Category: Cancer

Categories : Cancer GastrointestinalTags :

New Findings Reveal Immune Molecules that Drive Inflammatory Bowel Disease

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Irritable bowel syndrome. Credit: Scientific Animations CC4.0

Chronic inflammatory bowel disease is challenging to treat and carries a risk of complications, including the development of bowel cancer. Young people are particularly affected: when genetic predisposition and certain factors coincide, diseases such as ulcerative colitis or Crohn’s disease usually manifest between the ages of 15 and 29 – a critical period for education and early career development. Prompt diagnosis and treatment are crucial. Researchers at Charité – Universitätsmedizin Berlin have now discovered a therapeutic target that significantly contributes to halting the ongoing inflammatory processes. Their findings are published in the current issue of the journal Nature Immunology*.

Sometimes gradually, sometimes in flare-ups – accompanied by severe abdominal cramps, diarrhoea, weight loss, fatigue and a high level of emotional stress – this is how the two most common chronic inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, often begin. While ulcerative colitis only affects the inner lining of the large intestine, Crohn’s disease can involve the entire thickness of the intestinal wall, most commonly in the small intestine, but sometimes also the stomach and oesophagus. Ongoing inflammation can cause lasting tissue damage and increase the risk of cancer. While traditional treatments aim to suppress the immune system as a whole, newer therapies are more targeted: they interrupt the inflammatory process by blocking specific messenger substances that drive inflammation in the body.

The exact causes of severe systemic diseases are still not fully understood. In addition to genetic factors, environmental influences are also believed to play an important role in their development. Prof Ahmed Hegazy has been studying inflammatory processes in the gut and the immune system’s defence mechanisms at Charité’s Department of Gastroenterology, Infectiology and Rheumatology for several years. Together with his team, he has now succeeded in identifying the interaction between two messenger substances of the immune system as the driving force behind chronic intestinal inflammation: Interleukin-22, a protein that supports the cells lining the inside of the gut and helps maintain the protective barrier, and oncostatin M, a signalling molecule that plays a significant role in tissue repair and cell differentiation.

Uncontrolled chain reaction

“At the clinic, we mainly see young patients who just beginning their professional lives. So far, we have only been able to slow down the progression of the disease and alleviate symptoms. But not all patients respond well to existing treatments, so new therapeutic approaches are urgently needed,” says Ahmed Hegazy. In previous work, the research team closely examined the effects of oncostatin M, an inflammation-promoting messenger molecule. This protein, produced by certain immune cells, activates other inflammatory factors – setting off a chain reaction that triggers an excessive immune response. “It was especially interesting for us to see that patients with high levels of oncostatin M do not respond to several common therapies,” Ahmed Hegazy explains. “This means that Oncostatin M levels could help predict treatment failure and may serve as a biomarker for more severe disease. That’s exactly where we focused our efforts: we wanted to understand this signaling pathway better and find ways to block it with targeted treatments.”

The research team spent five years uncovering how the immune messenger oncostatin M triggers inflammatory responses. They began by using animal models, and later studies tissue samples from patients, to examine the different stages of chronic intestinal diseases, State-of-the-art single-cell sequencing showed that – compared to healthy tissue – a much larger number of unexpected cell types in the inflamed gut have receptors for oncostatin M. At the same time, additional immune cells start producing the inflammatory protein. Interestingly, interleukin-22, which normally protects tissue, also makes the gut lining more sensitive to oncostatin M by increasing the number of its receptors. “These two immune messengers work together and amplify the inflammation, drawing more immune cells into the intestine, like a fire that keeps getting more fuel and spreads,” as Ahmed Hegazy relates. “In our models, we specifically blocked the binding sites for oncostatin M and saw a clear reduction in both chronic inflammation and the associated of cancer.”

Targeted therapy for high-risk patients in sight

The researchers found a particularly high number of receptors for the messenger molecule oncostatin M around the tumours in tissue samples from patients with colorectal cancer caused by chronic intestinal inflammation, but not in the surrounding healthy tissue. This observation suggests that this signalling pathway may help promote cancer development. But chronic inflammation does not always lead to bowel cancer, and not every patient is affected in the same way, making treatment and prognosis difficult. With an understanding of oncostatin M’s amplifying effect on interleukin-22, new therapies may be possible.

The team’s experimental findings may soon translate into a real-world therapy: by specifically disrupting the harmful interaction between the immune messengers interleukin-22 and oncostatin M. “Our results provide a strong scientific basis for developing targeted treatments against this inflammation-promoting mechanism in chronic inflammatory bowel disease — particularly in patients with more severe forms of the illness,” explains Ahmed Hegazy. A clinical trial is already underway to test an antibody that blocks the receptors for Oncostatin M.

Source: Charité – Universitätsmedizin Berlin

Categories : Cancer General InterestTags :

Immune System the Focus of PhD’s Research at UKZN

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Elated at graduating with a doctoral degree is Dr Aviwe Ntsethe. Credit: University of KwaZulu-Natal

Dr Aviwe Ntsethe’s curiosity in the Medical field deepened when he started exploring the complexities of human physiology and the crucial role of the immune system in cancer, leading to him graduating with a PhD.

Growing up in the small town of Bizana in the Eastern Cape, Ntsethe attended Ntabezulu High School, where his passion for Medical Science took root. Despite facing significant challenges, including limited funding opportunities for his studies, he remained determined to advance in the discipline.

Throughout his PhD journey at UKZN, Ntsethe had to juggle multiple jobs to support himself and his studies while conducting his research. He worked at Netcare Education and the KwaZulu-Natal College of Emergency Care, and later took up a position as a contractual laboratory technician in the Department of Physiology at UKZN. It was with the guidance of his PhD supervisor, Professor Bongani Nkambule, that he learned critical work ethics and advanced laboratory techniques. The co-supervision of Professor Phiwayinkosi Dludla further enriched his research experience and contributed to his academic growth.

Ntsethe’s thesis focused on investigating B cell function and immune checkpoint expression in patients with Chronic Lymphocytic Leukaemia (CLL). The study found that patients with CLL had higher levels of immune checkpoint proteins in their B cell subsets, which play a crucial role in regulating the immune system.

Furthermore, using monoclonal antibodies that target these immune checkpoints, he found these patients could potentially benefit from immunotherapy. Specifically, immunotherapy may improve the function of B cells, key players in fighting infections and cancers, thereby offering new hope for better outcomes in patients with CLL.

He has published three papers from this study. ‘I am excited and proud when I reflect on my achievement of completing this significant journey which was both challenging and rewarding, pushing me to expand my knowledge and skills in ways I never imagined.’

Now, a lecturer at Nelson Mandela University, Ntsethe is committed to mentoring the next generation of Medical scientists. He continues to use the invaluable knowledge and experience he gained during his PhD studies to inspire students and cultivate their passions in research and health sciences. Looking ahead, Ntsethe hopes to expand his research, focusing on immune system interactions in chronic diseases while also encouraging students from diverse backgrounds to pursue careers in Medical Science.

Outside academia, Ntsethe enjoys travelling, staying physically active through workouts, playing chess and indulging in coding or programming.

Source: University of KwaZulu-Natal

Categories : Cancer Obstetrics & GynaecologyTags :

Do Bevacizumab’s Ovarian Cancer Clinical Trial Results Hold up in the Real World?

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Photo by Tima Miroshnichenko on Pexels

A real-world study based on information from an electronic health records–derived database reveals limited benefits of adding bevacizumab to first-line chemotherapy for patients with ovarian cancer, consistent with previous clinical trials. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor A that acts to inhibit malignant cell growth and blood vessel formation. It’s approved as a treatment for various types of cancer. In clinical trials of patients with ovarian cancer, adding bevacizumab to first-line chemotherapy did not prolong overall survival compared with chemotherapy alone, but this treatment strategy did improve overall survival in analyses limited to patients with high-risk prognostic factors—such as those with advanced disease and those who had residual cancer present after surgery. A final long-term analysis did not find an overall survival benefit associated with bevacizumab in the full patient cohort.

To investigate whether these findings also hold true in real-world clinical practice, researchers examined the electronic health records of 1,752 patients with stage III or IV ovarian cancer who initiated chemotherapy with or without bevacizumab in 2017–2023 and were followed for a median time of 1.5 years.

Among patients with high-risk prognostic factors, the median time to next treatment was significantly longer for those receiving chemotherapy plus bevacizumab compared with those receiving chemotherapy alone: 13.6 versus 11.7 months. (Time to next treatment is used to assess the duration of clinical benefit by measuring the time between initiating a treatment and starting the next line of therapy). In these patients, there was also a trend towards longer median overall survival for the combination therapy: 31.1 versus 27.4 months. Among patients without high-risk prognostic factors, outcomes did not differ with the addition of bevacizumab. Benefits therefore seemed limited to special subpopulations, mirroring the findings from clinical trials.

“Our results were similar to results from clinical trials,” said lead author Linda R. Duska, MD, MPH, of the University of Virginia School of Medicine. “Our findings suggest that clinicians should consider a patient’s risk factors before using bevacizumab with first-line chemotherapy in the treatment of advanced ovarian cancer.”  

Source: Wiley

Categories : CancerTags :

Localised Hypoxia Promotes Colon Cancer Growth

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Fig. 1. In healthy colon tissue, “good” fibroblasts help support tissue architecture. However, in colon cancer, these fibroblasts transform into “bad” fibroblasts in low-oxygen areas near the tumour surface. These “bad” fibroblasts block the formation of blood vessels, keeping their surroundings in an oxygen-deprived state, which supports their own survival. At the same time, they release growth-promoting factors that act like supplements for cancer cells. While it may seem unexpected that hypoxia supports tumour growth, this study reveals that localised hypoxic environments can accelerate cancer progression.

To effectively battle cancer, scientists must study the battlefield. Now, in a recent study published in Nature Communications, a multi-institutional research team including The University of Osaka has discovered some crucial intel: localised hypoxia in the colon cancer microenvironment can promote tumour growth.

Until recently hypoxia was thought to suppress tumour progression. Consequently, drugs that block the supply of oxygen to tumours were being used to treat cancers. But these treatments had mixed results; sometimes even accelerating tumour growth. Understanding why this happens has become an urgent question in cancer research.

“We uncovered a surprising mechanism by which hypoxia may promote tumour growth, and it involves the formation of cells called inflammatory fibroblasts,” explains lead author of the study, Akikazu Harada.

The research team found that when oxygen becomes scarce in certain areas of a colon tumour, the surrounding fibroblasts (normally ‘good’ cells that support tissue structure) transform into harmful inflammatory fibroblasts. The altered cells release factors that help tumours grow, such as epiregulin. In addition, they release Wnt5a protein, which helps maintain a low-oxygen state by inhibiting new blood-vessel formation at the site of its release, thereby maintaining hypoxia.

To validate the findings from the mouse model in human samples, the researchers pooled data from human samples obtained from patients with a healthy colon, colon cancer, and those with inflammatory bowel disease. Later, they analysed the data and compared their findings with data from mice.

“We found that the malignant transformation of fibroblasts and the induction of Wnt5a-secreting fibroblasts are commonly observed in both mouse models and human samples,” says Akira Kikuchi, senior author of the study.

This insight into the potential pathology of colon cancer and inflammation can provide the blueprints for a new cancer battle strategy: drug therapies that target Wnt5a-producing fibroblasts. As a result, fibroblasts are now being recognised as a key ‘third’ therapeutic target, complementing traditional treatments targeting cancer cells and immune cells.

This finding holds special importance for colon cancer, which is the leading type of cancer in Japan. Additionally, the observed pathological changes of fibroblasts could also apply to chronic inflammatory disorders like inflammatory bowel disease, offering fresh insights into their mechanisms and potential new treatment strategies for these challenging conditions.

Source: The University of Osaka

Categories : CancerTags :

New Study Reveals Why Common Leukaemia Treatments Fail in Some Patients

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Genetic mutations and cell maturity as key factors in acute myeloid leukaemia drug resistance

Photo by Tima Miroshnichenko on Pexels

An international study led by the University of Colorado Cancer Center has uncovered why a widely used treatment for acute myeloid leukaemia (AML) doesn’t work for everyone. The findings could help doctors better match patients with the therapies most likely to work for them.

The study was published in Blood Cancer Discovery.

Researchers analysed data from 678 AML patients, the largest group studied to date for this treatment, and found that both gene mutations and the maturity of leukaemia cells affect how patients respond to a drug combination of venetoclax and hypomethylating agents (HMA).

“Venetoclax-based therapies are now the most common treatment for newly diagnosed AML,” said Daniel Pollyea, MD, MS, professor of medicine at University of Colorado. “But not all patients respond the same way. Our goal was to figure out why and give doctors better tools to predict outcomes at the start.”

Mutations and maturity of leukaemia cells

AML is a fast-growing cancer of the blood and bone marrow, most often seen in older adults. Many patients can’t tolerate traditional chemotherapy, so doctors treat them with venetoclax plus HMA. This combination has improved survival for many, but some patients still relapse or don’t respond.

The study found that patients with a certain type of AML, called “monocytic,” had worse outcomes especially if they did not have a helpful gene mutation known as NPM1. These patients were also more likely to carry other mutations, such as KRAS, that are linked to drug resistance.

“Patients with monocytic AML and no NPM1 mutation were nearly twice as likely to die from the disease,” said Pollyea. “So, it’s not just about the gene mutations. It’s also about how developed or mature the cancer cells are when treatment begins.”

Previous research often focused only on either genetic mutations or cell type. Pollyea’s team looked at both, giving them a clearer understanding of how these two factors work together to influence treatment response.

Designing therapies that shut down cancer cell escape routes

“We learned that some cancer cells basically find a back door to evade the treatment,” said Pollyea. “By identifying how and why that happens, we can begin designing therapies that shut down those escape routes.”

This is a powerful new way to classify AML patients by risk, enabling doctors to better predict who is likely to respond to venetoclax and who might need another approach.

“This is a major step toward personalised medicine in AML,” said Pollyea. “We’re moving closer to a world where we can look at a patient’s leukaemia on day one and know which therapy gives them the best chance and ultimately improve survival rates.”

Pollyea and his team are working to expand the study with even more patient data and hope to design a clinical trial that uses this model to guide treatment decisions.

Source: University of Colorado Anschutz Medical Campus

Categories : Cancer Mental HealthTags :

SSRIs Could Help the Immune System Fight Cancer

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Photo by Danilo Alvesd on Unsplash

Selective serotonin reuptake inhibitors (SSRIs) could help the immune system fight cancer, according to recent UCLA research. The study, published in Cell, found that SSRIs significantly enhanced the ability of T cells to fight cancer and suppressed tumour growth across a range of cancer types in both mouse and human tumour models.

“It turns out SSRIs don’t just make our brains happier; they also make our T cells happier – even while they’re fighting tumours,” said Lili Yang, PhD, senior author of the new study. “These drugs have been widely and safely used to treat depression for decades, so repurposing them for cancer would be a lot easier than developing an entirely new therapy.”

According to the CDC, one out of eight adults in the US takes an antidepressant, and SSRIs are the most commonly prescribed. These drugs increase levels of serotonin the brain’s “happiness hormone” by blocking the activity of a protein called serotonin transporter, or SERT. 

While serotonin is best known for the role it plays in the brain, it’s also a critical player in processes that occur throughout the body, including digestion, metabolism and immune activity. 

Dr Yang and her team first began investigating serotonin’s role in fighting cancer after noticing that immune cells isolated from tumours had higher levels of serotonin-regulating molecules. At first, they focused on MAO-A, an enzyme that breaks down serotonin and other neurotransmitters, including norepinephrine and dopamine. 

In 2021, they reported that T cells produce MAO-A when they recognise tumours, which makes it harder for them to fight cancer. They found that treating mice with melanoma and colon cancer using MAO inhibitors, also called MAOIs – the first class of antidepressant drugs to be invented – helped T cells attack tumours more effectively. 

However, because MAOIs have safety concerns, including serious side effects and interactions with certain foods and medications, the team turned its attention to a different serotonin-regulating molecule: SERT. 

“Unlike MAO-A, which breaks down multiple neurotransmitters, SERT has one job – to transport serotonin,” explained Bo Li, PhD, first author of the study and a senior research scientist in the Yang lab. “SERT made for an especially attractive target because the drugs that act on it – SSRIs – are widely used with minimal side effects.” 

The researchers tested SSRIs in mouse and human tumour models representing melanoma, breast, prostate, colon and bladder cancer. They found that SSRI treatment reduced average tumour size by over 50% and made the cancer-fighting T cells, known as killer T cells, more effective at killing cancer cells. 

“SSRIs made the killer T cells happier in the otherwise oppressive tumour environment by increasing their access to serotonin signals, reinvigorating them to fight and kill cancer cells,” said Dr Yang, who is also a professor of microbiology, immunology and molecular genetics and a member of the UCLA Health Jonsson Comprehensive Cancer Center.

How SSRIs could boost the effectiveness of cancer therapies 

The team also investigated whether combining SSRIs with existing cancer therapies could improve treatment outcomes. They tested a combination of an SSRI and anti-PD-1 antibody – a common immune checkpoint blockade (ICB) therapy – in mouse models of melanoma and colon cancer. ICB therapies block immune checkpoint molecules that normally suppress immune cell activity, allowing T cells to attack tumours more effectively. 

The results were striking: the combination significantly reduced tumour size in all treated mice and even achieved complete remission in some cases. 

“Immune checkpoint blockades are effective in fewer than 25% of patients,” said James Elsten-Brown, a graduate student in the Yang lab and co-author of the study. “If a safe, widely available drug like an SSRI could make these therapies more effective, it would be hugely impactful.”

To confirm these findings, the team will investigate whether real-world cancer patients taking SSRIs have better outcomes, especially those receiving ICB therapies. About 20% of cancer patients are already taking the medication, Dr Yang said.

Dr Yang added that using existing FDA-approved drugs could speed up the process of bringing new cancer treatments to patients, making this research especially promising.

“Studies estimate the bench-to-bedside pipeline for new cancer therapies costs an average of $1.5 billion,” she said. “When you compare this to the estimated $300 million cost to repurpose FDA-approved drugs, it’s clear why this approach has so much potential.”

Source: University of California – Los Angeles Health Sciences

Categories : Cancer New Compounds and TreatmentsTags :

Scientific Breakthrough: Price of Costly Cancer Drug can be Halved

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Source: Unsplash CC0

Taxol is one of the most commonly prescribed chemotherapy drugs for breast, ovarian, cervical, and lung cancer. Yet producing the drug is complex, costly, and environmentally burdensome, as it currently relies on a complicated chemical semi-synthesis. For 30 years, scientists around the world have tried to understand how taxol, a natural compound derived from the Pacific yew tree, forms in nature. Decoding this process would allow for biotech-based production. But the final steps remained unknown – until now.

A research team from the University of Copenhagen has succeeded in finding the two missing pieces: They have identified the enzymes responsible for the two critical final steps in the biosynthetic pathway that makes Taxol active as a drug.

“Taxol has been the Holy Grail in this research field for decades because it’s an exceptionally complex molecule. But with the discovery of the final two enzymes, we now fully understand how it’s formed. This has allowed us to develop a biotechnological method to produce taxol in yeast cells,” says Sotirios Kampranis, Professor at the Department of Plant and Environmental Sciences and senior author of the study published in Nature Synthesis.

The method involves cloning the taxol-producing genes from the yew tree and inserting them into yeast cells. These engineered yeast cells then become host organisms or micro-factories with the full recipe to produce taxol.

Affecting women in developing countries

The research team from the University of Copenhagen has applied for patenting the method and is in the process of launching a spin-out company to manufacture biosynthetic Taxol. 

“Using this method, we can produce Taxol cheaper than current conventional methods. Looking ahead, once we refine the process further, we expect to be able to reduce the cost by half,” says Assistant Professor and first author Feiyan Liang.

Lower prices are especially crucial as ovarian cancer is on the rise globally. The prevalence of the disease is expected to increase by over 55% by 2050, with the vast majority of cases in low and middle-income countries. The number of women dying from ovarian cancer is projected to rise by nearly 70% in the same period.

Currently, taxol costs more than USD20 000 per kilogram, making it one of the most expensive active pharmaceutical ingredients in use.

“We see increasing demand for Taxol in many developing countries, where the high price is a major barrier. We hope our work will contribute to lower-priced drugs so that more people can have access to cancer treatment,” Feiyan Liang says.

Much more sustainable

The new method is not only more cost-effective but also more sustainable than chemical synthesis. One advantage is that the procedure does not involve harmful chemicals and solvents common in chemical production. Another advantage is that it allows the use of more crude, less purified extracts from yew needles as starting material – much cheaper than the ultra-pure inputs required in chemical semi-synthesis. On top of that, the materials can be recycled.

“We want to show that it’s possible to build a biotechnological drug production that is both sustainable and low-cost. There are very few examples of that today, but we now have the foundation to make it happen,” says Sotirios Kampranis. 

TWO TREES PER TREATMENT

  • Taxol was originally extracted from the inside bark of the Pacific yew tree (Taxus brevifolia), but as the taxol content in the bark is very low, harvesting it meant removing all the bark and as a result of this killing the tree.
  • Yew trees take 70 to 100 years to mature. Producing just one treatment required about two trees, making this method highly unsustainable. It was abandoned years ago, though wild yew trees are still under pressure in some regions.
  • Today’s most common method involves harvesting a similar compound from yew needles for chemical synthesis, but the cost of this process is still high, which is why the average price of taxol exceeds USD 20 000 per kilogram (source: pharmacompass.com).

Source: University of Copenhagen – Faculty of Science

Categories : CancerTags :

South African Study Identifies Two New Breast Cancer Genes in Black Women

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Genetic factors contribute to some 30% of breast cancer cases in SA, necessitating investment in genomic research in African contexts.

Photo by National Cancer Institute

A seminal genetic study published in Nature Communications has discovered two genetic variants linked to breast cancer in black South African women, deepening knowledge about the genetic basis for this disease in African populations.

The genome-wide association study (GWAS) of breast cancer is the first to have been done in African women living on the continent.

A GWAS is a powerful research method that scans the entire DNA of many people to find genetic differences associated with a specific disease or trait.

In this case, the scientists at the Sydney Brenner Institute for Molecular Bioscience (SBIMB) scanned for breast cancer and found consistent genetic patterns in black South African women.

The SBIMB researchers discovered genetic signals around the gene RAB27A, a member of the RAS oncogene family, and USP22, a gene which is highly active in breast cancer cells and associated with a poor health prognosis.

“These genes have not been associated with the disease before, which is an important advance in understanding breast cancer risk and biology in women of African ancestry,” says Dr Mahtaab Hayat, the lead author of the study.

The two new genetic variants were identified in black South African women with breast cancer enrolled in the Johannesburg Cancer Study, compared to women without cancer in the Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen) study.

Until now, most breast cancer genetics research has focused on European and Asian populations, with studies of African ancestry limited primarily to African- American women, who largely descend from West African populations.

A tool that estimates lifetime cancer risk based on DNA, the polygenic risk score (PRS), performed poorly in distinguishing South African women with breast cancer from those without.

“This is because most PRSs were developed in European populations, and their inaccuracy in African populations highlights the urgent need for ancestry-specific tools in cancer risk prediction,” says Dr Jean-Tristan Brandenburg, also in the SBIMB and a lead author.

Breast cancer is the second most common cancer in South Africa and the most common cancer in women globally, with genetic factors contributing to about 30% of cases. “Our study makes a compelling case for investing in genomic research rooted in African contexts,” notes Hayat.

The potential for precision medicine

If further studies confirm these findings, the USP22 and RAB27A genes could be specific targets for new drugs. “We could potentially target harmful cancer cells while sparing healthy tissue, which is ideally what we want when administering cancer treatment,” says Distinguished Professor at the SBIMB, Chris Mathew, and a lead project investigator.

Furthermore, if a specific gene is associated with poorer survival, it can be used as a biomarker to identify more aggressive cancers and help predict which patients may need more intensive treatment and monitoring.

Understanding the genetic architecture of complex diseases helps scientists figure out the biological processes leading to these conditions and find drug targets and treatments for groups of individuals with similar disease risk profiles.

Genomic diversity in Africa is unparalleled

African populations have more genetic variation than any other population in the world, but they have been significantly underrepresented in genomic research. This means that the global understanding of disease risk, and the tools and treatment developed from it, is limited.

“The study reveals that more people can benefit from genetic discoveries. It proves that new risk factors are still out there, waiting to be found,” says Hayat.

Source: University of the Witwatersrand

Categories : CancerTags :

A Downside of Taurine: It Drives Leukaemia Growth

On By Peter Van Dyk
SAG Leukaemia. Credit: Scientific Animations CC0

A new scientific study identified taurine, which is made naturally in the body and consumed through some foods, as a key regulator of myeloid cancers such as leukaemia, according to a paper published in the journal Nature.

The preclinical research shows that scientists are a step closer to finding new ways to target leukaemia, which is one of the most aggressive blood cancers. The Wilmot Cancer Institute investigators at the University of Rochester were able to block the growth of leukaemia in mouse models and in human leukaemia cell samples by using genetic tools to prevent taurine from entering cancer cells.

Led by Jeevisha Bajaj, PhD, the research team discovered that taurine is produced by a subset of normal cells in the bone marrow microenvironment, the tissue inside bones where myeloid cancers begin and expand. Leukaemia cells are unable to make taurine themselves, so they rely on a taurine transporter (encoded by the SLC6A6 gene) to grab taurine from the bone marrow environment and deliver it to the cancer cells.

The discovery occurred as scientists were mapping what happens within the bone marrow and its ecosystem—a longtime focus among Wilmot researchers, who have advanced the science around the microenvironment with the goal of improving blood cancer treatments.

“We are very excited about these studies because they demonstrate that targeting uptake by myeloid leukaemia cells may be a possible new avenue for treatment of these aggressive diseases,” said Bajaj, an assistant professor in the Department of Biomedical Genetics and a member of Wilmot’s Cancer Microenvironment research program.

Researchers also discovered that as leukaemia cells drink up taurine, it promotes glycolysis (a breakdown of glucose to produce energy) to feed cancer growth. Prior to this, the authors said, it was not known that taurine might have a cancer-promoting role.

Leukaemia has several subtypes and survival rates vary. This study finds that taurine transporter expression is essential for the growth of multiple subtypes including acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), and myelodysplastic syndromes (MDS), which all originate from blood stem cells in the bone marrow. Future studies will investigate signals from the microenvironment that promote the transition of MDS, a precursor to leukaemia, to acute leukaemia.

Source: University of Rochester Medical Center

Categories : Cancer NeurologyTags :

CAR-T Cell Therapy Causes ‘Brain Fog,’ Study Shows

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Killer T cells about to destroy a cancer cell. Credit: NIH

After treatment with CAR-T cells, immune cells engineered to attack cancer, patients sometimes tell their doctors they feel like they have “brain fog,” or forgetfulness and difficulty concentrating.

A new Stanford Medicine-led study shows that CAR-T cell therapy causes mild cognitive impairments, independent of other cancer treatments, and that this happens via the same cellular mechanism as cognitive impairment from two other causes: chemotherapy and respiratory infections such as flu and COVID-19. The study, conducted mostly in mice, which was published in Cell, also identifies strategies for reversing the problem.

Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers said.

“CAR-T cell therapy is enormously promising,” said senior author, Michelle Monje, MD, PhD, professor in paediatric neuro-oncology. “We need to understand all its possible long-term effects, including this newly recognised syndrome of immunotherapy-related cognitive impairment, so we can develop therapeutic approaches to fix it.”

The study’s lead authors are Anna Geraghty, PhD, senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez.

Cognitive impairment after CAR-T cell therapy is typically mild; patients are not developing dementia, for instance. But it is frustrating and may not resolve on its own, Monje said. In mice, her team reversed the impairment using compounds similar to existing medications or medications in clinical development – meaning a treatment could be available relatively quickly, she said.

“We’re deeply interested in how cancer therapies affect cognition because it affects patients’ quality of life,” Monje said. “And this is especially important for kids because their brains are still developing.”

Investigating brain fog

CAR-T cell therapy was approved in the US for acute lymphoblastic leukaemia in 2017. The treatment involves removing some of the patient’s own immune cells, known as T cells, and engineering them to attack targets on cancer cells. The modified T cells are returned to the patient’s body, where they recognise and destroy cancer.

In addition to leukaemia, CAR-T cells are now used to treat other blood cancers, including multiple myeloma and some kinds of lymphoma, and they are being tested in clinical trials for various solid tumours. Monje and her colleagues have an ongoing trial of CAR-T cells for deadly brain stem and spinal cord tumours in children, which is beginning to show success.

Although patients report brain fog after CAR-T cell therapy, studies to measure how much cognitive impairment the therapy causes are only just emerging.

The research team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. They studied mice that had tumours induced in the brain, blood, skin and bone. The researchers wanted to understand the influence on cognition of CAR-T cell treatment in combination with the tumours’ location (originating in, spreading to or staying outside the brain), as well as the degree to which the engineered cells evoked additional, accompanying immune responses. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how mice responded to a novel object and navigated a simple maze.

CAR-T therapy caused mild cognitive impairment in mice with cancers originating in, metastasizing to and located completely outside the brain. The only mice tested that did not develop cognitive impairment after CAR-T treatment were those that had bone cancer that causes minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.

“This is the first study to demonstrate that immunotherapy on its own is sufficient to cause lasting cognitive symptoms,” Monje said. “It’s also the first paper to uncover the mechanisms. We found the exact same pathophysiology we’ve seen in brain fog syndromes that occur after chemotherapy, radiation, and mild respiratory COVID-19 or influenza.”

The researchers demonstrated that the brain’s immune cells, called microglia, are key players in the problem. First, the microglia become activated by the body’s immune response. The activated, “annoyed” microglia produce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects throughout the brain. They are particularly harmful for oligodendrocytes, the brain cells responsible for making myelin, the fatty substance that insulates nerve fibres and helps nerves transmit signals more efficiently. Reduction in the nerves’ insulation translates into cognitive impairment.

Examining tissue samples

The scientists also analysed samples of brain tissue from human subjects who participated in the team’s ongoing clinical trial of CAR-T cells for spinal cord and brain stem tumours. Using post-mortem tissue samples, the researchers confirmed that microglia and oligodendrocytes appear dysregulated in the same way the team had observed in mice after CAR-T therapy.

In mice, the research team tested strategies to resolve the cognitive problems. They gave a compound that depleted microglia in the brains of the mice for a two-week period. After that transient depletion, the microglia  returned in the brain in a normal, non-reactive state. The mice were no longer cognitively impaired.

The researchers also gave the mice a medication that enters the brain and interferes with signals from damaging chemokines, blocking a specific receptor for these molecules.

“That alone rescued cognition,” Monje said, adding that the researchers are now exploring how to safely translate the two strategies – transiently depleting microglia or interrupting chemokine signals – in people who have had CAR-T cell therapy.

“This research further illustrates that there is a unifying principle underpinning brain fog syndromes,” said Monje, a member of the Stanford Cancer Institute. “And this particular study is so exciting because not only have we identified the cells central to this pathophysiology, we’ve found a molecular target we can investigate to treat it.”

Source: Stanford Medicine