Category: Cancer

Categories : CancerTags :

Osteoporosis Drug Zolendronate Could also Help Fight Breast Cancer

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Killer T cells about to destroy a cancer cell.

Triple-negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high probability of recurrence. Researchers from the University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells make them invisible for the immune system. Counteracting the metabolic change with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC. The research team was led by Prof Dr Susana Minguet and published in Cancer Immunology Research.

TNBC cells hide from gamma delta T cells

Gamma delta T cells recognise and kill cells that produce stress-induced molecules and phosphoantigens, a common characteristic of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that closely replicates the tumour properties found in human patients.

While the gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations of the cancer cells that let them stay unnoticed by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens – one of the classes of molecules that gamma T cells recognise. This escape mechanism likely also happens in patients with TNBC: analysis of public patient databases showed that reduced expression of key molecules of the mevalonate pathway correlate with a worse prognosis.

The immune evasion of TNBC cells is reversible

This newly discovered escape mechanism can be counteracted by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escapist cells with zolendronate, the gamma T cells became a lot more efficient in clearing the cancer. “Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success,” Minguet summarises. “We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer.”

Source: University of Freiburg

Categories : CancerTags :

Beta Blockers Plus Chemotherapy Cut Metastasis in Triple Negative Breast Cancer

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Breast cancer cells. Image by National Cancer Institute

A new international study has for the first time, identified that beta-blockers could significantly enhance the therapeutic effect of anthracycline chemotherapy in triple negative breast cancer (TNBC) by reducing metastasis. The results are published in Science Translational Medicine.

Anthracyclines are a class of drugs used in chemotherapy to treat many cancers, including TNBC.

Monash University researchers have previously shown in a clinical trial that beta blockers are linked with reduced metastasis. However, until now, it was unclear how beta-blockers would interact with common cancer treatments.

In this new study, the team used mouse models of cancer and analysed large-scale patient clinical data, in collaboration with the Cancer Registry of Norway, to discover that anthracycline chemotherapy on its own, in the absence of a beta-blocker, induces nerve growth in tumours.

However, adding a beta blocker to chemotherapy inhibited nerve fibre activity in tumours and stopped the cancer from coming back after treatment.

Lead author Dr Aeson Chang said the findings reveal an unanticipated insight into why chemotherapy treatment does not always work as it should.

“We set out to build on previous studies that have shown beta-blockers can halt the stress response experienced by cancer patients at the time of diagnosis and stop the cancer from spreading.

In this new study, not only did we discover the biological effect of beta-blockers when used alongside anthracycline chemotherapy, we also discovered why they are effective,” said Dr Chang.

“In mouse models of TNBC, we found that anthracycline chemotherapy was able to increase sympathetic nerve fibre activity in tumours. Activation of these stress neurons can help tumour cells spread and, fortunately, we found that beta blockers could stop this effect. Our hope is that this exciting discovery will pave the way for further research and, ultimately, lead to improved outcomes for patients.”

Senior author, Professor Erica Sloan, who has been exploring the use of beta-blockers as a novel strategy to slow cancer progression for a number of years, said the study provides important clues about why beta-blockers may help improve the clinical management of TNBC.

“While many patients will be cured by treatment, unfortunately, in some patients the cancer may return – this study has helped us understand why. Our findings show that anthracycline chemotherapy supports the growth of nerves, which can support cancer relapse. This is important, as it tells us that targeting nerves using a beta blocker can improve response to treatment,” said Professor Sloan.

“Beta blocker use has been consistently linked to reduced metastatic relapse and cancer-specific survival in TNBC patients. However, the lack of understanding of how beta blockers improve chemotherapy – which is a core component of the standard treatment for TNBC – has limited the translation of these findings into the cancer clinic,” said Professor Sloan.

“We believe this study presents an exciting opportunity to further explore the use of beta-blockers as a novel strategy in the treatment of TNBC.”

Source: Monash University

Categories : Cancer GastrointestinalTags :

Higher Risk of Lymphoma in Patients Suffering from IBD

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Source: CC0

Karolinska Institutet researchers have found that the risk of developing lymphoma is slightly elevated in inflammatory bowel disease (IBD) and, in recent years has been on the rise in patients with Crohn’s disease. Publishing in Clinical Gastroenterology and Hepatology, the researchers also observed a risk increase in patients taking modern IBD drugs, which was less strong for those not taking them. Thus, the lymphoma risk could be affected by both the medication and the disease activity itself.

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammation that can increase the risk of developing lymph node cancer (lymphoma), a disease that affects the immune system.  

“Previous studies of the lymphoma risk of IBD have been too small to draw reliable conclusions,” says the study’s first author Ola Olén, consultant and docent at the Department of Medicine (Solna), Karolinska Institutet. “The studies have not taken into account of important systematic errors or been representative of today’s IBD patients.”  

The present study included almost 170 000 IBD patients identified in Swedish and Danish national registries between 1969 and 2019. Compared to patients with a matched population without IBD, patients with both Crohn’s disease and ulcerative colitis had a higher risk of lymphoma. The highest risk was in patients with Crohn’s disease, the increase being driven mainly by T-cell lymphoma and aggressive B-cell lymphoma.

“We found an elevated relative risk of different types of lymphoma in both Crohn’s disease and ulcerative colitis, but we need to point out that the absolute risk is very low,” says the study’s last author Jonas F Ludvigsson, consultant and professor at Karolinska Institutet.

“The increase in risk equates to only one extra case of lymphoma in 1000 people with IBD, who were followed for ten years.”

“Both inflammation and treatment play a part”

The risk of lymphoma has increased in patients with Crohn’s disease over the past two decades, which coincides with the increasing use of immunomodulating drugs for IBD. While the highest risk of developing the cancer was observed in patients who had received these drugs, the researchers found that patients who were not on such medication were also at a higher risk of lymphoma. 

“This finding indicates that both the inflammation in itself and its treatment play a part,” says Dr Olén. “Since there’s a lot of talk about the lymphoma risk associated with immunomodulating drugs, it’s important to make it clear that also the disease and the inflammation per se seem to drive the development of lymphoma. One has to take account of this and discuss it when prescribing modern treatments where there might be a concern that they will increase the risk of lymphoma.” 

Dr Olén says the teamaims to use more detailed data to determine whether the disease itself or its treatment is more important in terms of lymphoma risk.

Source: Karolinska Institutet

Categories : Cancer ImmunologyTags :

Vitamin D may be Necessary for Effective Immunotherapy in Skin Cancer

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

Vitamin D has many effects on the body, including regulation of the immune system. New research indicates that for patients with advanced skin cancer, it may be important to maintain normal vitamin D levels when receiving immunotherapy in the form of immune checkpoint inhibitors. The findings are published in CANCER.

To see whether levels of vitamin D might impact the effectiveness of immune checkpoint inhibitors, investigators analysed the blood of 200 patients with advanced melanoma both before and every 12 weeks during immunotherapy treatment.

A favourable response rate to immune checkpoint inhibitors was observed in 56.0% of patients in the group with normal baseline vitamin D levels or normal levels obtained with vitamin D supplementation, compared with 36.2% in the group with low vitamin D levels without supplementation. Progression‐free survival in these groups was 11.25 and 5.75 months, respectively.

“Of course, vitamin D is not itself an anti-cancer drug, but its normal serum level is needed for the proper functioning of the immune system, including the response that anti-cancer drugs like immune checkpoint inhibitors affect,” said lead author Łukasz Galus, MD, of Poznan University of Medical Sciences, in Poland. “In our opinion, after appropriately randomised confirmation of our results, the assessment of vitamin D levels and its supplementation could be considered in the management of melanoma.”

Source: Wiley

Categories : Cancer Cardiovascular DiseaseTags :

Study Reveals Why Cancer Drugs Cause Cardiotoxicity

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While being effective at treating cancer, some cancer treatments can cause cardiotoxicity which can lead to heart failure – a phenomenon unexplained until now. An international study, published in the journal Science Advances, has identified proteins present in the blood that are linked to an increased risk of developing cardiac disease, including heart failure, and which are also affected by drugs used in cancer treatment.

The findings can explain how cancer drugs cause their damaging effects on the heart and could help to identify those at increased risk. In the long run, the researchers believe this will help to improve cancer treatments, with new drugs potentially being developed that can shrink tumours without affecting the identified proteins.

In addition, the study reveals new potential drug targets for treating heart diseases including heart failure. These may work by inhibiting proteins linked to higher disease risk, or activating proteins linked to lower risk.

The researchers first performed a genome-wide association study, searching through the DNA of nearly 37,000 people without heart disease enrolled in the UK Biobank study. This identified genetic variants linked to changes to the structure and function of the pumping chambers of the heart – the ventricles.

The researchers then pinpointed 33 proteins using Mendelian randomisation, coded for by these genetic variants, that are present in the blood and associated with the risk of developing several heart diseases. These included different types of heart failure, and atrial fibrillation (a common abnormal heart rhythm which increases the risk of stroke). Crucially, many of these proteins are the targets of drugs currently used to treat cancer.

Lead author Dr Floriaan Schmidt said: “The proteins identified in our study will help to accelerate future drug development, offering scientists a blueprint for new treatments for both cancer and heart diseases. This can help them to be more confident of the effects of the drugs that they design – whether that’s shrinking tumours without causing damage elsewhere or improving the heart’s pumping action.”

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said: “While there have been advances in treating cancer, one of the consequences has been a risk of heart damage from these drugs.

“This research points the way towards developing safer and more refined drugs so that, one day, worries about developing heart problems after cancer treatment might be a thing of the past.”

Source: University College London

Categories : CancerTags :

Gel Delivery Method Achieves 100% Cure for Glioblastomas in Mice

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Photo by Anna Shvets on Pexels

Anticancer drugs delivered by a novel gel cured 100% of mice with glioblastoma, one of the deadliest and most common brain tumours in humans. The results are published today in Proceedings of the National Academy of Sciences.

“Despite recent technological advancements, there is a dire need for new treatment strategies,” said chemical and biomolecular engineer Honggang Cui, who led the research. “We think this hydrogel will be the future and will supplement current treatments for brain cancer.”

Cui’s John Hopkins University team combined an anticancer drug and an antibody in a solution that self-assembles into a gel to fill the tiny grooves left after a brain tumour is surgically removed. The gel can reach areas that surgery might miss and current drugs struggle to reach to kill lingering cancer cells and suppress tumour growth.

The gel also seems to trigger an immune response that a mouse’s body struggles to activate on its own when fighting glioblastoma. When the researchers rechallenged surviving mice with a new glioblastoma tumour, their immune systems alone beat the cancer without additional medication. The gel appears to not only fend off cancer but help rewire the immune system to discourage recurrence with immunological memory, researchers said.

Surgery is still necessary; applying the gel directly in the brain without surgical resection resulted in a 50% survival rate.

“The surgery likely alleviates some of that pressure and allows more time for the gel to activate the immune system to fight the cancer cells,” Cui said.

The gel solution consists of nano-sized filaments made with paclitaxel, an FDA-approved drug for breast, lung, and other cancers. The filaments provide a vehicle to deliver an antibody called aCD47. By blanketing the tumour cavity evenly, the gel releases medication steadily over several weeks, and its active ingredients remain close to the injection site.

By using that specific antibody, the team is trying to overcome one of the toughest hurdles in glioblastoma research. It targets macrophages, a type of cell that sometimes supports immunity but other times protects cancer cells, allowing aggressive tumour growth.

One of the go-to therapies for glioblastoma is a wafer developed in the 1990s, with the commercial name Gliadel. This FDA-approved, biodegradable polymer also delivers medication into the brain after surgical tumour removal.

Gliadel showed significant survival rates in laboratory experiments, but the results achieved with the new gel are some of the most impressive the Johns Hopkins team has seen, said Betty Tyler, a co-author and associate professor of neurosurgery at the Johns Hopkins School of Medicine who played a pivotal role in the development of Gliadel.

“We don’t usually see 100% survival in mouse models of this disease,” Tyler said. “Thinking that there is potential for this new hydrogel combination to change that survival curve for glioblastoma patients is very exciting.”

The new gel offers hope for future glioblastoma treatment because it integrates anticancer drugs and antibodies, a combination of therapies researchers say is difficult to administer simultaneously because of the molecular composition of the ingredients.

“This hydrogel combines both chemotherapy and immunotherapy intracranially,” Tyler said. “The gel is implanted at the time of tumour resection, which makes it work really well.”

Johns Hopkins co-author Henry Brem, who co-developed Gliadel in addition to other brain tumour therapies currently in clinical trials, emphasised the challenge of translating the gel’s results in the lab into therapies with substantial clinical impacts.

“The challenge to us now is to transfer an exciting laboratory phenomenon to clinical trials,” said Brem, who is neurosurgeon-in-chief at Johns Hopkins Hospital.

Source: John Hopkins University

Categories : CancerTags :

Western Diet Increases Prostate Cancer Risk

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A study published in BJU International found that while adherence to healthy diets seems to have no effect on prostate cancer risk, following an unhealthy ‘Western’ diet may increase the risk of developing aggressive prostate cancer.

The study assessed the diets of 15 296 men recruited in Spain in from 1992–1996. Among these men, 609 prostate cancer cases were identified during a median follow-up of 17 years. Diets were categorised as Western, Prudent, or Mediterranean. The Western dietary pattern consisted of a high intake of high-fat dairy products, processed meat, refined grains, sweets, caloric drinks, convenience food, and sauces, and a low intake of low-fat dairy products and whole grains. The Prudent dietary pattern was characterised by a high intake of low-fat dairy products, vegetables, fruits, whole grains, and juices. The Mediterranean dietary pattern represented a high intake of fish, vegetables, legumes, boiled potatoes, fruits, olives, and vegetable oil, and a low intake of juices.

No effect over prostate cancer risk was detected for the Prudent and Mediterranean dietary patterns, but detrimental effect was observed with the Western dietary pattern. This effect was only observed for aggressive tumors.

“Our results indicate that avoiding unhealthy dietary habits could be the best nutritional strategy to prevent aggressive prostate cancer,” said lead author Adela Castelló-Pastor, PhD, of the Carlos III Institute of Health and CIBERESP, in Spain. “Substituting the intake of Western-type diet products by products characteristic of the Mediterranean diet could also decrease the risk of other chronic diseases,” added co–senior author Marina Pollán, PhD, of the Carlos III Institute of Health and CIBERESP, in Spain.

“The information provided by the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition – or EPIC – has contributed to improving scientific knowledge of the relationship between diet and cancer and other chronic diseases,” added co–senior author Maria-José Sánchez, MD, PhD, lecturer at the Andalusian School of Public Health, scientific director at ibs.GRANADA and researcher at CIBERESP, in Spain.

Source: Wiley

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How Cancer DNA Recovers after Heavy Ion Radiation Treatment

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Photo by Jo McNamara

A team of scientists has discovered a new type of DNA repair mechanism that cancer cells use to recover from next-generation heavy ion cancer radiation therapy. Their results are published in the journal Nucleic Acids Research.

Ionising radiation (IR) therapy is frequently used in the treatment of cancer and is believed to destroy cancer cells by inducing DNA breaks. The newest type of radiation therapy harnesses radiation produced by a particle accelerator, which consists of charged heavy particles such as carbon ions. The particle accelerator accelerates the carbon ions to about 70% of the speed of light, which collides with and destroys the DNA of cancer cells.

These ions have a high linear energy transfer (LET) and release most of their energy within a short range, called the Bragg peak. The next-generation cancer radiotherapy works by focusing the Bragg peak on the tumour, which has the added benefit of minimising damage to surrounding normal tissues compared to the commonly used low LET radiation such as gamma or x-rays.

DNA lesions generated by heavy ion bombardment (high LET radiation) are more “complex” than those induced by traditional radiation therapy (low LET radiation). The former carries additional DNA damage such as apurinic/apyrimidinic (AP) site and thymine glycol (Tg) in close proximity to the double-strand breaks (DSB) sites, which is far more difficult to repair than ordinary DNA damage. As a result, the advanced therapy is more cytotoxic per unit dose than low LET radiation.

This makes next-generation radiation therapy a potent weapon against cancer cells. However, it has not been fully investigated how these high LET-induced lesions are processed in mammalian cells, as DNA damage from heavy ion bombardment is a process that seldom occurs on Earth (though astronauts are subject to this in space). Figuring out the complex DSB repair mechanism is an attractive research interest since blocking the cancer cells’ repair mechanism can allow the new radiation therapy to become even more effective.

The researchers visited the QST hospital in Japan to use the synchrotron named HIMAC (Heavy Ion Medical Accelerator in Chiba), which has the ability to produce high LET radiation.

The research team discovered that DNA polymerase θ (POLQ) is an important factor when repairing complex DSBs such as those caused by heavy-ion bombardment. POLQ is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). This TLS activity was found to be the biologically significant factor that allows for complex DSB repair.

Ms SUNG Yubin, one of the joint first authors, explains, “We provided evidence that the TLS activity of POLQ plays a critical role in repairing hiLET-DSBs. We found that POLQ efficiently anneals and extends substrates mimicking complex DSBs” .

The researchers also discovered that preventing the expression of POLQ in cancer cells greatly increased their vulnerability to the new radiation treatment.

“We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation,” explains Mr. YI Geunil, another joint first author .

The research team used biochemical techniques and Fluorescence Resonance Energy Transfer (FRET) to find out that POLQ protein can effectively repair synthetic DNA molecules that mimic complex DSB. This means that POLQ can be a possible new drug target to increase the cancer cells’ vulnerability against complex radiation damage.

Source: Institute for Basic Science

Categories : Cancer GenderTags :

In Women, Certain Immune Cell Hinders Pancreatic Cancer Immunotherapy

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Photo by Tima Miroshnichenko on Pexels

Immunotherapy has limited effect for pancreatic cancer, and differs between men and women. A new study published in Cancer Research reveals certain immune cells in women with pancreatic cancer that, instead of fighting the tumour, interferes with the body’s immune response. These findings may pave the way for a more sex-specific treatment.

“More and more evidence is coming in that male and female hormones affect our immune system, but much remains to be done before sex can be included as a self-evident biological factor in medical research and therapy,” says the paper’s first author Fei He, former visiting researcher at Karolinska Institutet. “Our results provide new perspectives that can have high impact on the treatment of cancer.”

In recent years, immunotherapy, which stimulates the immune system to attack cancer cells, has contributed significantly to the treatment of different kinds of cancer, such as melanoma and lung, kidney and liver cancer. However, it is much less effective against pancreatic cancer, which remains one of the deadliest kinds of cancer that leaves patients, on average, with four to six months left to live after diagnosis.

Sex-biased differences in the immune response

Previous studies have shown that there are sex-bound biological differences in the male and female immune system that, amongst other effects, determine how tumours grow and the body’s ability to defend itself against them. The present study addressed what might cause such sex-related disparities in the immune response to pancreatic cancer.

The study revealed the presence of a subpopulation of myeloid cells in women that protect the tumour and prevents the immune system’s T cells from infiltrating the tumour and attacking the cancer cells.

“This sub-group of immune cells correlates with poor survival exclusively in female cancer patients,” says the study’s corresponding author and principal investigator Dhifaf Sarhan, assistant professor at the Department of Laboratory Medicine, Karolinska Institutet. “Our results show that the immune cells express a specific protein called FPR2 and can serve both as a sex-specific prognostic factor and a therapeutic target.”

New target for immunotherapy in women

The results can be useful to the development of diagnostic tools and immunotherapy for pancreatic cancer that take into account biological differences between men and women. The study used a combination of methods including single-cell RNA sequencing, proteomics, test tube and patient validation, and treatments of 3D pancreatic cancer models and mice.

“The next step is to follow up our new immunotherapy target for women,” says Dr Sarhan. “We’re also performing extensive analyses to understand how immunological sex differences drive tumour development in different ways in male and female cancer patients with the goal to find and develop immunotherapy targets for each group.”

Source: Karolinska Institutet

Categories : Cancer Diet and NutritionTags :

‘Eating the Rainbow’ Found to Reduce Prostate Cancer Risk and Improve Treatment

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Photo by Brad West on Unsplash

New research by scientists at the University of South Australia suggests that consumption of colourful fruits and vegetables on a regular basis reduces the risk of a prostate cancer (PC) diagnosis. These foods, rich in micronutrients, also help speed up recovery from radiotherapy for the disease.

The findings, from two studies published in the journal Cancers, highlight the importance of a Mediterranean or Asian diet that includes these foods. For the first study, researchers compared micronutrient plasma concentrations of prostate cancer patients with a healthy control group, revealing low levels of lutein, lycopene, alpha-carotene, and selenium in PC patients and high levels of iron, sulphur, and calcium in the same group, relative to controls.

The second study found increased DNA damage after radiation exposure was also associated with low lycopene and selenium in blood plasma.

Men with plasma concentrations lower than 0.25ug/mL) for lycopene and/or lower than 120ug/L for selenium have an increased risk of prostate cancer and are likely to be more sensitive to the damaging effects of radiation.

Foods that are rich in lycopene include tomatoes, melons, papayas, grapes, peaches, watermelons, and cranberries. Selenium-rich foods include white meat, fish, shellfish, eggs, and nuts.

Study co-author Dr Permal Deo says that studies show that eating foods rich in lycopene and selenium is preferable to taking supplements, where the benefits are limited.

“Our recommendation is to adopt a Mediterranean diet enlisting the help of a dietician because people absorb nutrients in different ways, depending on the food, the digestive system, the person’s genotype and possibly their microbiome,” Dr Deo says.

Prostate cancer remains one of the most common and fatal cancers in men, but the nutritional deficiencies associated with it remain largely unknown, hence this study. Other risk factors, such as ethnicity, family history and age have previously been linked to prostate cancer.

“There is strong evidence that being overweight and tall increases the risk of prostate cancer. Diets high in dairy products and low in vitamin E may also increase the risk but the evidence is less clear.”

Source: University of South Australia