Study shows that higher levels of physical activity are linked with less pain, and to a similar extent in adults with and without a history of cancer.
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People who have had cancer often experience ongoing pain, but a new study reveals that being physically active may help lessen its intensity. The study is published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
Although physical activity has been shown to lessen various types of pain, its effects on cancer-related pain are unclear. To investigate, a team led by senior author Erika Rees-Punia, PhD, MPH, of the American Cancer Society, and first author Christopher T.V. Swain, PhD, of the University of Melbourne, in Australia, analysed information pertaining to 51 439 adults without a history of cancer and 10,651 adults with a past cancer diagnosis. Participants were asked, “How would you rate your pain on average,” with responses ranging from 0 (no pain) to 10 (worst pain imaginable). Participants were also asked about their usual physical activity.
US guidelines recommend 150 minutes (2 hours 30 minutes) to 300 minutes (5 hours) a week of moderate-intensity, or 75 minutes (1 hour 15 minutes) to 150 minutes (2 hours 30 minutes) a week of vigorous-intensity aerobic physical activity.
Based on participants’ responses, the investigators found that, for individuals who had cancer in the past as well as for those without a history of cancer, more physical activity was linked with lower pain intensity. The extent of the association was similar for both groups of individuals, indicating that exercise may reduce cancer-related pain just as it does for other types of pain that have been studied in the past.
Among participants with a past cancer diagnosis, those exceeding physical activity guidelines were 16% less likely to report moderate-to-severe pain compared to those who failed to meet physical activity guidelines. Also, compared with people who remained inactive, those who were consistently active or became active in older adulthood reported less pain.
“It may feel counterintuitive to some, but physical activity is an effective, non-pharmacologic option for reducing many types of pain. As our study suggests, this may include pain associated with cancer and its treatments,” said Dr Rees-Punia.
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH
Calcium ions are essential for cells, but can be toxic in higher concentrations. A team of researchers has now designed and prepared a combination drug that kills tumour cells by modulating the calcium influx into the cell. An external calcium source is not necessary because only the calcium ions already present in the tumour tissue are used, according to the study published in the journal Angewandte Chemie.
Biological cells need calcium ions, among other things, for the proper functioning of the mitochondria, the powerhouses of the cells.
However, if there is too much calcium, the mitochondrial processes become unbalanced and the cell suffocates.
A research group led by Juyoung Yoon of Ewha Womens University in Seoul, South Korea, together with teams from China, has now taken advantage of this process and developed a synergistic antitumour drug that can open calcium channels and thus trigger a deadly calcium storm inside the tumour cell.
The researchers targeted two channels, the first one in the outer membrane, and the other was a calcium channel in the endoplasmic reticulum, a cell organelle that also stores calcium ions.
The channel located in the outer membrane opens when it is exposed to a large amount of reactive oxygen species (ROS), while the channel in the endoplasmic reticulum is activated by nitric oxide molecules.
To generate the ROS that open the outer membrane calcium channel, the researchers used the dye indocyanine green.
This bioactive agent can be activated by irradiation with near-infrared light, which not only triggers reactions that lead to ROS, but it also heats up the environment.
The team explains that the high local temperature activates the other active agent, BNN-6, to release nitric oxide molecules that open the channel in the endoplasmic reticulum.
Following successful trials in tumour cell lines, the team tested an injectable formulation in tumour-implanted mice.
To create a biocompatible combined drug, the researchers loaded the active ingredients into tiny modified porous silica beads that are not harmful to the body, but can be recognized by tumour cells and transported into the cell.
After injecting the beads into the bloodstream of the mice, the researchers observed that the drug accumulated in the tumour.
Exposure to near-infrared light successfully triggered the mechanism of action, and the tumour disappeared after a few days in mice that received the preparation.
The authors emphasise that this ion influx approach may also be useful in related biomedical research areas where a similar mechanism could activate ion channels different from calcium in order to find new therapeutic approaches.
Immunotherapy in combination with chemotherapy has become an important therapeutic treatment option in some patients with metastatic breast cancer. Which patients will benefit the most, however, remains unclear; current biomarkers such as PD-L1 that are used to predict response are mediocre at best. Vanderbilt researchers led a clinical trial combining atezolizumab, an immunotherapy, in combination with chemotherapy in patients with metastatic triple-negative breast cancer to both evaluate the efficacy of the treatment combination and to understand biomarkers of response to immunotherapy.
Atezolizumab became the first approved immunotherapy for breast cancer when the Food and Drug Administration granted it accelerated approval in 2019, but two years later, its maker voluntarily withdrew the indication after additional data from a follow-up clinical trial failed to corroborate its efficacy. Atezolizumab had been approved for metastatic PD-L1-positive triple-negative breast cancer in combination with the chemotherapy nab-paclitaxel. Results from Vanderbilt’s clinical trial, published in JAMA Oncology, indicate that this immunotherapy does have a clinically meaningful benefit with a different chemotherapy partner and the correlative analyses provide insight to which patients will respond.
The clinical trial combined atezolizumab with carboplatin – a chemotherapy that works differently than nab-paclitaxel. The new combination significantly improved progression-free and overall survival of patients with metastatic triple-negative breast cancer. Atezolizumab with carboplatin lengthened progression-free survival from a median of 2.2 months to 4.1 months. Overall survival increased from a median of 8.6 months for the control group, who received carboplatin alone, to 12.6 months for those who received the combination therapy.
The phase 2 randomized clinical trial was conducted at six cancer centers through the Translational Breast Cancer Research Consortium and involved 106 patients of diverse ethnicities.
“Triple-negative breast cancer is difficult to treat because we don’t have a clear target, and understanding the underlying factors that affect response to a treatment is key. This study is so important because we were able to collect biopsies in all of the participants and really understand factors that affect response,” said Vandana Abramson, MD, the Donna S. Hall Professor in Cancer Research and co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center.
The researchers hypothesised that atezolizumab would have superior efficacy to carboplatin because the chemotherapy is a platinum agent, which causes structural DNA changes and generates neoantigens that may stimulate an immune response. Nab-paclitaxel chemotherapy works differently: it is a microtubule-stabilising agent that stops cancer cell division.
“The tremendous knowledge gained from our multidisciplinary analyses of the patients and their tumours will continue to be important for clinical decision-making. After our first description of the triple-negative breast cancer subtypes over 10 years ago, more recently, we refined the subtypes further into four, which were analysed in this study: two basal-like subtypes, a mesenchymal subtype and a lumen androgen receptor-expressing subtype. When we refined the triple-negative breast cancer subtypes, we revealed an immune-modulatory descriptor or correlation.
“This JAMA Oncology study and others continue to confirm that lymphocytes, as measured by the immune-modulatory correlation, have predictive value for better relapse-free survival for triple-negative patients. Further, this study provides evidence that the luminal androgen receptor subtype is more like oestrogen receptor-positive (or ER+) disease. Prior studies investigating immunotherapy in breast cancers have shown that patients with ER+ disease have less benefit from immunotherapy, and we found that to be the case with patients with luminal androgen-positive tumours in this trial,” said Jennifer Pietenpol, PhD, the study’s corresponding author.
Interestingly, patients with higher body mass indexes and uncontrolled blood glucose levels had greater benefit from atezolizumab with carboplatin. The researchers noted that these patients may have more immune cells upon which anti-PD1/PD-L1 therapies can act. A lower risk of disease progression was also associated with high mutation burden and increased tumour-infiltrating lymphocytes.
“In this study, we observed that patients received benefit with atezolizumab even if the tumours were PD-L1 negative. We also show that, like prior clinical trials in melanoma and renal and lung cancers, tumours with high mutation burdens and the presence of immune cells within or around the tumour receive greater benefit from immunotherapy. This makes sense because each mutation has the potential to be recognised as non-self by the immune system, increasing the probability of immune cells already positioned around the tumour to recognise and target the cancer,” said Brian Lehmann, PhD, Research Associate Professor of Medicine and lead correlative scientist on the study.
“One surprising finding was the trend toward greater benefit for patients with higher body mass indexes and patients with uncontrolled blood glucose at prediabetic and diabetic levels while on the study. Both obesity and diabetes are linked to systemic inflammation, and the increased benefit may be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as Type 2 diabetes. Further studies are necessary to validate these findings and delineate the effects of blood glucose and obesity on immunotherapy,”
The combination therapy was generally well-tolerated, and toxic effects were consistent with previous reports for atezolizumab. The most common drug complications on the combination arm of the clinical trial were low blood platelet counts, anaemia, lymphocytopenia, nausea, fatigue and increased liver enzymes. The participants identified as 69% white, 19% African American, 10% unknown and 1% Asian.
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.
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.
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.”
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.”
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.
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 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.”
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.
