Tag: cancer treatment

The Quest to Repurpose Existing Drugs for Lung Cancer that Metastasised to the Brain

Lung cancer metastasis. Credit: National Cancer Institute

The largest review of papers for brain metastases of lung cancer has found abnormalities in their genetic mutations and for which licensed drugs could be clinically trialled to find out if they could treat the disease. The research led by the University of Bristol and published in Neuro-Oncology Advances also uncovered differences in those mutations between smokers and non-smokers.

Brain metastases most commonly occur from lung and breast cancer, and in the majority of cases are fatal. The genetic mutations in primary lung cancers have been widely studied, but less is known about the changes in the cancer once it has metastasised to the brain.

The research team wanted to find out the genetic changes in brain metastasis from non-small cell lung cancer (NSCLC) and whether there are drugs already available that could potentially be offered to these patients.

The researchers carried out a review from 72 papers of genetic mutations in brain metastasis of NSCLC from 2346 patients’ data on demographics, smoking status, genomic data, matched primary NSCLC, and PD-L1 – a protein found on cancer cells.

The study found the most commonly mutated genes were EGFR, TP53, KRAS, CDKN2A, and STK11.

Common missense mutations – mutations that lead to a single amino acid change in the protein coded by the gene – included EGFR L858R and KRAS G12C

In certain cases the genetic mutations were different in the brain metastasis from the primary lung cancer.

There were also differences in the genetic mutations in smokers versus patients who had never smoked. Brain metastases of smokers versus non-smokers had different missense mutations in TP53 and EGFR, except for L858R and T790M in EGFR, which were seen in both subgroups.

The research team found from the top ten commonly mutated genes which had primary NSCLC data, 37% of the specific mutations assessed were different between primary NSCLC and brain metastases.

The researchers suggest Medicines and Healthcare products Regulatory Agency-approved drugs already licensed could potentially be tested to treat the disease in clinical trials.

The genetic landscape of the different subtypes of NSCLC is well known. TP53 and LRP1B mutations are common to all NSCLC subtypes, but certain subtypes also have specific alterations.

Lung adenocarcinoma is the most common type of lung cancer and has higher frequencies of KRAS, EGFR, KEAP1, STK11, MET, and BRAF somatic mutations – changes that have accumulated in the cancer genome.

Some studies suggested that the genomic landscape of NSCLC in smokers vs non-smokers differ independent of subtype.

One study found EGFR mutations, ROS1 and ALK fusions to be more prevalent in non-smokers, whereas KRAS, TP53, BRAF, JAK2, JAK3 and mismatch repair gene mutations were more commonly mutated in smokers.

Kathreena Kurian, Professor of Neuropathology and Honorary Consultant at North Bristol NHS Trust, Head of the Brain Tumour Research Centre at the University of Bristol and co-author of the paper, said: “Our research recommends that all patients should have their brain metastasis examined for mutations in addition to their primary lung cancer because they may be different.

“This evidence could form the backbone for new clinical trials for patients with brain metastasis in non-small cell lung cancer using drugs that are already available.”

The team suggest the next steps for the research would be to consider whole genome sequencing on brain metastasis to look for other types of mutations, such as, common insertions/deletions for which drugs are already available.

Source: University of Bristol

Copper and Ozone are the Secret Ingredients for Cheaper Cancer Drug Production

Photo by National Cancer Institute on Unsplash

Part of the reason cancer is such a devastatingly costly disease to treat is because cancer drugs are often require very expensive, specialised ingredients to produce. But thanks to pathbreaking research by UCLA chemists, led by organic chemistry professor Ohyun Kwon, the price of drug treatments for cancer and other serious illnesses may soon plummet.  

For example, one chemical used in making some anti-cancer drugs costs US$3200 per gram – 50 times more than a gram of gold. The UCLA researchers devised an inexpensive way to produce this drug molecule from a chemical costing just US$3 per gram. They were also able to apply the process to produce many other chemicals used in medicine and agriculture for a fraction of the usual cost.

Their breakthrough, published in the journal Science, involves a process known as “aminodealkenylation.” Using oxygen as a reagent and copper as a catalyst to break the carbon-carbon bonds of many different organic molecules, the researchers replaced these bonds with carbon-nitrogen bonds, converting the molecules into derivatives of ammonia called amines.

Amines interact strongly with molecules in living plants and animals, so they are widely used in pharmaceuticals, as well as in agricultural chemicals. Familiar amines include nicotine, cocaine, morphine and amphetamine, and neurotransmitters like dopamine. Fertilisers, herbicides and pesticides also contain amines.

Industrial production of amines is therefore of great interest, but the raw materials and reagents are often expensive, and the processes can require many complicated steps to complete. Using fewer steps and no expensive ingredients, the process developed at UCLA can produce valuable chemicals at a much lower cost than current methods.

“This has never been done before,” Kwon said. “Traditional metal catalysis uses expensive metals such as platinum, silver, gold and palladium, and other precious metals such as rhodium, ruthenium and iridium. But we are using oxygen and copper, one of the world’s most abundant base metals.”

The new method uses ozone to break the carbon-carbon bond in alkenes (a form of hydrocarbon with double carbon-carbon bonds) and a copper catalyst to couple the broken bond with nitrogen, turning the molecule into an amine. In one example, the researchers produced a c-Jun N-terminal kinase inhibitor – an anti-cancer drug – in just three chemical steps, instead of the 12 or 13 steps previously needed. The cost per gram can thus be reduced from thousands of dollars to just a few dollars.

In another example, the protocol took just one step to convert adenosine – a neurotransmitter and DNA building block that costs less than 10 US cents per gram – into the amine N6-methyladenosine. The amine plays crucial roles in controlling gene expression in cellular, developmental and disease processes, and its production cost has previously been US$103 per gram.

Kwon’s research group was able to modify hormones, pharmaceutical reagents, peptides and nucleosides into other useful amines, showing the new method’s potential to become a standard production technique in drug manufacturing and many other industries.

Source: University of California – Los Angeles

When it Comes to Personalised Cancer Treatments, AI is no Match for Human Doctors

Cancer treatment is growing more complex, but so too are the possibilities. After all, the better a tumour’s biology and genetic features are understood, the more treatment approaches there are. To be able to offer patients personalised therapies tailored to their disease, laborious and time-consuming analysis and interpretation of various data is required. In one of many artificial intelligence (AI)projects at Charité – Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, researchers studied whether generative AI tools such as ChatGPT can help with this step.

The crucial factor in the phenomenon of tumour growth is an imbalance of growth-inducing and growth-inhibiting factors, which can result, for example, from changes in oncogenes.

Precision oncology, a specialised field of personalised medicine, leverages this knowledge by using specific treatments such as low-molecular weight inhibitors and antibodies to target and disable hyperactive oncogenes.

The first step in identifying which genetic mutations are potential targets for treatment is to analyse the genetic makeup of the tumour tissue. The molecular variants of the tumour DNA that are necessary for precision diagnosis and treatment are determined. Then the doctors use this information to craft individual treatment recommendations. In especially complex cases, this requires knowledge from various fields of medicine.

At Charité, this is when the “molecular tumour board” (MTB) meets: Experts from the fields of pathology, molecular pathology, oncology, human genetics, and bioinformatics work together to analyse which treatments seem most promising based on the latest studies.

It is a very involved process, ultimately culminating in a personalised treatment recommendation.

Can artificial intelligence help with treatment decisions?

Dr Damian Rieke, a doctor at Charité, and his colleagues wondered whether AI might be able to help at this juncture.

In a study just recently published in the journal JAMA Network Open, they worked with other researchers to examine the possibilities and limitations of large language models such as ChatGPT in automatically scanning scientific literature with an eye to selecting personalised treatments.

AI ‘not even close’

“We prompted the models to identify personalised treatment options for fictitious cancer patients and then compared the results with the recommendations made by experts,” Rieke explains.

His conclusion: “AI models were able to identify personalised treatment options in principle – but they weren’t even close to the abilities of human experts.”

The team created ten molecular tumour profiles of fictitious patients for the experiment.

A human physician specialist and four large language models were then tasked with identifying a personalised treatment option.

These results were presented to the members of the MTB for assessment, without them knowing where which recommendation came from.

Improved AI models hold promise for future uses

Dr. Manuela Benary, a bioinformatics specialist reported: “There were some surprisingly good treatment options identified by AI in isolated cases. “But large language models perform much worse than human experts.”

Beyond that, data protection, privacy, and reproducibility pose particular challenges in relation to the use of artificial intelligence with real-world patients, she notes.

Still, Rieke is fundamentally optimistic about the potential uses of AI in medicine: “In the study, we also showed that the performance of AI models is continuing to improve as the models advance. This could mean that AI can provide more support for even complex diagnostic and treatment processes in the future – as long as humans are the ones to check the results generated by AI and have the final say about treatment.”

Source: Charité – Universitätsmedizin Berlin

Redispensing Unused Cancer Pills could Save Millions

Photo by Stephen Foster on Unsplash

Redispensing cancer drugs reduces both medical costs and environmental impact, according to research from Radboudumc pharmacy published in JAMA Oncology. The annual savings could amount to tens of millions.

Cancer drugs as pills are not always used up by patients. The drugs are mostly expensive and environmentally damaging, both in production and (waste) disposal. In her PhD research, Lisa-Marie Smale of Radboudumc investigated whether these unused drugs can be collected and reissued. Does such an approach ultimately lead to lower environmental impact and costs?

Redispense medication

When redispensing medications, the quality must be guaranteed. Therefore, in this study the medications were packaged separately and fitted with a sensor, which registers whether returned medications were kept within the required temperature. Smale: “If packaging, temperature and expiration date are in order, the returned medications can be redispensed. For two years we investigated this procedure in cooperation with the pharmacies of four Dutch hospitals; Radboudumc, UMC Utrecht, Jeroen Bosch hospital and St Antonius hospital. Over a thousand patients who were taking oral cancer medications at home participated in the study during that period.”

Saving tens of millions

The results look promising. The investment in the method, such as packaging with a temperature sensor, amounts up to 37 euros per patient per year. This is offset by savings of 613 euros. Annually, this results in a net saving per patient of 576 euros. Smale: “In the Netherlands, we can save between 20 and 50 million euros annually with this redispensing of medication. Meanwhile, we have further optimised the process, making a net saving of 655 euros per patient possible. In the Netherlands, we have relatively low drug prices. If you look at the US, where the price of new drugs is over 300 percent higher, in principle much more money can be saved there.”

Large-scale consequence

Of all wasted medicine packaging, two-thirds could be reissued. Project leader Charlotte Bekker of Radboudumc says, “Based on the results, the study will be expanded to 14 hospitals. Again, we are looking at cancer pills. Reissue is only allowed in the context of a scientific study because of European rules. We hope that the approach can eventually be used nationwide, as well as for other drugs.”

Sustainability and social impact also benefit

“This approach is cost-effective for expensive drugs,” Smale says, “but ultimately there are other factors you want to consider, such as sustainability or social impact. Think of the environmental impact you can reduce by not destroying drugs but redispensing them; this can also be beneficial for drugs that are in short supply.”

Broad interest

To the researcher’s knowledge, this study the first to examine drug redispensing with guaranteed quality. The topic is attracting strong interest, not only in the medical community but also beyond. Several parties are committed to make further expansion possible. In addition to the participating hospitals, the Dutch Association of Hospital Pharmacists (NVZA) is also closely involved. And it is part of the Green Deal objectives to make healthcare more sustainable. Smale: “We are happy to work with all parties to address and reduce the cost and environmental impact of wasted medicines.”

Source: Radboud University Medical Center

Turning Everyday Vaccines into Cancer Killers

Photo by National Cancer Institute

A study in Frontiers in Immunology has demonstrated that, in animal models, a protein antigen from a childhood vaccine can be delivered into the cells of a malignant tumour to refocus the body’s immune system against the cancer, effectively halting it and preventing its recurrence.

Instead of using vaccines tailored with tumour-specific antigens to prime the immune system to attack a particular cancer, this method makes use of the immune system’s encounter with common vaccines. The bacteria-based intracellular delivering (ID) system uses a non-toxic form of Salmonella that releases a drug, in this case a vaccine antigen, after it’s inside a solid-tumour cancer cell.

“As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients,” writes senior author Neil Forbes, professor of chemical engineering, in the recently published article.

The research, carried out in Forbes’s lab, offers promise toward tackling difficult-to-treat cancers, including liver, metastatic breast and pancreatic tumours.

“The idea is that everybody is vaccinated with a whole bunch of things, and if you could take that immunisation and target it towards a cancer, you could use it to eliminate the cancer,” Forbes explains. “But cancers obviously aren’t going to display viral molecules on their surface. So the question was, could we take a molecule inside the cancer cell using Salmonella and then have the immune system attack that cancer cell as if it was an invading virus?”

To test their theory that this immune treatment could work, Forbes and team genetically engineered ID Salmonella to deliver ovalbumin (chicken egg protein) into the pancreatic tumour cells of mice that had been immunised with the ovalbumin ‘vaccine’. The researchers showed that the ovalbumin disperses throughout the cytoplasm of cells in both culture and tumours.

The ovalbumin then triggered an antigen-specific T-cell response in the cytoplasm that attacked the cancer cells. The therapy cleared 43% of established pancreatic tumours, increased survival and prevented tumour re-implantation, the paper states.

“We had complete cure in three out of seven of the pancreatic mice models,” Forbes says. “We’re really excited about that; it dramatically extended survival.”

The team then attempted to re-introduce pancreatic tumours in the immunised mice. The results were exceedingly positive. “None of the tumours grew, meaning that the mice had developed an immunity, not just to the ovalbumin but to the cancer itself,” Forbes says. “The immune system has learned that the tumour is an immunogenic. I’m doing further work to figure out how that’s actually happening.”

In preliminary research, the team previously showed that injecting the modified Salmonella into the bloodstream effectively treated liver tumours in mice. They advanced their findings with the current research on pancreatic tumours.

Before clinical trials can begin, the researchers will repeat the experiments on other animals and refine the ID Salmonella strain to ensure its safety for use in humans. Liver cancer would be the first target, followed by pancreatic cancer.

Source: University of Massachusetts Amherst

Doing the Impossible: New Drug Kills 100% of Solid Tumours by Hitting ‘Undruggable’ Target

Assembled human PCNA (PDB ID 1AXC), a sliding DNA clamp protein that is part of the DNA replication complex and serves as a processivity factor for DNA polymerase. The three individual polypeptide chains that make up the trimer are shown. Source: Wikimedia CC0

A ‘cure for cancer’ has long been something of a holy grail for medical research – but experience has shown that cancers are highly individualised and respond differently to therapy, adapting to resist them. Now, in an early study, researchers have tested a cancer drug that kills all solid cancer tumours while leaving other cells unharmed and resulting in no toxicity. The new molecule targets a common key cancer cell protein, the proliferating cell nuclear antigen (PCNA), that is key to helping them grow and metastasise – a target previously believed to be ‘undruggable’.

The new drug, AOH1996, was tested in vitro against 70 different cancer cell lines, including breast, prostate, brain, ovarian, cervical, skin, and lung cancer. It proved effective against all of them, as well as sparing healthy cells. What’s more, developing resistance against the drug is unlikely due to the nature of PCNA as a mistranslation rather than a mutation. The results were published in Cell Chemical Biology. Instructions for synthesis were included in supplementary material.

The last great breakthrough in cancer treatment was immunotherapy, and since then cancer research has looked for the next big leap. A search of journal articles in the Pubmed database showed that “cancer” has grown from 6% of all results in 1950 to 16% by 2016. More recent development in cancer therapies has included gene-based approaches, naked nucleic acids based therapy, targeting micro RNAsoncolytic virotherapy, suicide gene based therapy, targeting telomerasecell mediated gene therapy, and CRISPR/Cas9 based therapy.

Shutting down the hub

The research was led by Dr Linda Malkas, a professor at City of Hope Hospital, who said that the molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells unaffected. Animal models also showed a reduction of tumour burden with no apparent adverse effects, with the no observed adverse effect level (NOAEL) calculated being six times higher than the administered dose.

She explained the drug in simple terms to the Daily Mail: “Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant,” she said. “PCNA is like a major airline terminal hub containing multiple plane gates.

“Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells. Our cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells.”

Dr Malkas said results so far have been ‘promising’ as the molecule can suppress tumour growth on its own or in combination with other cancer treatments without resulting in toxicity.

The development of AOH1996 is the culmination of nearly two decades of work by City of Hope Hospital in Lose Angles.

Decades in the making

PCNA in breast cancer was identified as a potential target in 2006 since it is an isomer, allowing antibodies to target it. The researchers’ first attempts with antibodies to target PCNA were unsuccessful as these were too big to penetrate into solid tumours. Next, they tried a small molecule, which appeared to work in vitro but in vivo proved to have a half-life of only 30 minutes. But they were able to tweak that molecule and arrive at the current drug, AOH1996. It was named after Anna Olivia Healy who died in 2005 from neuroblastoma, and she became the inspiration for the research.

“She died when she was only 9 years old from neuroblastoma, a children’s cancer that affects only 600 kids in America each year,” Malkas said. “I met Anna’s father when she was at her end stages. I sat him down for two hours in my office and showed him all of my data on this protein I had been studying in cancer cells.”

At the time, Dr Malkas was researching breast cancer, studying a protein found in cancer cells but not normal cells. Dr Malkas eventually took Anna’s father, Steve, and his wife, Barbara, to see her lab.

“[Steve] asked if I could do something about neuroblastoma and he wrote my lab a cheque for $25 000,” Dr Malkas said. “That was the moment that changed my life – my fork in the road. I knew I wanted to do something special for that little girl.”

Scientists Find a Protein That Keeps Melanoma Hidden from the Immune System

3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

New research has helped explain how melanoma evades the immune system and may guide the discovery of future therapies for the disease. The study found that a protein known to be active in immune cells is also active inside melanoma cells, helping promote tumour growth. The findings, published in the journal Science Advances, suggest that targeting this protein with new drugs may deliver a powerful double hit to melanoma tumours.

“The immune system’s control of a tumour is influenced by both internal factors within tumour cells, as well as factors from the tumour’s surroundings,” says first author Hyungsoo Kim, PhD, a research assistant professor at Sanford Burnham Prebys in the lab of senior author Ze’ev Ronai, PhD. “We found that the protein we’re studying is involved in both, which makes it an ideal target for new cancer therapies.”

“Immunotherapy is the first-line therapy for several cancers now, but the success of immunotherapy is limited because many cancers either don’t respond to it or become resistant over time,” says Kim. “An important goal remains to improve the effectiveness of immunotherapy.”

To find ways to boost immunotherapy in melanoma, the research team analysed data from patient tumours to identify genes that may coincide with patients’ responsiveness to immunotherapy. This led to the identification of a protein that helps tumours evade the immune system – called NR2F6 – which was found not only in tumour cells, but also in the surrounding noncancerous cells.

“Often we find that a protein has the opposite effect outside of tumours compared to what it does within a tumour, which is less effective for therapy,” says Kim. “In the case of NR2F6, we found that it elicits the same change in the tumour and in its surrounding tissues, pointing to a synergistic effect. This means that treatments that block this protein’s activity could be twice as effective.”

In a mouse model, the researchers then deleted the NR2F6 protein in both melanoma tumours and in the tumours’ environment. This inhibited melanoma growth more strongly, compared to when this effect occurs in either the tumour or its microenvironment alone. The cancer’s response to immunotherapy was also enhanced upon loss of NR2F6 in both tumours and their microenvironment.

“This tells us that NR2F6 helps melanoma evade the immune system, and without it, the immune system can more readily suppress tumour growth,” adds Kim.

To help advance their discovery further, the team is working with the Institute’s Conrad Prebys Center for Chemical Genomics to identify new drugs that can target NR2F6.

“Discovering drugs that can target this protein are expected to offer a new way to treat melanomas, and possibly other tumours, that would otherwise resist immunotherapy,” says Kim.

Source: Sanford Burnham Prebys

Defeating Cancer Cells by Knocking out their Extra Chromosomes

Chromosomes. Credit: NIH

Most cancer cells are aneuploid, having extra chromosomes, and they depend on those chromosomes for tumour growth, a new study in the journal Science reveals. Eliminating them prevents the cells from forming tumours, which suggests that selectively targeting extra chromosomes may lead to a new form of cancer treatment which could spare healthy tissue which has the typical 23 pairs.

“If you look at normal skin or normal lung tissue, for example, 99.9% of the cells will have the right number of chromosomes,” said senior study author Jason Sheltzer, assistant professor of surgery at Yale School of Medicine. “But we’ve known for over 100 years that nearly all cancers are aneuploid.”

However, it was unclear what role extra chromosomes played in cancer, such as whether they cause cancer or are caused by it.

“For a long time, we could observe aneuploidy but not manipulate it. We just didn’t have the right tools,” said Sheltzer. “But in this study, we used the gene-engineering technique CRISPR to develop a new approach to eliminate entire chromosomes from cancer cells, which is an important technical advance. Being able to manipulate aneuploid chromosomes in this way will lead to a greater understanding of how they function.”

Using their newly developed approach, which they dubbed Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT), the researchers targeted aneuploidy in melanoma, gastric cancer, and ovarian cell lines. Specifically, they removed an aberrant third copy of the long portion, or ‘q arm’, of chromosome 1, which is found in several types of cancer, is linked to disease progression, and occurs early in cancer development.

“When we eliminated aneuploidy from the genomes of these cancer cells, it compromised the malignant potential of those cells and they lost their ability to form tumours,” said Sheltzer.

Based on this finding, the researchers proposed cancer cells may have an ‘aneuploidy addiction’ – a discovery that eliminating oncogenes, which can turn a cell into a cancer cell, disrupts cancers’ tumour-forming abilities. This finding led to a model of cancer growth called ‘oncogene addiction’.

When investigating how an extra copy of chromosome 1q might promote cancer, the researchers found that multiple genes stimulated cancer cell growth when they were overrepresented – because they were encoded on three chromosomes instead of the typical two.

This overexpression of certain genes also pointed the researchers to a vulnerability that might be exploited to target cancers with aneuploidy.

Previous research has shown that a gene encoded on chromosome 1, known as UCK2, is required to activate certain drugs. In the new study, Sheltzer and his colleagues found that cells with an extra copy of chromosome 1 were more sensitive to those drugs than were cells with just two copies, because of the overexpression of UCK2.

Further, they observed that this sensitivity meant that the drugs could redirect cellular evolution away from aneuploidy, allowing for a cell population with normal chromosome numbers and, therefore, less potential to become cancerous. When researchers created a mixture with 20% aneuploid cells and 80% normal cells, aneuploid cells took over: after 9 days, they made up 75% of the mixture. But when the researchers exposed the 20% aneuploid mixture to one of the UCK2-dependent drugs, the aneuploid cells comprised just 4% of the mix nine days later.

“This told us that aneuploidy can potentially function as a therapeutic target for cancer,” said Sheltzer. “Almost all cancers are aneuploid, so if you have some way of selectively targeting those aneuploid cells, that could, theoretically, be a good way to target cancer while having minimal effect on normal, non-cancerous tissue.”

More research needs to be done before this approach can be tested in a clinical trial. But Sheltzer aims to move this work into animal models, evaluate additional drugs and other aneuploidies, and team up with pharmaceutical companies to advance toward clinical trials.

“We’re very interested in clinical translation,” said Sheltzer. “So we’re thinking about how to expand our discoveries in a therapeutic direction.”

Source: Yale University

mRNA ‘Trojan Horse’ Tricks Cancer Cells into Self-destruction

Graphical abstract. Credit: Theranostics (2023). DOI: 10.7150/thno.82228

Tel Aviv University researchers have hit upon a novel method of cancer treatment by creating an mRNA ‘Trojan horse’ that instructed cancer cells to produce a toxin lethal to themselves, eventually killing them with a success rate of about 50%. This ground-breaking study was led by PhD student Yasmin Granot-Matok and Prof Dan Peer, a pioneer in the development of RNA therapeutics. The study’s results were published in Theranostics.

Prof Peer explains: “Many bacteria secrete toxins. The most famous of these is probably the botulinum toxin injected in Botox treatments. Another classic treatment technique is chemotherapy, involving the delivery of small molecules through the bloodstream to effectively kill cancer cells. However, chemotherapy has a major downside: it is not selective, and also kills healthy cells. Our idea was to deliver safe mRNA molecules encoded for a bacterial toxin directly to the cancer cells – inducing these cells to actually produce the toxic protein that would later kill them. It’s like placing a Trojan horse inside the cancer cell.”

First, the research team encoded the genetic info of the toxic protein produced by bacteria of the pseudomonas family into mRNA molecules (resembling the procedure in which genetic info of COVID-19’s ‘spike’ protein was encoded into mRNA molecules to create the vaccine). The mRNA molecules were then packaged in lipid nanoparticles developed in Prof Peer’s laboratory and coated with antibodies to ensure they would reach their target, the cancer cells. These particles were injected into the tumours of animal models with melanoma skin cancer. After a single injection, 44–60% of the cancer cells vanished.  

“In our study, the cancer cell produced the toxic protein that eventually killed it,” says Prof Peer. “We used pseudomonas bacteria and the melanoma cancer, but this was only a matter of convenience. Many anaerobic bacteria, especially those that live in the ground, secrete toxins, and most of these toxins can probably be used with our method. This is our ‘recipe’, and we know how to deliver it directly to the target cells with our nanoparticles. When the cancer cell reads the ‘recipe’ at the other end it starts to produce the toxin as if it were the bacteria itself and this self-produced toxin eventually kills it. Thus, with a simple injection to the tumour bed, we can cause cancer cells to ‘commit suicide’, without damaging healthy cells. Moreover, cancer cells cannot develop resistance to our technology as often happens with chemotherapy – because we can always use a different natural toxin.”

Source: Tel Aviv University

New Radiotherapy Technique Hits The Bullseye on Tumours

Photo by National Cancer Institute on Unsplash

Researchers in Japan have developed a new radiotherapy technique that has the potential to treat several kinds of cancer, with fewer negative side effects than currently available methods. Published in Chemical Science, the proof-of-concept study showed that tumours in mice grew almost three times less and survival was 100% after just one injection of an alpha-particle emitting radioisotope inside of cancer cells, killing them but sparing healthy tissue.

The side effects of standard chemotherapy and radiation treatment can be devastating, and the eradication of all cancer cells is not guaranteed, especially when the cancer has already metastasised and spread throughout the body. Therefore, the goal of most research these days is to find a way to specifically target cancer cells so that treatments only affect tumours. Some targeted treatments do exist, but they cannot be applied to all cancers. Researchers led by Katsunori Tanaka at the RIKEN Cluster for Pioneering Research (CPR) in Japan and Hiromitsu Haba at the RIKEN Nishina Center for Accelerator-Based Science (RNC) developed this new approach.

“One of the greatest advantages of our new method,” says Tanaka, “is that it can be used to treat many kinds of cancer without any targeting vectors, such as antibodies or peptides.”

The new technique relies on basic chemistry and the fact that a compound called acrolein accumulates in cancer cells. A few years ago, Tanaka’s team used a similar technique to detect individual breast cancer cells. They attached a fluorescent compound to a specific type of azide – an organic molecule with a group of three nitrogen atoms (N3) at the end. When the azide and acrolein meet inside a cancer cell, they react, and the fluorescent compound becomes anchored to structures inside the cancer cell. Because acrolein is almost absent from healthy cells, this technique acted like a probe to light up cancer cells in the body.

In the new study, rather than simply detecting cancer cells, the team targeted those cells for destruction. The logic was fairly simple. Instead of attaching the azide to a fluorescent compound, they attached it to something that can kill a cell without harming surrounding cells. The chose to work with astatine-211, a radionuclide that emits a small amount of radiation in the form of an alpha particle as it decays. Compared to other forms of radiation therapy, alpha particles are a little more deadly, but they can only travel about one twentieth of a millimetre and can be stopped by a piece of paper. In theory, when astatine-211 is anchored to the inside a cancer cell, the emitted alpha particles should damage the cancer cell, but not much beyond.

Once the team figured out the best way to attach astatine-211 to the azide probe, they were able to perform a proof-of-concept experiment to test their theory. They implanted human lung-tumour cells into mice and tested the treatment under three conditions: simply injecting astatine-211 into the tumour, injecting the astatine-211-azide probe into the tumour, and injecting the astatine-211-azide probe into the bloodstream. The found that without targeting, tumours continued to grow, and mice did not survive. As expected, when the azide probe was used, tumours grew almost three times less and many more mice survived – 100% when it was injected into the tumour and 80% when injected into the blood.

“We found that just one tumour injection with only 70kBq of radioactivity was extremely effective at targeting and eliminating tumour cells,” says Tanaka. “Even when injecting the treatment compound into the bloodstream, we were able to achieve similar results. This means we can use this method to treat very early-stage cancer even if we don’t know where the tumour is.” The fluorescent probe version of this technique is already being tested in clinical trials as a way of visualising and diagnosing cancer at the cellular level. The next step is to find a partner and begin clinical trials using this new method to treat cancer in humans.

Source: RIKEN