Tag: medical research

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 : 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 : HIVTags :

HIV Cure A Step Closer With Rare Immune System Discovery

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Photo by CDC on Unsplash

Scientists have taken a step closer to understanding how some rare people’s immune systems can suppress HIV.

The innate immune response mounts a fast-acting, general response against pathogens or supports the adaptive immune response, made up of antibodies and T cells that learn to fight specific pathogens after infection or vaccination

In recent years, researchers discovered that some components of the innate immune response can, under certain conditions, also be trained in response to infectious pathogens, such as HIV. 

In a study recently published in the Journal of Clinical Investigation, it was shown that elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells, part of the innate immune response, that display traits of a trained innate immune cell.

“Using RNA-sequencing technology, we were able to identify one long-noncoding RNA called MIR4435-2HG that was present at a higher level in elite controllers’ myeloid dendritic cells, which have enhanced immune and metabolic states,” explained Xu Yu, MD, a Core Member of the Ragon Institute of MGH, MIT and Harvard. “Our research shows that MIR4435-2HG might be an important driver of this enhanced state, indicating a trained response.”

Myeloid dendritic cells’ main role is the support of T cells, which are key to the elite controllers’ ability to control HIV infection. Since MIR4435-2HG was found to be higher only in the cells of elite controllers, Dr Yu explained, it may be part of a learned immune response to infection with HIV. Myeloid dendritic cells with elevated MIR4435-2HG also had greater levels of a protein known as RPTOR, which drives metabolism. Because of this boosted metabolism, the myeloid dendritic cells may better support the T cells controlling the HIV infection.

“We used a novel sequencing technology, called CUT&RUN, to study the DNA of these cells,” says postdoctoral fellow Ciputra Hartana, MD, Ph.D., the paper’s first author. “It allowed us to study epigenetic modifications like MIR4435-2HG, which are molecules that bind to the DNA and change how, or if, the DNA is read by the cell’s machinery.”

The team found that MIR4435-2HG’s mechanism could function by attaching to the DNA near the location of the RPTOR gene. The bound MIR4435-2HG would then prompt cellular machinery to synthesise more RPTOR protein, from the instructions in the RPTOR gene. This kind of epigenetic modification, a ‘trained’ response to HIV infection, would keep the myeloid dendritic cells in a state of heightened metabolism, providing long-term support to the T cells battling the virus.

“Myeloid dendritic cells are very rare immune cells, accounting for only 0.1-0.3% of cells found in human blood,” said Dr Yu. “We were fortunate and thankful to have access to hundreds of millions of blood cells from the many study participants who have donated their blood to support our HIV research. These donations were key to making this discovery.”

A core component of HIV cure research is to figure out exactly how elite controllers’ immune systems can keep HIV under control. By understanding how elite controllers keep the deadly virus in check, scientists could develop treatments to enable other people living with HIV to replicate the same immune response. This would take away the need for daily medication to control the virus, achieving what is known as a ‘functional cure’.

Source: Medical Xpress

Journal information: Ciputra Adijaya Hartana et al, Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers, Journal of Clinical Investigation (2021). DOI: 10.1172/JCI146136

Categories : CancerTags :

Most Glucose Consumption in Non-cancer Cells, Upending Century-old View

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A study has found that cancer cells are not the main consumers of glucose in tumours, challenging an observation held for over a century.

“The field of cancer metabolism has really exploded over the last 20 years, but it has been based on this observation that Otto Warburg published in 1922—that cancer cells can consume glucose at a very high rate,” said Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and director of the Vanderbilt Center for Immunobiology. “We now know that tumors include many types of cells, and it’s surprising that non-cancer cells are actually the major glucose consumers in the tumor.”

One application of the Warburg effect is where cancer cells are picked out based on their glucose metabolism in positron emission tomography (PET), a radioactive tracer of glucose (FDG). However, this doesn’t always yield the results expected by clinicians.

“I had been curious about why PET scans are ‘hot’ or ‘not hot’ for many years because the kidney cancer type that I study, from what we understand about the biology, should light up hot on PET and often doesn’t,” said W. Kimryn Rathmell, MD, PhD, Hugh J Morgan Professor and Chair of the Department of Medicine. “Jeff and I have had many conversations about which cells are using the glucose: is it the cancer cells; is it the immune cells; how does it all fit together? You can just imagine our dinner table.”

A pair of MD-PhD students from their labs, Bradley Reinfeld and Matthew Madden, decided to resolve this conundrum. They administered two different PET tracers (one for glucose, one for glutamine) to mice with tumours, isolated the tumors and separated them into various cell types and then measure the radioactivity in the cells. Six different tumour models were used, including colorectal, kidney and breast cancer. The results showed that, in each case, myeloid immune cells (primarily macrophages) had the highest uptake of glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake.

“We think this is a general phenomenon that extends across cancer types,” Madden said.

The researchers showed that, instead of limiting nutrients, certain cellular signaling pathways drove the differences in glucose and glutamine uptake. The prevailing view is rather of metabolic competition taking place in the tumour microenvironment, where the cancer cells “win” to deplete nutrients and suppress immune cells.

“The idea has been that the cancer cells are gobbling up all of the glucose, and consequently, immune cells can’t get enough glucose and can’t do their job,” Madden said. “Our data suggest that nutrients aren’t limiting. Instead, cells are programmed to consume certain nutrients, and there is partitioning of nutrients between cells: cancer cells pick up glutamine and fatty acids; immune cells pick up glucose.”

Knowing that cells in the tumour microenvironment use different nutrients “may allow for specifically targeting particular cell types—for new therapies or for imaging people’s tumors,” Reinfeld said.

Kimryn Rathmell added, “We’re in a good place now to be able to have more sophisticated PET radiotracers. It’s time to think about testing fluoridated glutamine or other nutrient probes in patients.”

The study’s findings also have implications for interpreting FDG-PET imaging results, she said. “We order FDG-PET scans all the time, and we need to have a good sense of what that information is providing us. We use it to judge tumor response, but it may be telling us about inflammatory response and not tumor response.”

Source: Medical Xpress

Journal information: Cell-programmed nutrient partitioning in the tumour microenvironment, Nature (2021). DOI: 10.1038/s41586-021-03442-1

Categories : Medical Research & TechnologyTags :

Harnessing Tailocins, Antibacterial ‘Homing Missiles’

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A Berkeley Lab-led team is investigating how to harness tailocins, antibacterial nanomachine ‘weapons’ akin to phages but produced by certain bacteria in suicide attacks against other strains.

“Tailocins are extremely strong protein nanomachines made by bacteria,” explained Vivek Mutalik, a research scientist at Lawrence Berkeley National Laboratory (Berkeley Lab) who studies tailocins and phages, the bacteria-infecting viruses that tailocins appear to be remnants of. “They look like phages but they don’t have the capsid, which is the ‘head’ of the phage that contains the viral DNA and replication machinery. So, they’re like a spring-powered needle that goes and sits on the target cell, then appears to poke all the way through the cell membrane making a hole to the cytoplasm, so the cell loses its ions and contents and collapses.”

Many bacteria can produce tailocins, seemingly under stress conditions. However, the tailocins are only lethal to specific strains, and seem to be used by bacteria to compete with rivals. Since they are so similar to phages, scientists believe that tailocins are repurposed from DNA that was injected into bacterial genomes from viral infections.

According to Mutalik, tailocins kill the bacteria that produce them as they erupt through the membrane, much the way replicated viruses do. However, once released, the tailocins selectively target certain strains and not the host lineage cells.

“They benefit kin but the individual is sacrificed, which is a type of altruistic behavior. But we don’t yet understand how this phenomenon happens in nature,” Mutalik commented. Scientists also don’t know precisely how the stabbing needle plunger of the tailocin functions.

These topics, and tailocins as a whole, are an area of hot research due to the many possible applications. Mutalik and his colleagues in Berkeley Lab’s Biosciences Area along with collaborators at UC Berkeley are interested in harnessing tailocins to better study microbiomes. Other groups are keen to use tailocins as an alternative to traditional antibiotics -which indiscriminately wipe out beneficial strains alongside the bad and are increasingly ineffective due to the evolution of drug-resistance traits.
There is also great interest in using tailocins as an alternative to antibiotics, due to increasing antibiotic resistance and the fact that conventional antibiotics wipe out beneficial strains along with the disease-causing ones.

In their most recent paper, the collaborative Berkeley team explored the genetic basis and physical mechanisms governing how tailocins attack specific strains, and looked at genetic similarities and differences between tailocin producers and their target strains.

Upon examination of 12 strains of tailocin-using soil bacteria, the researchers found that differences in the lipopolysaccharides on the outer membranes determined whether they were targeted by a particular tailocin.

“The bacteria we studied live in a challenging, resource-poor environment, so we’re interested to see how they might be using tailocins to fight for survival,” said co-lead author Adam Arkin, a senior faculty scientist in the Biosciences Area and technical co-manager of the Ecosystems and Networks Integrated with Genes and Molecular Assemblies (ENIGMA) Scientific Focus Area. Arkin observed that although bacteria can easily be induced to produce tailocins in the lab, as well as scale up for mass production for medicinal applications, it is not well understood how bacteria deploy tailocins in their natural environment, and how or why particular strains are so precisely targeted.

“Once we understand the targeting mechanisms, we can start using these tailocins ourselves,” Arkin added. “The potential for medicine is obviously huge, but it would also be incredible for the kind of science we do, which is studying how environmental microbes interact and the roles of these interactions in important ecological processes, like carbon sequestration and nitrogen processing.”

At the moment, it is difficult to observe what is happening in a bacterial community, but tailocins could remove individual strains with precision to allow a better understanding of the situation.

Follow-up studies being conducted involve taking atomic-level images of the taolicins in action.

Source: SciTech Daily

Journal information: “Systematic discovery of pseudomonad genetic factors involved in sensitivity to tailocins” by Sean Carim, et al., 1 March 2021, The ISME Journal. DOI: 10.1038/s41396-021-00921-1

Categories : CancerTags :

The Effect of Hypoxia on Cancer Cells is a Matter of Timing

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A new study from the University of Colorado School of Medicine shows that the effect of hypoxia on cancer cells varies in the short term versus the long term, opening new possibilities for cancer treatment.

How cancer cells adapt to hypoxia, where insufficient oxygen reaches cells, is a key aspect of cancer biology.

“Most tumours cannot grow unless they figure out a way to induce formation of new blood vessels to supply them with oxygen and other nutrients,” explained Matthew Galbraith, PhD. “So, what happens inside of solid tumours is they undergo intermittent periods of low oxygen between rounds of new blood vessel formation.”

Previous research focussed on hypoxia in the long term, characterising it as oncogenic, or cancer promoting. However some studies showed that hypoxia-sensing factors, known as hypoxia inducible factors, or HIFs, can in some situations suppress tumour growth. To solve this, senior researcher Joaquin Espinosa, PhD and colleagues studied the immediate acute response to hypoxia.

“We employed a cutting-edge genomics technology that nobody had employed in this field before that allowed us to see what happens to cancer cells within minutes of depriving them of oxygen,” Dr Espinosa said.

Employing this technology, they identified hundreds of hypoxia-inducible genes activated shortly upon oxygen deprivation. Using computational biology approaches on large, publicly available datasets, they inferred the function of these genes on hundreds of lab-grown cancer cell lines and hundreds of tumour samples from cancer patients.

They found that when a cell is hypoxic, it reacts by ceasing growth to preserve its existing nutrients and oxygen. Thus, hypoxia causes a tumour-suppressive reaction at this point, mostly by preventing protein synthesis. Only after prolonged periods of hypoxia do cells metastasise and spread out in search of oxygen.

“There’s been a lot of debate about whether these hypoxia-inducible factors promote tumour growth or prevent tumour growth,” Dr Espinosa said. “The conclusion we came to is that everyone was right to a degree. Hypoxia-inducible factors can suppress tumour growth by preventing protein synthesis early on, but they can also advance tumour growth at later stages by promoting the ability of cancer cells to invade neighboring tissues. It depends on when you’re looking at it.”

The tumour suppression and promotion mechanisms elicited by HIFs can be exploited as drug targets. Tumour suppression is mediated by inhibition of an enzyme known as mTOR, which in turn can be inhibited by available drugs often used in cancer therapies. “mTOR inhibitors could mimic the tumour suppressive effects of HIFs,” Dr Galbraith explained.

When deprived of oxygen for a longer amount of time, the HIFs switch on a set of enzymes that can degrade the extracellular matrix that holds them in place, allowing the cancer cells to escape the oxygen-deprived tumour. The cancer cells can then enter the bloodstream and invade nearby tissues.

“These results emphasise the importance of developing inhibitors of hypoxia-inducible enzymes that degrade collagen and other components of the extracellular matrix,” Espinosa said.

Dr Espinosa and his team hope that their research will help new cancer treatments to be developed, which also target the cancer at the right times. 

“People have been trying to target the hypoxia-inducible factors with different therapeutics, but this research would suggest that you may want to exercise some caution about when you apply those therapeutics, given that the HIFs can be tumour suppressive in the early stages of hypoxia,” Dr Galbraith said.

“Since the hypoxic response can be tumour suppressive in some contexts and oncogenic in other contexts, it’s not a good idea to issue a blanket statement that we should always try to shut it down,” Dr Espinosa added. “Instead, we should be thinking about what aspect of the hypoxic response to target, and that’s the aspect where hypoxia drives invasion and metastasis.”

Hoping that other researchers would make use of the map his team developed, Dr Espinosa said, “I would say this is a definitive improvement in the mapping of the early events of hypoxia. And the beauty of that is that once you have a good map of the land, a lot of people can use it.”

Source:  Medical Xpress

Journal information: Zdenek Andrysik et al, Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response, Nature Communications (2021). DOI: 10.1038/s41467-021-21687-2

Categories : CancerTags :

Duo of Existing Drugs Punishes Ravenous Cancer Cells

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Preclinical research from VCU Massey Cancer Center published recently in the Proceedings of the National Academy of Sciences shows that the combination of two existing drugs can kill aggressive neuroblastoma cancer cells by exploiting their metabolic ‘hunger’.

A cancer of the nervous system, neuroblastomas are one of the deadliest childhood cancers, and if the MYCN gene is overexpressed, the prognosis is even worse. Although paediatric blood cancers are more treatable thanks to medical advancements, it has been much harder to treat neuroblastomas mostly due to the difficulty of targeting MYCN.

“MYCN is a transcription factor, and it’s very difficult to drug transcription factors,” said study senior author Anthony Faber, PhD, co-leader of the Developmental Therapeutics research programme and Natalie N and John R.Congdon, Sr. Endowed Chair of Cancer Research at VCU Massey Cancer Center and associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry. “So, the next best thing is to target what MYCN does in the cell. One thing it does is to crank up metabolic activity – what it’s doing to keep the cell alive – and we can work that against itself.”

Since these ravenous cells burn cellular energy stores as quickly as they can be replenished Prof Faber’s team looked for a method to kick their metabolism over the edge without harming normal cells.

Screening 20 metabolic drug combinations in cancer cells originating from nearly 1000 different patients, the researchers found that neuroblastoma with high MYCN expression was particularly sensitive to a cocktail containing two drugs: phenformin and AZD3965..

Phenformin was developed in 1957 to treat diabetes. It blocks complex I on the surface of mitochondria, the organelle where energy production occurs.

Although phenformin was taken off the US market in the 1970s after a number of deaths, it’s still in use elsewhere in the world and is finding new application in the US as a cancer drug. Right now, phenformin is being tested in phase I clinical trial for melanoma.

Meanwhile, AZD3965 is a much newer type of drug under phase I clinical investigation. It works by blocking MCT1 rectors on the surface of cells, in this case as a cancer treatment. MCT1 receptors ferry lactate, another energy source, out of the cell. Blocking MCT1 causes lactate to accumulate, causing the cell to stop using it to make energy.

Simultaneously targeting energy production with the two different pathways used by the drugs should result in disruption of the cellular power supply, stressing and finally killing the cells.

This idea was put to the test by using mice seeded with MYCN-amplified neuroblastoma patient cells. Greater tumour reduction was seen from the cocktail than either drug given alone, with the cocktail being well tolerated.

“The data we got with AZD3965 in combination with phenformin might get people to reconsider phenformin,” said study lead author Krista Dalton, MEng, PhD Student, Virginia Commonwealth University Philips Institute for Oral Health Research. “In combination, where we can use lower doses, phenformin might have better tolerability than it previously did on its own.”

Source: News-Medical.Net

Journal information: Dalton, K. M., et al. (2021) Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2009620118.

Categories : Cardiovascular DiseaseTags :

Study Reveals Additional Pathway From Brain to Cardiovascular System

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Researchers at  University of Tsukuba in Japan have uncovered a previously unknown pathway from the brain to the cardiovascular system.

Though the cardiovascular system has a degree of autonomy to allow their independent functioning from the brain, the brain still has some control over it in order to respond to life-threatening situations. This control is exerted through the sympathetic and parasympathetic systems of the autonomic nervous system.

“From an evolutionary standpoint, the brain has had an incredibly important function in protecting the individual from predators,” says the lead author of the study Professor Tadachika Koganezawa. “But even in the absence of predators, our bodies react to stressful situations. In this study, we wanted to determine how the brain regulated the cardiovascular system via the autonomic nervous system.”

Located deep within the brain, the lateral habenula (LHb) has been known to elicit strong behavioural and cardiovascular responses to stressful events. But how it did so was still unclear. so to find out the researchers electrically stimulated the LHb in rats. This resulted in bradycardia and increased mean arterial pressure (MAP). The researchers then turned off the parasympathetic system by means of cutting the main parasympathetic nerve, the vagal nerve, or using a drug to antagonise it. 
Though this suppressed the LHb’s effect on the heart rate, the MAP was unchanged. Antagonising the sympathetic system had the opposite effect—decreasing the MAP but there was no effect on the heart rate.

To understand the mechanism by which the LHb elicits these cardiovascular responses, the researchers focused on the neurotransmitter serotonin, which plays an important role in the brain in modulating mood, cognition, and memory, among other functions.

While blocking all serotonin receptors significantly reduced the LHb’s effect on both the MAP and heart rate, the researchers found that specific subtypes of serotonin receptors were particularly involved in the process.

“These are striking results that show how the lateral habenula controls the cardiovascular system,” said study author Professor Masayuki Matsumoto , University of Tsukuba. “Our results demonstrate the mechanism of a neural circuit that plays an important role in stress-induced behavioral responses.”

Source: News-Medical.Net

Journal information: Doan, T. H., et al. (2021) Lateral Habenula Regulates Cardiovascular Autonomic Responses via the Serotonergic System in Rats. Frontiers in Neuroscience. doi.org/10.3389/fnins.2021.655617.

Categories : Genetics Medical Research & TechnologyTags :

New Bioluminescent System Illuminates Biological Processes

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Scientists at the Federal University of São Carlos (UFSCar) have developed a new bioluminescent system that can enable greatly improved imaging of biological and pathological processes in organisms.

Luciferases are enzymes that catalyse the oxidation of luciferins present in organisms such as fireflies, which results in bioluminescence in the visible light spectrum. Images of cell cultures and live animal models are made using the luciferin-luciferase system found in fireflies. For example, this can show the structure and activity of tumours, or follow the viral process in cells, helping physicians develop treatments.

“We obtained a novel luciferin-luciferase system that produces far-red light at the wavelength of 650 nanometres and emits the brightest bioluminescence ever reported in this part of the spectrum,” said principal investigator Professor Vadim Viviani, biochemist at UFSCar. “It’s a highly promising result for bioluminescence imaging of biological and pathological processes in mammalian tissues.”

“Red bioluminescence is preferred when imaging biological or pathological processes in mammalian tissues because haemoglobin, myoglobin and melanin absorb little long-wavelength light. Detection is best of all in the far red and near-infrared bands, but bioluminescent systems that naturally emit far red light don’t exist,” Prof Viviani added.

“Some genetically modified forms of luciferase and synthetic analogs of natural luciferins are produced commercially. In conjunction, they produce light at wavelengths as long as 700 nanometers, but the light produced by these artificial systems is generally much weaker and more short-lived than light from natural bioluminescent systems.”

Prof Viviani and collaborators genetically modified luciferase from the Railroad worm Phrixothrix hirtus, the only luciferase that naturally emits red light, and combined with luciferin analogues synthesised by colleagues at the University of Electro-Communications in Tokyo. The resulting luciferin-luciferase generates a much more efficient far-red bioluminescence.

“Our best combination produces far-red at 650 nanometres, three times brighter than natural luciferin and luciferase, and roughly 1000 times brighter than the same luciferase with a commercial analog,” Viviani said.

“Besides the long-wavelength and intense brightness, our combination has better thermal stability and cell membrane penetrability. Above all, it produces more lasting continuous bioluminescence, taking at least an hour to decay and significantly facilitating the real-time imaging of biological and pathological processes.”

Source: News-Medical.Net

Journal information: Viviani, R. V, et al. (2021) A Very Bright Far-Red Bioluminescence Emitting Combination Based on Engineered Railroad Worm Luciferase and 6′-Amino-Analogs for Bioimaging Purposes. International Journal of Molecular Sciences. doi.org/10.3390/ijms22010303.