Category: Cancer

Categories : CancerTags :

Cells in the Centres of Kidney Tumours are The Most Aggressive

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Researchers have found that cells from different parts of kidney tumours behave differently, and cells within the centre of a tumour are the most aggressive and most likely to spread around the body.

Metastasis, where cancer cells from tumours spread to other parts of the body, is the main cause of death in cancer patients. 

In this multidisciplinary study published in Nature Ecology and Evolution, scientists analysed 756 cancer biopsy samples from different regions within tumours from the TRACERx Renal study.

They discovered that, in contrast to the cells at the outside of tumours, the cells in the centres of tumours have more unstable genomes, and a higher potential for metastasis. The cells on the outside had lower growth rates and had less genetic damage.

“Cancer cells in the central zone of the tumour face harsh environmental conditions, as there’s a lack of blood supply and oxygen. They have to adapt to survive, which makes them stronger and more aggressive. This also means they are more likely to successfully evolve into cells that can disseminate and take hold in distant organs,” explained Kevin Litchfield, paper author and group leader at the UCL Cancer Institute.

These findings show that it is important to focus on the tumour centre for a better understanding of how cancer spreads, and identify the most dangerous cells. Also, in order to wipe out the most aggressive tumour cells, treatment development must target the unique environmental conditions found within the tumour core.

The scientists also examined how genetically different populations of cancer cells grow within a tumour. With a unique mapping tall that reconstructed the growth of tumour cells, they discovered that, while tumours tend to follow a pattern where populations of cells grow in the local area, in two cases, cells took hold in a new region of the tumour by seemingly ‘jumping’ over other populations of tumour cells.

For their next steps, the researchers aim to reconstruct 3D tumour maps, providing even better visualisation of the tumours’ internal structure.

Samra Turajlic, head of the Crick’s Cancer Dynamics Laboratory, Consultant Medical Oncologist at the Royal Marsden NHS Foundation Trust and the Chief Investigator of TRACERx Renal, said: “Cancer spread is one of the biggest barriers to improving survival rates. In the context of the TRACERx Renal study we previously resolved the genetic make up of different tumour areas, but until now, there has been no understanding of how these differences relate spatially. The most critical question is the part of the tumour from which cancer cells break away and migrate making cancer incurable.

“Using this unique clinical cohort and a multidisciplinary approach, including mathematical modeling, we identified with precision the place in the tumour where genetic chaos emerges to give rise to metastases. Our observations shed light on the sort of environmental conditions that would foster emergence of aggressive behaviour. These findings are a critical foundation for considering how we target or even prevent distinct populations of cells that pose the biggest threat.”

Source: Francis Crick Institute

Categories : Cancer Metabolic DisordersTags :

Rise in Obesity Impeding Cancer Fight

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Though cancer death rates have fallen dramatically in the United States, those from obesity-related cancers are falling much more slowly.

In a study published this week in JAMA Network Open, researchers found that obesity-related cancer deaths are improving, but at a slowing pace.

Researchers at the University of North Carolina Gillings School of Global Public Health drew on mortality data for 50 million people, cancer deaths not associated with obesity — such as lung or skin cancer – are declining at a rate almost three times faster than obesity-related cancers, such as stomach, colorectal, uterine, thyroid and postmenopausal breast cancer.

“These are cancers where we could see even larger mortality improvements with creative and practical tools to combat obesity,” said study senior author Hazel B Nichols, PhD, associate professor in the Department of Epidemiology at the UNC Gillings School.

Most Americans are over the recommended body weight, and being overweight or obese puts them at risk for certain cancers.  

Extra body fat can lead to changes in the body that can contribute to cancer development, such as long-lasting inflammation and higher than normal levels of insulin and hormones that can fuel cell growth, according to the U.S. Centers for Disease Control and Prevention.

Discordant progress

Researchers use cancer death rates to track progress against cancer over time. The study authors set out to find out if obesity was stalling progress against cancer the way it did against heart disease. After 2011, heart disease mortality rates slowed their decline, a phenomenon which may be due to obesity.

“What was puzzling was that we didn’t see the same pattern of slower improvements when looking at cancer overall, which is surprising because obesity contributes to both cancer risk and heart disease risk,” said Dr Nichols. “When we focused on the differences between obesity-related cancers and non-obesity related cancers, we saw that improvements for obesity cancers were not as impressive — consistent with the pattern for heart disease.”

For example, the study showed that in 2011, 110 people out of 100 000 died from cancers not related to obesity. In 2018, the mortality rate for those cancers fell to 93.8 deaths per 100 00 people — a 2.29% annual decline.

During the same period, the decline for obesity-related cancers was much slower, changing from 58.4 to 54.9 deaths per 100 000 people, a rate of .83% — a rate one-third the decrease in non-obesity related cancers.

Obesity may also be contributing to more of the cancer deaths in the US. The study found that cancers not associated with obesity accounted for 66.8% of cancer deaths in 1999, decreasing to 62.6% in 2018.
The good news is that if we’re able to make these changes as a society, we will be able to improve the health of a nation. Christy Leigh Avery, PhD

Falls in cancer deaths are the result of fewer smokers, along with better screening and treatments, according to the American Cancer Society.

But the findings by UNC researchers reinforce the impact of obesity on cancer. 

“Obesity is a risk factor for many, but not all, types of cancer,” Nichols Dr said. “We need to make maintaining a healthy weight an obtainable goal for everyone in terms of safe public spaces, the availability and affordability of nutritious foods, and other structural factors. The good news is that if we’re able to make these changes as a society, we will be able to improve the health of a nation.”

Source: University of North Carolina

Journal information: Avery CL, Howard AG, Nichols HB. Comparison of 20-Year Obesity-Associated Cancer Mortality Trends With Heart Disease Mortality Trends in the US. JAMA Netw Open. 2021;4(5):e218356. doi:10.1001/jamanetworkopen.2021.8356

Categories : Cancer GeneticsTags :

Oesophageal Cancer Unleashes ‘Fossil Viruses’ Hidden in Human DNA

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Colorectal cancer cells. Photo by National Cancer Institute on Unsplash.

Scientists have discovered that many oesophageal cancers turn on ancient viral DNA that was embedded in our genome hundreds of millions of years ago.

“It was surprising,” said principal investigator Adam Bass, MD, the Herbert and Florence Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center. 

“We weren’t specifically searching for the viral elements, but the finding opens up a huge new array of potential cancer targets that I think will be extremely exciting as ways to enhance immunotherapy.”

The idea that bits of ancient retroviruses within the human genome—known as endogenous retroviral elements, or ERVs—play a role in cancer is not new. About 8% of our genome is made up of these remnants of viral infections that have accumulated over the last 100 million years. While ERV sequences have degraded over the aeons and cannot produce viral particles, the viral fossils sometimes wind up inside other genes, disrupting their normal activities, or act as switches that turn on cancer-causing genes.

Recent research however shows that ERVs may also have a cancer fighting role if they are transcribed into strands of RNA.

“When cells activate lots of ERVs, a lot of double-stranded RNA is made and gets into the cell cytoplasm,” Dr Bass explained. “That creates a state that’s like a viral infection and can cause an inflammatory response. In that way, ERVs may make the cancer more susceptible to immunotherapy, and many researchers are working on ways to trick cancer cells into activating ERVs.”

In the new study, Bass and colleagues created organoids of oesophageal mouse tissue to follow the development of cancer from normal cells to malignancy.

With these organoids, Bass discovered that a specific cancer-promoting gene in oesophageal cancers called SOX2 triggers the expression of many ERVs.  

As ERV expression and the accumulation of double-stranded RNAs that can result can be toxic to cells, the researchers found that there is a specific enzyme called ADAR1 that rapidly degrades these double-stranded RNAs.

ADAR1 has been implicated in oesophageal cancer by other researchers, although its role had been unclear. Levels of ADAR1 are known to correlate with poor survival. “The cancers are dependent on ADAR1 to prevent an immune reaction that can be very toxic to the cells,” Bass says.

Some patients with oesophageal cancer are currently treated with immunotherapy, which has been shown to increase survival by several months. “We have a lot of enthusiasm that blocking ADAR1 may both have direct efficacy for oesophageal cancers and that ADAR1 inhibition may have even great effects by enhancing the efficacy of cancer immunotherapy in patients with oesophageal cancer,” Bass said.

Beyond the results regarding ADAR1 and ERVs, the process of modelling the development of oesophageal cancer via genomic engineering of organoids also uncovered a variety of other processes in oesophageal cancer that could help develop new therapies.

“The way we used organoids to build cancers up from the normal cell is a powerful system for uncovering cancer-causing activities and testing therapeutic targets,” said Bass. “By making individual genome alterations in these models one at a time, we can see which combinations of genetic alterations lead to cancer and then determine specific mechanisms of tumor formation.”

In this study, the organoids started with overexpression of the SOX2 gene, a commonly amplified factor that promotes the development of squamous cancers.

In the study, Dr Bass’ team built a panel of organoids emulating conditions ranging from normal oesophagus to fully transformed cancer.

By comparing normal and cancerous organoids, the team could dissect how the activity of SOX2 differs in normal and cancerous tissues. “It’s important to understand the difference, since potential treatments need to target the cancer functions but have lesser impact upon normal tissue,” he says. “It’s relatively easy to kill cancer cells. The problem is, how do you kill cancer cells but spare other cells?”

Results from the organoids showed that when SOX2 is overactive—and two tumour suppressors are inactivated—SOX2 interacts with other factors, activating an array of cancer-causing genes in addition to their effects upon induction of ERVs.  

“These findings reveal new vulnerabilities in SOX2 oesophageal cancers,” Bass said, “that will now allow us to begin developing therapies that can precisely target the cancer cell and improve the treatment of patients.”

Source: Columbia University Irving Medical Center

Journal information: Zhong Wu, et al. Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics, 2021; DOI: 10.1038/s41588-021-00859-2

Categories : Cancer New Compounds and TreatmentsTags :

Lenvatinib Produces Impressive Results Against Tough Tumours

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Image by doodlartdotcom from Pixabay

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI) induced a strong tumour response in patients with advanced gastrointestinal or pancreatic tumours, according to results from a phase II trial.

The study focused on previously treated advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). An overall response rate (ORR) of 29.9% was seen in the trial, with a particularly high ORR — 44.2% — in patients with pancreatic NETs. 

“This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other targeted agents, suggesting the potential value in the treatment of advanced GEP-NETs,” wrote Jaume Capdevila, MD, PhD, of Vall Hebron University Hospital in Barcelona, and colleagues.

TKIs are a group of pharmacologic agents that disrupt the signal transduction pathways of protein kinases by several modes of inhibition. Since sunitinib maleate (Sutent), another multitargeted TKI, was approved ten years ago, investigators have been evaluating newer-generation TKIs that target VEGF receptors (VEGFRs), among other receptors, both in pancreatic and non-pancreatic NETs.

Lenvatinib targets VEGFR 1-3, fibroblast growth factor receptors (FGFR) 1-4, and platelet-derived growth factor receptor alpha.

The researchers noted that studies have demonstrated its particular effectiveness against FGFR-1, which is a key driver of resistance to antiangiogenic drugs, “suggesting that it could potentially also reverse primary and acquired resistance to anti-VEGFR treatments or to other targeted agents.”

A total of 111 patients were enrolled in the study; 55 had histologically confirmed grade 1-2 pancreatic NETs, while 56 had gastrointestinal NETs. Patients were administered 24-mg lenvatinib once daily until disease progression or treatment intolerance. Median follow-up was 23 months.

The ORR was 16.4% for patients with gastrointestinal NETs, and median duration of response was 19.9 months for patients with pancreatic NETs and 33 months for gastrointestinal NETs. The median progression-free survival (PFS) for both groups was 15.7 months.

These results compare well with PFS outcomes reported in phase III trials, including those evaluating sunitinib and surufatinib, the authors noted.

“Interestingly, the ORR in pancreatic NETs was 44%, a rate not seen before with targeted agents,” Jonathan Strosberg, MD, head of the neuroendocrine tumor division at Moffitt Cancer Center in Tampa, told MedPage Today.

Dr Strosberg, who was not involved with this research, noted that the study group had been heavily treated beforehand, and that 29% had received prior sunitinib. “In contrast, the response rates with other TKIs have been <20% in this population, even in less heavily treated populations. The ORR for gastrointestinal NETs was more modest, but still impressive,” he added.

The most common grade 3/4 adverse events was hypertension (22.7%), while a majority of patients needed either a dose reduction or a pause.

“This suggests that lower starting doses might be considered in this population, and that particularly close monitoring of blood pressure is necessary,” said Dr Strosberg.

The study results “suggest that lenvatinib is more than just a ‘me-too’ competitor to sunitinib,” he noted. “It actually seems to have superior activity, potentially due to its ability to target both the VEGF and FGF receptors. Moreover, it appears to have activity in patients who have progressed on sunitinib. Randomized phase III studies with this drug are warranted, both for pancreatic and GI/lung NETs.”

Source: MedPage Today

Journal information: Capdevila J, et al “Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT trial (GETNE1509)” J Clin Oncol 2021; DOI: 10.1200/JCO.20.03368.

Categories : Cancer Diet and NutritionTags :

Could Cutting Sugary Drinks Reduce Cancer Risk in Women?

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A higher intake of sugar-sweetened beverages (SSBs) in adulthood and adolescence was linked to an increased risk of early-onset colorectal cancer (CRC) in women, according to data from a large prospective study.

The Nurses’ Health Study II followed over 95 000 registered nurses from 1991 to 2015. Those consuming at least two SSB servings a day in adulthood had more than double the early-onset CRC risk of those consuming less than one serving a week. This rose by 16% with each extra serving per day.

In the adolescent years of ages 13 to 18, each serving-per-day increment was associated with a 32% higher risk of early-onset CRC. Meanwhile, replacing each SSB serving per day for adults with a serving of a non-SSB drink was associated with a 17-36% lower risk.

“Considering the well-established, adverse health consequences of SSBs and the highest consumption being characterized in adolescents and young adults under age 50 years, our findings reinforce the public health importance of limiting SSB intake for better health outcomes,” Yin Cao, ScD, MPH, of Washington University in St. Louis, and co-researchers wrote.

Although CRC has been on the decline, the age of early onset — that is, diagnosed before age 50 — has been increasing the past two decades. In comparison to adults born around 1950, those born around 1990 had twice the colon cancer risk and four times the rectal cancer risk.

An estimated 12% of the US population currently consume more than three SSB servings per day, as shown by National Health and Nutrition Examination Survey data. SSBs in the US are often include high fructose corn syrup as an ingredient, as opposed to South Africa which uses cane sugar.

In this study, the population consisted overwhelmingly of white females, ages 25 to 42, with an average age of approximately 42 at enrollment. Over up to 24-plus years of follow-up, 109 cases of early-onset CRC were recorded.

The researchers found that those with higher SSB intakes in adulthood tended to be less physically active and more likely to have a lower endoscopy history, to use non-steroidal anti-inflammatory drugs, and consume red and processed meats. They were also less likely to take multivitamins and to have a reduced intake of alcohol, fibre, folate, and calcium, and to have a poorer diet overall.

No association was found between intake of artificially sweetened beverages or fruit juice in adulthood and risk of early-onset CRC, mirroring past research.

The investigators listed a number of possible pathways for the effect of SSBs on early-onset CRC. 

For example, compared with isocaloric solid foods, energy-containing beverages do not create a feeling of satiation, leading to weight gain. SSBs also initiate rapid blood glucose response and insulin secretion, possibly leading to insulin resistance, inflammation, obesity, and type 2 diabetes — metabolic conditions which are linked to heightened CRC risk.

Other possibilities include intestinal dysbiosis and endotoxemia caused by high fructose levels , the principal sweetener in SSBs in the US and certain other countries, which can impair gut barrier function, increasing gut permeability, and possibly promote cancer formation. A recent experimental study suggested that the high-fructose corn syrup in SSBs from the US enhanced the growth of aggressive tumours in mice, regardless of weight and metabolic syndrome.

High-fructose corn syrup has also been linked to metabolic dysregulation, regardless of obesity.

Fortunately, overall SSB intake has been trending downward in recent years, and Dr Cao and co-authors concluded that further limiting consumption may be “an actionable strategy to curb the rising incidence of [early-onset] CRC.”

Study limitations, the researchers said, included possible unknown confounding variables, the few early-onset CRC cases prevented pinpointing the window of exposure, and there weren’t enough diabetic participants to stratify by a personal history of diabetes. Since the participants were mostly white women, the results were not readily generalisable to other ethnic groups or to men.

Source: MedPage Today

Source Reference: Hur J, et al “Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women” Gut 2021; DOI: 10.1136/gutjnl-2020-323450.

Categories : CancerTags :

Nanoparticles Deliver Chemotherapy to Cancer Cell’s Doorsteps

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Fanciful depiction of nanoparticles. Photo by Landon Arnold on Unsplash

New research has developed a nanoparticle system that can deliver large, unwieldy protein-based chemotherapy drugs right to the doorsteps of cancer cells.

Some cancer treatments make use of antibodies’ ability to recognise specific cancer cells in order to target those cells with small active agents, but have not been able to deliver larger protein-based drugs.

Research published in the journal Angewandte Chemie shows how, using a new protein transport system, proteins can arrive at their target intact, protected from destructive proteases by polymer brushes.

Two problems keep coming up when scientists try to develop new anticancer drugs. Firstly, an active agent needs to be able to kill the body’s cells at the root of the cancer, and secondly it should be active in target cancer cells rather than in healthy cells. To this end, some medical researchers are  trying to implement a cargo package as a method of delivery. The active agent stays protected and packaged until it reaches the target location, while antibodies that only attach to cancer cells help with “finding the right address”. 

These antibodies recognise specific receptor structures on the outer membrane of cancer cells, attaching to these structures with the cell absorbing the active agent. However, this strategy is unsuccessful when the active agents are large proteins. 

These large proteins are usually water soluble, and unable to penetrate the cell membrane. The body’s own protease enzymes throw in another complication, because they break down the protein cargoes before they can reach their target location.

Sankaran Thayumanavan and colleagues at the University of Massachusetts in Amherst, USA, have now developed a protected nanosized cargo package, which meets both requirements of targeted delivery and keeping the cargo intact. For the container, they use miniscule beads made of silicon dioxide with a diameter of just 200 nanometres. The surface of these beads is coated with brush-like polymer strands made of polyethylene glycol (PEG) that can be doubly functionalised, giving tiny “brush beads”. This is termed a protein-antibody conjugate (PAC).

With simple click chemistry, the researchers attach the desired active-agent protein and antibodies to the polymer bristles. The finished bead-shaped packages have antibodies on the outermost layer, with the proteins safely concealed in the forest of polymer strands.

Besides the ability to transport water-soluble proteins, this PAC also possessed another advantage: a possible high protein-antibody ratio. The researchers said that, at least in theory, over 10 000 proteins could be transported per (expensive) antibody using the researchers’ PACs, compared to the maximum of four active agents per antibody in previous antibody-drug combinations.

The team tested their system on various cell cultures with different antibodies and test proteins. The test was a success; the PACs delivered their deadly cargoes to their cellular targets as planned.
The team is now going to figure out if and how the packages can be shielded from macrophages. They are optimistic about this because the PEG functionalities and the surface antibodies are designed for a quick delivery while minimising clearance by macrophages.

Source: News-Medical.Net

Journal information: Liu, B., et al. (2021) Protein–Antibody Conjugates (PACs): A Plug‐and‐Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins. Angewandte Chemie International Edition. doi.org/10.1002/anie.202103106.

Categories : CancerTags :

Fooling Cancer Cells into Taking in Anti-cancer Drugs

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Stress Fibres and Microtubules in Human Breast Cancer Cells. Photo by National Cancer Institute on Unsplash

Attaching anti-cancer drugs to a common protein and making a ‘poison pill’ that cancer cells take in could increase the effectiveness of chemotherapy, according to researchers at Massachusetts General Hospital (MGH).

In order to kill cancer cells effectively, enough anticancer drugs need to be delivered into a tumour as possible, which is often difficult. A new approach involves binding the drugs to albumin, the most abundant protein in blood. Tumours have a strong appetite for protein nutrients to fuel malignant growth. When they consume albumin, the tumour will also take in the drugs bound to this protein.

One commonly used albumin-bound drug is nanoparticle albumin-bound paclitaxel (nab-PTX), which has been successfully used in the treatment of advanced lung and pancreatic cancers. “Not all patients respond to nab-PTX, though, and the effectiveness of its delivery to tumours has been mixed, owing to an incomplete understanding of how albumin impacts drug delivery and actions,” said senior author Miles Miller, PhD, a principal investigator in the MGH Center for Systems Biology and assistant professor of Radiology at Harvard Medical School.

To improve their understanding, Prof Miller and colleagues examined the delivery of nab-PTX to tumours at a single-cell resolution in mouse models of cancer. Using 3D microscopy and tissue clearing technology, the team found that cancer cells can take up a significant amount of nab-PTX. They also found that the consumption of these drugs is controlled by signaling pathways involved in the cells’ uptake of nutrients such as albumin.

“This discovery suggested that if we could manipulate these pathways, we might be able to trick cancer cells into a nutrient-starved state, thereby enhancing their consumption of nab-PTX,” explained Ran Li, PhD, first author on the study and an instructor in the MGH Department of Radiology and the Center for Systems Biology. Indeed, treating tumours with an inhibitor of insulin-like growth factor 1 receptor, an important component of one of the signaling pathways, improved the accumulation of nab-PTX in tumours and boosted its effectiveness.

“These results offer new possibilities to improve delivery of albumin-bound drugs in patients with diverse types of cancer,” said Prof Miller.

Source: Phys.Org

Journal information: Ran Li et al, Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer, Nature Nanotechnology (2021). DOI: 10.1038/s41565-021-00897-1

Categories : Cancer COVID General InterestTags :

Young Cancer Researchers Strive On Despite Pandemic

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DNA Fragmentation. A dye marker on agarose gel used to separate DNA by a female scientist. The smaller fragments move faster, the larger ones move slower. This separation process is used to analyse the size of DNA fragments, to map DNA, to separate fragments of DNA to create clones. Photo by National Cancer Institute on Unsplash

Although long hours in the lab are standard, some young cancer researchers have told BBC’s Radio 1 Newsbeat that, in order to continue their work, the pandemic is forcing them to work longer, harder days with no pay.

Many relished the easing of COVID rules in the UK at the beginning of the summer months. However Dr Alba Rodriguez-Meira, 28, said that those sunny weeks were like an “extended lockdown”.

At the time, labs had been shut for nearly four months and Dr Rodriguez-Meira worked more than 90 hours a week – equivalent to 13 hours a day, 7 days a week – to catch up her leukaemia research at the University of Oxford.

“That was fine during the first month but it becomes a bit disruptive in terms of life quality if you try to do it for much longer,” Dr Rodriguez-Meira said.

Her weekly hours are slowly returning to her usual 60 a week – but she’s still feeling the pressure.

“I’ve lost a lot of productivity – sometimes I think I’ve not been as happy or as passionate as I used to be.

“Working under these circumstances has made me lose a bit of that. And I am sometimes so, so, absolutely tired.”

Social distancing rules mean that even though labs have reopened, not everyone can be there at the same time.

This is affecting the work of PhD student Laurien van de Weijer, 24, who is studying meningioma, a kind of tumour which makes up over a third of primary central nervous system tumours.

An important experiment she was running at her lab at the University of Plymouth over Easter weekend in April failed because she could not get in to provide nutrients to the tumour cells, which subsequently died. She is apprehensive about the 18 months she has left to finish her doctorate.

“I’ll be so overloaded… because I lost lots of time in the early stage, I really have to catch up, so I probably will do crazy hours.

“I really don’t look forward to being in the lab in the middle of the night.”

Laurien is also concerned that the longer she takes to get her research done, “the longer there won’t be any good drugs” for people with meningiomas.

The Institute of Cancer Research (ICR) says the COVID pandemic will add on an extra two years to the lag time between new treatments being discovered and cancer patients being able to use them.

“We don’t have the luxury of time – that’s the truth – to wait for two extra years,” says Amani Liaquat, 23, who has an aggressive cancerous brain tumour known as a glioblastoma multiforme, and according to doctors has between 12 and 18 months to live.

Amani is now trying a new drug called ONC201 which is still in trials, after chemotherapy and radiotherapy have both failed to shrink the tumour

Amani says she “can’t really put into words” how grateful she is to researchers going into labs during the pandemic, “risking their own health to try and help others”.

“The fact that people are still out there, trying their best in such difficult circumstances is really important,” she says.

Spurred on by stories like Amani’s, some groups of so-called “wet lab” researchers, whose work is experiment-heavy, have come up with shifts that allow them in to labs while observing social distancing.

It’s often after midnight when Beshara Sheehan begins her cycle home from the ICR lab in Sutton, south London.

Beshara Sheehan, 28, whose research is on improving prostate cancer therapy, works a lot of late shifts, often cycling home at midnight. She finds it “difficult to switch off” from work, having to still communicate with on-shift colleagues..

Fiona Want, 25, works at the same site as Beshara, albeit in a different research team, but prefers early morning shifts over late ones.

“It took a bit of getting used to having that real jumble of routine,” said Fiona, who has walked half her day at the lab and half at home.

Her research is on bladder cancer, and works up to 55 hours a week, 10 hours more than pre-COVID. She is driven on by the death of her fiance’s dad from cancer at the end of last year.

“That’s been a real source of motivation for me to keep working hard and a reminder that everyone’s life is, in some way, impacted by cancer,” she said.

“It is so important that we don’t let research slow down and keep pushing forward with discoveries that ultimately save lives.”

Source: BBC News

Categories : Cancer GeneticsTags :

‘Chemical Nose’ Sniffs Out Cancer-causing DNA Folds

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Artistic depiction of DNA double helix. Image by lisichik from Pixabay

Small folds in DNA structure have been implicated in breast cancer and other diseases have been elusive until a team of researchers developed a “chemical nose” to seek them out.

In the journal Nature Chemistry, chemists at  UC Riverside describe the development and testing of a “chemical nose” enabling them to “smell” unusual folds in DNA.

“If a DNA sequence is folded, it could prevent the transcription of a gene linked to that particular piece of DNA,” explained study author and UCR chemistry professor Wenwan Zhong. “In other words, this could have a positive effect by silencing a gene with the potential to cause cancer or promote tumors.”

DNA folding could also have a negative effect, however.

“DNA folds could potentially keep viral proteins from being produced to minimize immune response,” Prof Zhong said.

DNA folds have also been examined as potential targets for chemotherapy.   

To date, scientists have been unable to easily determine the effects of DNA folding on living organisms, as they lacked the proper tools to study them. In order to create one that can study the tiny structures, TUCR organic chemistry professor Richard Hooley and colleagues modified an existing concept that has previously been used to detect other things, such as chemical components in different vintages of wine.

The chemical system could be configured to seek out any kind of molecule, but it could not detect DNA in the way it was currently used. The addition of nonstandard components Prof Hooley’s group enabled the nose to sniff out its DNA target.

“Humans detect smells by inhaling air containing odor molecules that bind to multiple receptors inside the nose,” explained Prof Hooley. “Our system is comparable because we have multiple receptors able to interact with the DNA folds we’re looking for.”

The chemical nose consists of three parts: host molecules, fluorescent guest molecules, and DNA, which is the target. The guest molecules glow when the sought-after folds are present in a sample.

DNA is made of four nucleic acids: guanine, adenine, cytosine and thymine which are combined into the familiar double helix of DMA. Sections that are rich in guanine sometimes fold differently and create what’s called a G-quadruplex.

The parts of the genome that make these quadruplex structures are extremely complex, though the researchers have found that their folds are known to regulate gene expression, and aid in maintaining cell health.

The researchers sought to demonstrate that they could detect a single type of quadruplex composed of four guanines. Prof Zhong said that having accomplished this, the research team will try to build on their success.

“Now we think we can do more,” she said. “There are other three-dimensional structures in DNA, and we want to understand those as well.”

For their next step, the researchers will examine how effects that damage DNA influence the ways they fold. In addition, they also plan to study RNA folding since RNA is also important for cellular functioning.

“RNA has even more complex structures than DNA, and is more difficult to analyze, but understanding its structure has great potential for disease research,” Prof Zhong said. 

Source: UC Riverside News

Categories : CancerTags :

New Radiotherapy Treatment for Metastatic Cancers is Safe

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MRI machine. Image by Michal Jarmoluk from Pixabay

A phase I trial showed that stereotactic body radiotherapy (SBRT) proved safe for treating cancer patients with multiple metastases. However, some late adverse effects underscored the need for long-term follow-up.

SBRT is a new radiotherapy treatment method that delivers high doses of ionising radiation to tumours with great precision, minimising damage to other parts of the body while killing tumour cells.

Increasingly used by clinicians, SBRT can improve survival in cancer patients with multiple metastases, explained first author Steve Chmura, MD, PhD, of University of Chicago Medicine, and colleagues, but there is little evidence as to its safety in this application.

“Existing data include mostly treatment of 1 or 2 metastases separated widely from each other and use of differing radiation doses, toxicity reporting, image guidance, and normal tissue constraints,” they wrote. “Given the critical need, NRG Oncology NRG-BR001 trial sought to determine the safety of delivering curative-intent SBRT to patients with 3 to 4 metastases or 2 metastases within close proximity to each other.”

Patients in the study had metastatic breast, prostate, or non-small-cell lung carcinoma (NSCLC). Each metastasis was assigned to a metastatic location based on the potential for toxicity.

Dose-limiting toxicity (DLT; side effects severe enough to discontinue treatment) was the primary study outcome, defined as specific AEs of grades 3 to 5 related to SBRT within 180 days of treatment. Dose levels were considered to be safe if DLTs were seen in no more than one of six patients per location with metastases.

Of the evaluable 35 patients, 12 (34.3%) had breast cancer, 10 NSCLC (28.6%), and 13 (37.1%) prostate cancer, with a median of three metastases per patient.

DLT analysis WAS based on six evaluable patients in all of the metastatic locations save the liver (five evaluable patients). The authors reported there were no protocol-specified DLTs in any of the seven metastatic locations within 180 days of the initiation of treatment.

There were 50 grade 3 or 4 AEs reported in 18 patients, and eight were deemed to be linked to the treatment. Of those eight, six (including bone pain, pulmonary fibrosis, bronchial fistula, bronchial stenosis, spinal fracture, and humeral fracture) were reported in six patients over 180 days from the start of the treatment. No treatment-related deaths occurred, according to the authors.

The authors suggested that, with the number of late AEs reported in this trial, patients should be monitored closely for late toxic effects.

“Given the potential for ablative radiotherapy to improve outcomes of patients with oligometastatic cancer, the finding that SBRT is safe when delivered to 3 to 4 metastases or 2 metastases in close proximity to one another is important, and serves as the foundation for ongoing randomized trials,” wrote the authors. They noted that these include studies such as the phase II/III NCI-sponsored NRG-BR002 trial.

Source: MedPage Today

Journal information: Chmura S, et al “Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases” JAMA Oncol 2021; DOI: 10.1001/jamaoncol.2021.0687.