News
RANKL/RANK suppression as a potential new target for the therapy of colon cancer metastases
In a recent publication, researchers have confirmed the role of a TNF receptor superfamily member and its ligand as a driver of Colorectal cancer (CRC) progression and metastasis. Treg-derived RANK and its ligand RANKL were found to cause the production of the chemokine, CCL20 by tumour cells, which would interact with more Tregs, leading to more Tregs being recruited. This positive feedback loop in turn leads to promotion of cancer cell stemness and metastasis. The research conducted in this study was built upon previous findings of RANK/RANKL’s association with CRC. The findings from this study are highly encouraging as they may become an effective drug target to reduce cancer spread, and the disease burden of metastasis.
New colorectal cancer cell-free DNA blood test approved by FDA and used in patients in the United States
Guardant Health, a biotechnology company based in Palo Alto, California, USA, has had one of its blood tests for colon cancer approved by the FDA. Shield is advertised as a, ‘a colon cancer screening option to get excited about’ for patients. The public regards colonoscopies as a screening option not to be excited about. A blood sample is taken and sent to Guardant Health for the Shield test. The test identifies colorectal cancer-specific alterations in cell-free DNA and is for use in colorectal cancer screening in individuals at risk for colorectal cancer aged 45 years or older.
While excellent as a preliminary diagnostic tool, the test has several limitations. Shield has limited detection of Stage I colorectal cancer and has limited effectiveness at detecting precancerous lesions. Shield is effective in detecting Stage II-IV colorectal cancers. Shield is marketed towards the general public who are otherwise healthy. It is not intended for patients with a family history of colorectal or other cancers, or with a previous positive result in the last 6 months. It is also not intended for patients with Inflammatory Bowel Disease, chronic ulcerative colitis, or Crohn’s Disease. While it doesn't replace colonoscopies and is intended as a routine test for otherwise healthy patients, doctors are optimistic about its potential to improve screening rates.
Dr. Arvind Dasari from MD Anderson Cancer Center called the approval a “welcome development” but noted, “We’ll have to wait and see what the impact will be.” Another doctor, Dr. William Grady from Fred Hutchinson Cancer Centre highlighted the importance of screening, saying, “What breaks my heart is that it’s preventable, one of my biggest joys is when I’m doing a colonoscopy and I can take out polyps that, if left alone, would have progressed to cancer.” emphasizing that colonoscopy remains the most accurate method but noting that a blood test is convenient for many people.
Gut microbes – the key to handling stress?
Stress can have huge impacts on our body, suppressing our immune system and increasing our risk of diseases like cancer, as well as mental health issues like anxiety and depression. An exciting new study published in Nature Mental Health shows resilience to stress may lie within our gut.
The latest research from UCLA shows that people who are resilient in the face of stress have unique brain activity and microbial composition in their gut. This study recruited 116 people without mental health diagnoses and evaluated their resilience using a psychological scale. Participants then underwent magnetic resonance imaging (MRI) for brain activity and gave stool samples to assess their gut microbial composition.
The study found that highly resilient people had greater brain activity in areas associated with emotion regulation and mindfulness and lower activity in areas associated with anxiety and depression, as measured by MRI. Within the microbiome of these highly resilient people, they found the presence of gut bacterial signatures associated with anti-inflammatory processes, improved gut barrier function, and increased environmental adaptation.
This research shows an unappreciated link between the gut and the brain, particularly the ability of gut microbes and microbial compounds to influence brain processes, including our response to stress.
Source: https://www.nature.com/articles/s44220-024-00266-6
Blood plasma can be analysed using infrared light to identify Crohn’s disease
A team of researchers in France have demonstrated the use of infrared spectroscopy to detect Crohn’s disease from patient’s plasma with an accuracy of 97 %. Infrared spectroscopy is a non-destructive technique that detects the characteristic absorptions of infrared light (light with longer wavelengths than what we can see) by molecules to give a “spectral fingerprint” relating to molecular composition. In plasma samples this spectral fingerprint gives information on the composition and relative abundance of biomolecules. These biomolecules are present in slightly different levels between Crohn’s disease and control patients. The researchers were able to use this spectral fingerprint with multivariate data analysis techniques to create a classification model to distinguish between Crohn’s disease and control patients. This type of technology needs to be further assessed and developed in larger studies before implementing in clinic, but it is an exciting field to follow and I hope to see it developed to a level that aids the diagnostic pathway for Crohn’s disease in the future.
How does having inflammatory bowel diseases affect your eating and physical activity habits?
A disease flare often makes it difficult to eat well or be as physically active as normal. Research from other countries suggest that people with inflammatory bowel diseases (IBD) like Crohn’s or colitis, eat differently and exercise less compared to people without IBD, but these habits are not known in New Zealand.
A recent University of Otago research known as the IBD exercise and dietary (IBDeat) study, found that around 69% of people with IBD avoided trigger foods to manage their symptoms. These were mainly gluten (from wheat, barley, rye), dairy products, or high fibre foods including fruits and vegetables. Many people also felt that fatigue, stomach cramps, bowel symptoms, and joint pain were the main challenges to being active.
It is well known that eating a balanced diet and being physically active are the few key steps to maintaining good health. A balanced diet means trying to eat a variety of grain foods, dairy products or fortified plant milks, protein foods, and a rainbow of fruits and vegetables. Although this can be fairly challenging at times for many people with IBD, some studies have shown that it is possible to achieve with proper guidance.
Based on those studies, the IBD Lifestyle Food & Exercise (IBDLiFE) study aims to find out whether providing credible resources and/or support can help people with IBD to make the desired lifestyle changes while managing their symptoms. This research will provide valuable insights to practical lifestyle advice for people with IBD.
Just over half of NZ Patients with Inflammatory Bowel Disease have ‘Good’ Medication Adherence: a look at how well patients take their medication
As former US Surgeon General, Dr C. Everett Koop, said: “Drugs don't work in patients who don't take them.” Hence, it is very important for patients to take their medications as prescribed i.e. practice medication adherence (MA). This is essential particularly for patients with Inflammatory Bowel Disease (IBD) as IBD has no cure; so, it is mainly managed using life-long medication therapy with disease monitoring, besides other interventions.
IBD is a chronic gut disease made up of Crohn’s Disease, Ulcerative Colitis and IBD-unclassified. Patients with IBD may experience periods of active disease with ‘flare-ups’ and ‘quiescent’ periods at other times. They may also have symptoms including (bloody) diarrhoea, urgency, constipation, abdominal pain, weight loss amongst others; all of which limit their quality of life and productivity.
Researchers at the University of Otago, Department of Medicine, investigated the nationwide MA levels of patients with IBD using national pharmacy dispensing claims and hospitalisation data. They found that the average MA over three years, for 4654 patients, was moderately high at 77.4%. Likewise, average MA over five years was also moderately high at 74.9% for 3148 patients. These were measured using a novel formular called daily polypharmacy possession ratio (DPPR) which calculates MA to multiple medications taken at the same time.
The picture was a bit different when they calculated how many patients had ‘good adherence’ i.e. patients whose MA was at least 80%. Only 54% and 51% of patients over three and five years, respectively, met this threshold. These findings suggest that a closer look needs to be paid into the long-term MA patterns and, importantly, the factors impacting how patients with IBD take their medications.
New radiotracer quickly detects gastrointestinal cancer biomarker and helps to identify patients for targeted therapy
Gastrointestinal (GI) cancers occur in the digestive system. It is among the most common types of cancer worldwide. Diagnosis typically involves a combination of endoscopy, imaging (like CT scans and PET scans), biopsies, and blood tests. Treatment options depend on the cancer type and stage and may include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Early detection generally leads to better outcomes, but many GI cancers are diagnosed at an advanced stage, which can complicate treatment and worsen prognosis. A new synthesized PET scan radiotracer, 68Ga-NC-BCH, helps doctors see a protein called Claudin18.2 (an important GI cancer biomarker) that is often found in high amounts in GI cancers. Uptake of 68Ga-NC-BCH is correlated with the amount of Claudin18.2. 68Ga-NC-BCH lets doctors take detailed images in one day, unlike older methods that might take longer and be more invasive. It specifically targets the Claudin18.2 protein. This means doctors can get a clear view of where the cancer is and how much of the protein is in the body. Compared to traditional methods, this new tool is non-invasive and provides quick, accurate results. It can help doctors make better treatment decisions and track how well treatments are working.
Liver transplant added to chemotherapy improves survival in advanced colorectal cancer
The incidence of colorectal cancer continues to rise worldwide. Colorectal cancers originate in the bowel but have the potential to spread or metastasize to other organs. The most common site of spread of colorectal cancer is the liver and to date the most effective treatment for this surgery is to remove the liver, usually in combination with chemotherapy. Unfortunately, only twenty percent of people with liver metastases from colorectal cancer will be able to have surgery to remove the cancer. To date there have been no other treatments that offer a potential cure for people with liver metastases that cannot be surgically removed.
In this clinical trial people with liver metastases from colorectal cancer that are unable to be removed with surgery were randomized to receive either liver transplant and chemotherapy or chemotherapy alone. Promisingly, those patients who underwent liver transplantation had better survival rates compared with those who did not. The combination of liver transplantation and chemotherapy may offer a potential cure to those people who would otherwise have a poor long-term outcome.
Source: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00187-1/fulltext
SOX17 enables immune evasion of early colorectal adenomas and cancers
Being able to treat colorectal cancer (CRC) with the right treatment and early is key to improving the health outcomes and long-term survival of patients. One of the ways cancers establish and progress is by blunting the immune defence. This study by Goto et al (2024) has shown that protein, SOX17, helps tumours escape the immune system in early tumour development. SOX17 plays a role in embryonic development and is not usually expressed in the healthy gut lining of adults. The researchers grew mini tumours with common CRC-associated mutations and transplanted them into the colons of mice. The researchers observed an increase in SOX17 expression and decreased cancer-fighting T cells and reduced activity of immune protein, interferon gamma. When the research team generated colorectal tumours that were unable to express SOX17, these tumours became susceptible to the anti-cancer immune response. These findings show that SOX17 is playing a role in the tumours ability to hide from the immune system. The research team validated that human colorectal cancers express SOX17 and, at higher levels in early CRC compared to late stage CRC, suggesting that SOX17 is important for tumour establishment and development by preventing immune surveillance.
Next steps will involve identifying other proteins in this immunosuppressive pathway mediated by SOX17, which may reveal new therapeutic targets. In the bigger picture, it may be important to consider how early CRC and pre-cancerous growths are detected and how we can utilise ‘early’ treatments when they are needed. This study evidences a new immune evasion mechanism facilitated by SOX17 in the early stages of CRC development.
Promising new immune checkpoint inhibitor for colorectal cancer
In New Zealand, colorectal cancer (CRC) is the most diagnosed cancer and the second most common cause of death due to cancer. Overall survival rates of people are highly variable even with advancements in therapy. One form of therapy, known as immune checkpoint inhibitors (ICI), aims to reinvigorate the immune response to help destroy tumour cells. However, immune checkpoint inhibitors have only been effective in people with microsatellite instable high or mismatch repair deficient CRC, which represent about 4% of CRC types. ICI therapy has been elusive for the more common form of CRC known as the microsatellite stable CRC.
In a recently concluded phase 1 clinical trial, a new ICI botensilimab (antiCTLA4) was used in conjunction with balstilimab (antiPD1) was studied for safety in patients with microsatellite stable CRC that were not responding to chemotherapy. The study involved 101 patients that were followed for 6 months after receiving therapy. Promisingly, 61% of the patients had some form of response (either tumour shrinkage or stable disease). Furthermore, the most common side effects reported by the patients in the study were diarrhoea and fatigue. The treatment modality has now entered into late-stage clinical trials.
Gut microbiome signatures modulate cardiovascular disease risk
New antibody treatment shows promise for coeliac disease
Coeliac disease affects millions of people worldwide yet the only current treatment for coeliac disease is through adherence to a strict gluten-free diet. This form of disease management is considered suboptimal as it is highly restrictive, difficult to maintain and does not always promote intestinal mucosal healing.
A recent study by the Japanese pharmaceutical company, Chugai Pharmaceuticals, has presented a successful antibody treatment, DONQ52 for coeliac disease. This treatment targets HLA-DQ2.5 gluten peptides that are present in 85% of individuals with the disease. By blocking gluten-specific T cells, DONQ52 prevents immune damage to the small intestine upon gluten ingestion in individuals with coeliac disease.
This study examined the gluten-specific immune response in blood samples from participants with coeliac disease following the consumption of wheat, rye and barley products. A significant reduction in the gluten-specific T cell response was observed. Importantly, treatment with DONQ52 did not affect the T cell responses to non-gluten antigens, making DONQ52 a promising drug candidate.
This research provides an exciting new targeted treatment for those with coeliac disease that could improve quality of life by reducing the need for a strict gluten-free diet.
Source: https://www.sciencedirect.com/science/article/pii/S1521661624003681?via%3Dihub