adhering to the mucosa for extended periods. This advancement holds the potential to enhance patient access to lung cancer treatment, as the simplified inhalation-based drug administration could be self-managed at home. Furthermore, this approach may significantly improve patients’ quality of life by reducing the need for hospital visits.
Professor Hyung Joon Cha, who spearheaded the collaborative research at POSTECH, stated, “The findings from our study have the potential to substantially enhance both the precision and efficacy of lung cancer treatments, while significantly improving patients’ quality of life.”
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
Researchers at the National University of Singapore (NUS) have developed a non-invasive method to improve the effectiveness of chemotherapy while reducing its harmful side effects.
By applying brief, localised pulses of magnetic fields, the team demonstrated a significant increase in the uptake of doxorubicin (DOX), a widely used chemotherapy drug, into breast cancer cells, with minimal impact on healthy tissues. This selective uptake enables more precise targeting of cancer cells, potentially improving treatment outcomes and reducing the adverse effects often associated with chemotherapy.
The study, led by Associate Professor Alfredo Franco-Obregón at NUS, is the first to systematically show how pulsed magnetic fields enhance DOX uptake in cancer cells. The team also showed that this approach could suppress tumours at lower drug doses.
The team’s research was published in the journal Cancers. It builds on earlier work from 2022, which first revealed that certain cancer cells are more vulnerable to magnetic field therapy.
Better chemotherapy outcomes and fewer side effects
DOX is a commonly used chemotherapy drug for breast cancer. It works by binding to DNA components and disrupting cell replication and respiration, which then kills off cancer cells. Despite its efficacy, it is a non-selective drug, which means it can also damage healthy tissues, leading to side effects ranging from mild to severe, including cardiomyopathy and muscle atrophy.
To address these challenges, the NUS researchers developed a novel approach that uses brief pulses of magnetic fields to selectively increase DOX uptake into breast cancer cells. Their study revealed the role of a calcium ion channel known as TRPC1, which is often found in aggressive cancers, including breast cancer. Magnetic field exposure activates TRPC1, enhancing its ability to facilitate the entry of DOX into cancer cells.
The researchers conducted experiments comparing the effects of the magnetic field therapy on human breast cancer cells and healthy muscle cells. They found that breast cancer cells took in significantly more DOX when exposed to magnetic pulses, while normal tissues were not targeted as much. A 10-minute magnetic field exposure reduced the drug concentration needed for similar amount of cancer killing by half, particularly at low doses of the drug.
In contrast, healthy muscle cells did not show an increase in cell death in response to the combination of DOX and magnetic pulses indicating greater protection for non-cancerous tissues.
The team also demonstrated that reducing TRPC1 expression or blocking its activity eliminated this effect, which confirms the crucial role of TRPC1 channels in the process. “Importantly, when we increased the amount of TRPC1, we observed an increase in DOX uptake – this means that TRPC1 can be used as a viable therapeutic target for aggressive cancers,” said first author Mr Viresh Krishnan Sukumar, PhD candidate at NUS Centre for Cancer Research (N2CR).
“What’s promising is that this mechanism works strongest at low drug concentrations, enabling us to target cancer cells more effectively while reducing the burden of chemotherapy on healthy tissues,” Assoc Prof Franco-Obregón added.
With breast cancer remaining the leading cause of cancer-related deaths among women worldwide, the need for novel treatment strategies is urgent. “The majority of women who undergo chemotherapy experience side effects from treatment, and in some cases, doses of chemotherapy need to be reduced, or in severe cases, stopped prematurely,” said Assistant Professor Joline Lim, Principal Investigator at N2CR and Senior Consultant, Department of Haematology-Oncology, National University Cancer Institute, Singapore. “Moreover, prolonged exposure to high-dose chemotherapy can also lead to drug resistance. This targeted approach represents an excellent opportunity to potentially improve treatment outcomes while preserving patients’ quality of life.”
Advancing the frontier of precision oncology
The team’s magnetic-assisted approach addresses one of the biggest challenges of chemotherapy, namely its toxic effects on healthy tissues. By selectively enhancing drug uptake into cancer cells, this method has the potential to drastically reduce the systemic side effects often experienced by breast cancer patients. This not only improves treatment outcomes and quality of life, but also encourages earlier treatment for those hesitant about treatment side effects. The study also underscores the role of biomarkers, such as elevated TRPC1 expression, in transforming cancer care by enabling precision-driven treatment options.
Future work will focus on translating these findings into clinical practice by localising magnetic field exposure specifically to tumours in patients. This would further validate the potential to reduce systemic DOX doses while maximising localised drug delivery in cancer cells.
“Our approach will be patented and form the foundation for a startup specialising in breast cancer treatment. We are currently in discussions with potential investors in Southeast Asia and the United States to translate this technology from bench to bedside,” shared Assoc Prof Franco-Obregón. National University Cancer Institute, Singapore. “Moreover, prolonged exposure to high-dose chemotherapy can also lead to drug resistance. This targeted approach represents an excellent opportunity to potentially improve treatment outcomes while preserving patients’ quality of life.”
When it comes to cancer, aging is a double-edged sword, researchers are increasingly learning. Age is considered the most important risk factor for cancer, due to the buildup of genetic mutations over time.
Now a study from researchers at Memorial Sloan Kettering Cancer Center (MSK) and their collaborators provides new evidence about how advanced age can also be protective against cancer. The study, conducted in a mouse model of lung cancer, was published in Nature.
“We know that as people get older, they’re more likely to get cancer,” says study first author Xueqian Zhuang, PhD, postdoc in the lab of senior study author Tuomas Tammela, PhD. “But there’s still a lot that’s unknown about how aging actually changes the biology of cancer.”
As with many types of cancer, lung cancer is diagnosed in most people around age 70, Dr Zhuang says. But once you get to 80 or 85, the incidence rate starts to come down again.
“Our research helps show why,” she adds. “Aging cells lose their capacity for renewal and therefore for the runaway growth that happens in cancer.”
Overall, the findings have two key implications, the researchers say:
First, they point to the underappreciated role that iron plays in aging cells’ ability to regenerate — suggesting that therapies that target iron metabolism may work better in younger people than older ones.
Second, they underline the potential value of early intervention and prevention efforts, targeting the window when most cancers initiate.
Cells’ regeneration ability linked to iron metabolism
To investigate why cancer incidence peaks in the early senior years and then starts to decline again, the MSK research team studied a genetically modified mouse model of lung adenocarcinoma, a common type of lung cancer that accounts for about 7% of all cancer deaths worldwide.
One of the things that makes it challenging to study aging in laboratory models is that mice take two years to develop to an age that’s equivalent to 65–70 years in people. The scientists found that as the mice get older, they make more of a protein called NUPR1. More NUPR1 makes the cells in the lungs function as if they are iron deficient.
“The aging cells actually have more iron, but for reasons we don’t yet fully understand, they function like they don’t have enough,” Dr Zhuang says.
Since the cells in the older mice functioned as though they didn’t have enough iron, they lost some of their ability to regenerate. And because that regenerative capacity is directly linked to the rise of cancer, the older mice developed far fewer tumours than their younger counterparts.
Intriguingly, this effect could be reversed by giving the older mice additional iron or by reducing the amount of NUPR1 in their cells.
“We think this discovery may have some immediate potential to help people,” Dr. Tammela says. “Right now, millions of people, especially following the COVID-19 pandemic, live with insufficient lung function because their lungs didn’t fully heal from an infection, or for some other reason. Our experiments in mice showed that giving iron can help the lungs regenerate, and we have really good ways of delivering drugs directly to the lungs – like asthma inhalers.”
But this is also where the double-edged nature of the discovery comes into play. By restoring the ability of the cells in the lungs to regenerate, one is also increasing the tissue’s ability to develop cancer, the study showed.
“So this type of approach might not be appropriate for people who are at a high risk of developing cancer,” he adds.
Older and younger patients may respond differently to iron-metabolism targeting treatments
The team’s findings also have important implications for therapies based on a type of cell death called ferroptosis, which is triggered by iron. Ferroptosis was discovered in 2012, and there are a number of ferroptosis-inducing small molecule compounds, as well as drugs previously approved by the FDA, that are being investigated for their potential to kill cancer cells.
Older cells are far more resistant to ferroptosis than younger cells because they function as if they don’t have enough iron, the researchers found. This means treatments that target ferroptosis may not be as effective in older patients as they are in younger ones.
“One of the things that we showed exploring all of this iron biology is that ferroptosis is tumour suppressive, as everybody suspected – but much more profoundly in younger animals,” Dr Tammela says.
Dr Zhuang adds: “To us, this says that because the biology of cells changes with aging, the sensitivity to drugs also changes. So doctors might need to really be careful in clinical trials, for example, to look at the effects in both older and younger patients.”
And for Dr Tammela, the research ultimately has an even bigger takeaway.
“What our data suggests in terms of cancer prevention is that the events that occur when we’re young are probably much more dangerous than the events that occur later,” he says. “So, preventing young people from smoking, or from tanning, or from other obvious carcinogenic exposures are probably even more important than we thought.”
A new study describes an innovative method of analysing mammograms that significantly improves the accuracy of predicting the risk of breast cancer development over the following five years. Using up to three years of previous mammograms, the new method identified individuals at high risk of developing breast cancer 2.3 times more accurately than the standard method, which is based on questionnaires assessing clinical risk factors alone, such as age, race and family history of breast cancer.
“We are seeking ways to improve early detection, since that increases the chances of successful treatment,” said senior author Graham A. Colditz, MD, DrPH, associate director, prevention and control, of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. “This improved prediction of risk also may help research surrounding prevention, so that we can find better ways for women who fall into the high-risk category to lower their five-year risk of developing breast cancer.”
This risk-prediction method builds on past research led by Colditz and lead author Shu (Joy) Jiang, PhD, a statistician, data scientist and associate professor at WashU Medicine. The researchers showed that prior mammograms hold a wealth of information on early signs of breast cancer development that can’t be perceived even by a well-trained human eye. This information includes subtle changes over time in breast density, which is a measure of the relative amounts of fibrous versus fatty tissue in the breasts.
For the new study, the team built an algorithm based on artificial intelligence that can discern subtle differences in mammograms and help identify those women at highest risk of developing a new breast tumour over a specific timeframe. In addition to breast density, their machine-learning tool considers changes in other patterns in the images, including in texture, calcification and asymmetry within the breasts.
“Our new method is able to detect subtle changes over time in repeated mammogram images that are not visible to the eye,” said Jiang, yet these changes hold rich information that can help identify high-risk individuals.
At the moment, risk-reduction options are limited and can include drugs such as tamoxifen that lower risk but may have unwanted side effects. Most of the time, women at high risk are offered more frequent screening or the option of adding another imaging method, such as an MRI, to try to identify cancer as early as possible.
“Today, we don’t have a way to know who is likely to develop breast cancer in the future based on their mammogram images,” said co-author Debbie L. Bennett, MD, an associate professor of radiology and chief of breast imaging for the Mallinckrodt Institute of Radiology at WashU Medicine. “What’s so exciting about this research is that it indicates that it is possible to glean this information from current and prior mammograms using this algorithm. The prediction is never going to be perfect, but this study suggests the new algorithm is much better than our current methods.”
AI improves prediction of breast cancer development
The researchers trained their machine-learning algorithm on the mammograms of more than 10 000 women who received breast cancer screenings through Siteman Cancer Center from 2008–2012. These individuals were followed through 2020, and in that time 478 were diagnosed with breast cancer.
The researchers then applied their method to predict breast cancer risk in a separate set of 18 000 women who received mammograms from 2013–2020. Subsequently, 332 women were diagnosed with breast cancer during the follow-up period, which ended in 2020.
According to the new prediction model, women in the high-risk group were 21 times more likely to be diagnosed with breast cancer over the following five years than were those in the lowest-risk group. In the high-risk group, 53 out of every 1000 women screened developed breast cancer over the next five years. In contrast, in the low-risk group, 2.6 women per 1000 screened developed breast cancer over the following five years. Under the old questionnaire-based methods, only 23 women per 1000 screened were correctly classified in the high-risk group, providing evidence that the old method, in this case, missed 30 breast cancer cases that the new method found.
The mammograms were conducted at academic medical centres and community clinics, demonstrating that the accuracy of the method holds up in diverse settings. Importantly, the algorithm was built with robust representation of Black women, who are usually underrepresented in development of breast cancer risk models. The accuracy for predicting risk held up across racial groups. Of the women screened through Siteman, most were white, and 27% were Black. Of those screened through Emory, 42% were Black.
Treatment for more advanced and difficult-to-treat head and neck cancers can be improved with the addition of polyvinyl alcohol (PVA), the same ingredient used in children’s glue. Researchers found that combining PVA with a boron-containing compound, D-BPA, improved the effects of a type of radiation therapy for cancer, compared to currently clinically used drugs. The PVA made the drug more selective of tumour cells and prolonged drug retention, helping to spare healthy cells from unnecessary radiation damage.
Japan became the first country to approve boron neutron capture therapy (BNCT), a type of targeted radiotherapy for cancer, in 2020. Doctors administer a boron-containing drug to patients, which is designed to selectively accumulate in tumour cells. The patients are then exposed to low-energy neutrons, which react with the boron, destroying cancer cells without damaging healthy cells.
The advantages of BNCT are that it targets only boron-containing cells, meaning that damage to healthy cells is less compared to some other treatments. It has also been found to be effective against some more challenging and recurring cancers. However, because low-energy neutrons are quite weak, their use is limited to certain areas of the body. Currently, they are approved for head and neck cancers, which are nearer the surface. Their effectiveness also depends on both the level and retention of boron within tumour cells for the duration of the treatment.
In newly published research, special research student Kakeru Konarita and Associate Professor Takahiro Nomoto from the University of Tokyo found that adding PVA to the boron-containing compound greatly improved both its accumulation and retention in cancer cells.
“We discovered that PVA, which is used in liquid glue, dramatically improves the efficacy of a compound called D-BPA, that until now has been removed from drug ingredients because it was considered useless,” explained Nomoto.
Neither PVA nor D-BPA exhibit pharmacological activity when administered alone. However, combining these compounds resulted in remarkably elevated tumour accumulation, prolonged retention and potent therapeutic efficacy, even when compared with a clinically used drug.”
Currently, the chemical substance L-BPA is the only approved boron compound for BNCT. It accumulates well within cancer cells, but, depending on the location of the cancer, can also enter some healthy cells. This makes it unsuitable for treating certain tumours. D-BPA is the enantiomer of L-BPA, meaning that its molecular structure is the mirror image of L-BPA but it is otherwise chemically identical. D-BPA appealed to the researchers because it appears to be more selective of cancer cells. However, on its own it doesn’t accumulate, which is why it was considered useless.
The team previously found that mixing PVA with L-BPA improved its effectiveness. In this latest research, they combined PVA with D-BPA and were surprised to see even higher levels of boron accumulating and more prolonged retention.
“There are many demands in the development of drugs for cancer treatment and much recent research and development has focused on complex combinations of expensive molecules,” said Nomoto. “However, we are concerned that such methods, when put into practice, will be so expensive that only a limited number of patients will benefit. In this study, we aimed to develop a drug with a simple structure and high functionality at a low cost.”
Now the team is promoting joint industry-academia collaboration to further this research and hope to apply this achievement to the treatment of other challenging cancers.
A new study has shed light on a previously poorly understood aspect of breast cancer recurrence: how cancer cells survive in bone marrow despite targeted therapies. The paper appears in the Journal of Clinical Investigation.
Oestrogen receptor positive (OR+) breast cancer is the most common form of the disease, and cancer cells of this kind can live for years in bone marrow after remission. The persistence of these cells in marrow leads to the disease recurring about 40% of patients. This return can take the form of especially aggressive bone cancer with symptoms such as bone fractures and hypercalcaemia.
The cells can also spread to other organs, causing recurrent disease that is currently incurable.
To better understand how these cancer cells survive, and why they cause such aggressive returning disease, researchers investigated what happens to these dispersed cells in bone marrow.
Their key finding was the mechanism by which a normal cell type, mesenchymal stem cells, in the bone marrow supports the cancer cells.
“We discovered that the breast cancer cells require direct contact with mesenchymal stem cells,” said Gary Luker, MD, senior author on the paper.
“The cancer cells physically borrow molecules – proteins, messenger RNA – directly from the mesenchymal stem cells. Essentially the mesenchymal stem cells act as very generous neighbours in donating things that make the cancer cells more aggressive and drug resistant.”
In laboratory experiments, contact between cancer cells and mesenchymal stem cells induced changes in hundreds of proteins. Further analysis of which proteins allowed for survival of breast cancer cells led researchers to focus on GIV, also known as Girdin. The paper notes that GIV drives “invasiveness, chemoresistance, and acquisition of metastatic potential in multiple cancers.”
GIV makes these cancer cells specifically resistant to oestrogen-targeted therapies, such as the drug Tamoxifen. The researchers hope this understanding of the mechanism of cancer cell survival will one day lead to treatments that prevent OR+ breast cancers from returning.
Sleeper cells can awaken
“Sleeper cells can be reawakened and cause oestrogen receptor positive breast cancers to relapse years –in some cases as long as a decade – after patients were believed to be in remission,” said study author Pradipta Ghosh, M.D., a professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine.
“Since these cancer cells ‘borrow’ essential proteins from stem cells in the bone marrow through cellular tunnels – much like smuggling – approaches for targeting the tunnels or proteins they smuggle could help prevent the relapse and metastasis of oestrogen receptor positive breast cancer.”
