Friday, November 25, 2022

Colon cancer: Might dietary changes help starve tumors?


 

Colon cancer occurs when cells in the colon or rectum grow out of control. The United States National Cancer Institute estimates that the condition accounted for 7.9%Trusted Source of new cancer cases in the U.S. in 2022, and 8.6% of cancer deaths.

Studies show that nutrient-sensing molecules known as mTORC1 contributeTrusted Source to tumor growth and are hyperactivatedTrusted Source in around more than 70% of human cancers, including colon cancer. Animal studiesTrusted Source demonstrate that inhibiting mTORC1 inhibits tumor growth.

Although drugs that inhibit the signaling pathway for mTORC1 have been proven to be clinicallyTrusted Source effective, they are limited in use as tumors often return after treatment ends, and side effects include immunosuppression.

Studies showTrusted Source that amino acids activate mTORC1, and dietary protein restriction may inhibit tumor growth by reducing mTORC1.

Further research into how restricting dietary protein affects mTORC and tumor growth could improve cancer treatments.

Recently, researchers investigated the effects of low protein diets on mTORC1 activation in animal and human tissue models.

“We observed that feeding human-derived colon cancer cells with low amino acids and treating them with chemotherapies synergizes to kill cancer cells,” Dr. Sumeet Solanki, research investigator in Molecular and Integrative Physiology at the University of Michigan, first author of the study, told Medical News Today.

The study was published in Gastroenterology.

The researchers first assessed colon cancer cells in mice. They found that mTORC1 activation was higher in the presence of amino acids.

The researchers next investigated how these findings translated into live mice. To do so, they assessed the effects of a low protein diet on mouse models of colon cancer for two weeks, followed by a month of chemotherapy. Whereas mouse diets are typically 21% protein, they fed mice diets with just 4% protein.

They found that mice on a low protein diet displayed less early tumor growth and more cancer cell death than controls. These mice also had reduced mTORC1 activation and proliferation.

The researchers noted that this suggests that amino acids regulate mTORC1 activity and that limiting amino acids may inhibit early tumor growth.

From in-vitro tests, the researchers next found that a low protein diet—and specifically reduction of amino acids leucine and cystine—altered nutritional signals to mTORC1 via GATOR1 and GATOR2 protein complexes.

When amino acids are abundant, GATOR2 activates mTORC1. However, when amino acids are low, GATOR1 deactivates mTORC1.

When asked what ‘feeds’ cancer cells, Dr. Solanki noted that cancer cells need large amounts of nutrients, including glucose, amino acids, and nucleotides, to proliferate. While some of these nutrients can be synthesized inside cells, others, like amino acids, must be taken from dietary sources.

He continued that sensing pathways such as GATOR and mTORC1 detect nutrient levels and signal cellular mechanisms to divide, grow and proliferate.

“As body nutrients are influenced by diet, we found that feeding a low protein diet to animals created a demand versus supply crisis in colon cancer cells which resulted in massive cancer cell death,” he said.

“Thus, these cancers are metabolically vulnerable, and a low protein diet along with chemotherapy may kill cancer cells in these settings as their demand is high, and supply is low,” he noted.

“Feeding or starving cancer cells is clearly complicated, but this research shows that depriving certain amino acids influences the mTORC-1 pathways leading to cell death.”
— Dr. Jeffrey Nelson, surgical director at The Center for Inflammatory Bowel and Colorectal Diseases, Mercy Medical Center, Baltimore, who was not involved in the study, speaking to MNT

 

Tuesday, November 22, 2022

Scientists move a step closer to advancing personalized cancer treatment



In a step likely to advance personalized cancer treatment, scientists have for the first time shown in patients that levels of biomarkers are not enough to tell which patients are likely to respond best to immunotherapy.

Instead, clinicians need to understand how immune cells and tumors are interacting within a patient, rather than simply the levels of each associated proteins present, to prescribe the best treatment.

The research team, from the University of Bath's Centre for Therapeutic Innovation (CTI-Bath) alongside colleagues in Bordeaux, France have published the study in the journal Cancers, as a featured article.

The results validate a quantitative imaging platform used at CTI-Bath which can predict whether a cancer patient would respond to immunotherapy treatment.

Cancers evade detection by the immune system, making themselves invisible to the natural anti-tumor response and actively blocking it. One type of immunotherapy, called immune checkpoint inhibitors, are antibodies that remove the brakes which the tumor has applied to the immune system. This re-activates the patients' natural anti-cancer response, which then destroys the tumor.

Currently clinicians use commercial methods to determine levels of immune check point regulators (proteins) within patients to evaluate whether immunotherapy is needed.

However not all patients respond well and the therapy can have serious side effects, so a more refined way to identify which patients will benefit from the treatment is crucial.

To investigate the role of these types of the immune check point regulators in cancer patients, the research team from the Bergonie Cancer Institute (Bordeaux France), and University of Bath Professors Banafshe Larijani (Director of the Centre for Therapeutic Innovation (CTI-Bath), and Stephen Ward (Professor of Leukocyte Biology), recruited patients with metastatic lung tumors who were undergoing a treatment called radiofrequency ablation (RFA) at Bergonie Cancer Institute.

In some cases, treating tumors in one lung using RFA can cause tumors in the other lung to also reduce in size. This effect is thought to be due to the cancer treatment provoking an anti-tumor immune response but can be limited by the interactions of the immune check point regulators. In this process the proteins interact like a lock and key, with regulator proteins entering their immune system protein targets and closing them – thus compromising the immune response.

The researchers compared levels of these regulators and their targets with how they were actually interacting – the level of 'engagement' (and therefore their activation state) – using the immune-FRET molecular imaging platform which was developed by Professor Larijani and co-workers in UK and the EU. iFRET can establish how molecules interact at a nanoscale level in single cells and tissue samples.

This is the first time these interactions have been quantified within RFA patients, and they show that engagement did not correlate with the quantity of protein present – meaning that the prescribing based on the levels of proteins present is unlikely to be suitable.

Professor Banafshe Larijani said: "These results show that you can get a better picture of what's happening within a patient by measuring engagement of immune checkpoint interactions, thus more accurately predicting level of immune suppression and likely response to RFA treatment, instead of simply the levels of the proteins involved. Ultimately we hope this can result in a change in how immunotherapy is prescribed to RFA patients so it's personalized to an individual.

"Moreover, we're delighted that the study shows iFRET provides a method for advanced quantitative immune surveyance, as opposed to qualitative immune surveyance, of patients, which will greatly increase patient access to precision medicine."

This work emphasizes the importance of developing personalized approaches to cancer therapies that are more targeted and thus likely to be more effective. This is beneficial not just to patients who will receive treatments most likely to work for them, but also to the NHS, and other health services, which will be more efficient in terms of both positive patient outcome and treatment costs."

Stephen Ward, Professor of Leukocyte Biology

The team now hopes to do further work, involving other cancers and other ablative techniques such as cryoablation.

The study was funded by the "groupe interregional de recherche Clinique et d'innovation (GIRCI)" and by Boston Scientific.

Thursday, November 17, 2022

Whole-genome sequencing reveals five new subgroups of chronic lymphocytic leukemia


A collaborative study led by the University of Oxford as part of the UK's 100,000 Genomes Project, published in Nature Genetics today, has defined five new subgroups of the most common type of blood cancer, chronic lymphocytic leukemia (CLL) and associated these with clinical outcomes. This new method for risk-stratifying patients could lead to more personalized patient care.

This is the first study to analyze all the relevant changes in DNA across the entire cancer genome, rather than targeted regions, to classify patients with cancer and link these subgroups to clinical outcomes.

Professor Anna Schuh, Department of Oncology, University of Oxford who led the study said: 'We know that cancer is fundamentally a disease caused by changes in DNA that are acquired over the lifetime of an individual. The lab tools we currently use to predict whether or not a patient is likely to respond to a given therapy usually focus on single abnormalities in the cancer DNA and do not accurately predict the patient's clinical outcome. This is why we asked the simple question: can we increase the precision of current testing by looking at all the acquired DNA changes in cancer at once?'

This study analyzed the entire genome sequences1 from 485 patients with CLL who were enrolled in national clinical trials led by the Universities of Liverpool and Leeds, provided samples for the UK CLL Biobank in Liverpool and consented for their samples to be used in the 100,000 Genomes Project run by Genomics England. By comparing the whole genome sequencing data from the cancer and healthy tissues in these patients, the team were able to map known and newly identified DNA changes, structural alterations, cancer mutational signatures and other global measures associated with CLL throughout the genome. They identified 186 distinct and recurrent genomic alterations and used these to define five genomic subgroups of CLL that associate with different clinical outcomes.

Following additional validation in patients receiving a wider range of treatments than those included in this study, particularly targeted therapies, these new genomic subgroups for CLL could be used to better guide the selection of therapies for improved patient outcomes.

This study paves the way for routine clinical application of whole genome analyses for risk stratification in other cancer types.

The team's analysis also identified 148 new putative genetic drivers of CLL. Future research on these drivers may uncover new mechanisms in CLL initiation and progression, with potential for the development of novel therapeutics.

Professor Sir Mark Caulfield, Vice Principal for Health for Queen Mary University of London and former Chief Scientist and lead of the 100,000 Genomes Project at Genomics England said: 'This is the largest international genomic analysis of this blood cancer, which excitingly demonstrates the real value of whole genome sequencing from the 100,000 Genomes Project. It also harnesses the high-quality blood cancer samples from the Liverpool Chronic Lymphocytic Leukaemia Biobank and associated clinical data collected by the Clinical Trial Units at Liverpool and Leeds universities as part of multi-centre National Cancer Research Institute-supported clinical trials.

Our work shows that the entire genome is superior in classifying patients into groups compared to the conventional targeted approaches and that we can predict response to treatment more precisely and in more patients.'

Professor Andrew Pettitt, founding Director of the UK CLL Biobank and Chief Investigator for two of the contributing clinical trials, said: 'This ground-breaking study is a paradigm for what can be achieved through a nationally coordinated approach to collaborative working that allows the application of cutting-edge science to a large number of high-quality samples obtained from uniform, well-defined patient cohorts and linked to high-quality clinical outcome data.'

A new CLL patient classifier would allow patients of the future to be offered the best treatment first time according to their CLL subgroup, saving unnecessary treatments with potentially toxic side effects. It will also aid in selecting the most appropriate patients for trials of new, targeted therapies. This work has a potentially huge, positive impact on patients with CLL and importantly demonstrates the feasibility of this approach in other cancer types."

Jackie Martin, patient representative for the Genomics England hematology project

 

Tuesday, November 15, 2022

Lung cancer screening saves lives. So why do so few of those at risk get one?




Lung cancer screening has been proven to save lives.

But according to a new study, only 5.8% of people eligible for a free, low-dose CT scan  actually get screened for lung cancer – far below levels seen for colorectal, breast and cervical cancer screens.

Debra Ritzwoller knows the challenges firsthand.

Ritzwoller is a senior investigator in economics and cancer research with the Kaiser Permanente Colorado Institute for Health Research. Part of her job via a grant from the National Cancer Institute is to study and promote the use of lung cancer screening among Kaiser's patients and other health systems. But in five years of trying, she hasn't managed to get a high-risk close relative screened for the disease.

The relative's doctor insisted he wasn't at elevated risk, because he'd quit smoking a decade earlier. Ritzwoller ended up talking to her family member while at the doctor's and explaining that his age, heavy smoking history, plus having a family member with the disease did put him at high risk. The doctor agreed and ordered the screening exam.

When she last spoke with the family member, he still hadn't been screened, because he didn't know how to schedule the screen.

"There's a lot of folks out there who we're not reaching," Ritzwoller said.

LATEST:Is weed more harmful to your lungs than cigarettes? A study suggests it may be.

Lung cancer remains the deadliest cancer in the United States, claiming an estimated 130,000 lives this year. About 60% are caught after the tumor has spread beyond the lung and is past the point of being cured, said Zach Jump, National Senior Research Director for Epidemiology and Statistics with the American Lung Association, who helped lead the new study.


Still, Jump said he's seen the five-year survival rate from lung cancer climb from about 15% when he started working for the lung association, to more than 25% today. Catching tumors early offers the possibility of even more lives saved, he said. Studies show screening leads to at least a 20% reduction in death from lung cancer.

Screening, which involves a quick CT scan, fully clothed with no advance preparation, has only been recommended by the federal government since 2014. In March 2021, criteria were modified to nearly double the number of people eligible for the free scan.

Now, anyone can get the free screen if they are between ages 50 to 80, currently smoke or quit within the past 15 years, and have a 20 pack-year smoking history, meaning they smoked at least 20 cigarettes a day for 20 years or 10 cigarettes daily for 40 years. (The American Lung Association offers a pack-year calculator here.)

That's a more complicated list of criteria than for other cancer screens, which might be one reason people have been slow to adopt lung cancer screening,

Ritzwoller's family members' medical chart didn't indicate how much he had smoked, which is likely why his doctor initially dismissed the idea of screening. Many doctors know only whether their patients are current smokers, not their smoking history.

"There's a knowledge gap for both the patients and for the providers," Ritzwoller said.

Then, as with her family member, many people don't know what to do if they do qualify. The screens are required to be provided at no cost to patients under the Affordable Care Act. People who are part of a program, as at Kaiser, where they're helped through the process and reminded annually, are more likely to get screened, her data shows.

Lung cancer screening can vary substantially by doctor and treatment facility, suggesting that some are better than others at prioritizing the screens.

In a recent study of the Veterans Health Administration from 2013 to 2021, researchers found that the facility where a patient received care accounted for 36% of the variation in screening rates and the doctor accounted for 19% of the difference – more than personal characteristics of the veteran.

Now, anyone can get the free screen if they are between ages 50 to 80, currently smoke or quit within the past 15 years, and have a 20 pack-year smoking history, meaning they smoked at least 20 cigarettes a day for 20 years or 10 cigarettes daily for 40 years. (The American Lung Association offers a pack-year calculator here.)

That's a more complicated list of criteria than for other cancer screens, which might be one reason people have been slow to adopt lung cancer screening,

Ritzwoller's family members' medical chart didn't indicate how much he had smoked, which is likely why his doctor initially dismissed the idea of screening. Many doctors know only whether their patients are current smokers, not their smoking history.

"There's a knowledge gap for both the patients and for the providers," Ritzwoller said.

Then, as with her family member, many people don't know what to do if they do qualify. The screens are required to be provided at no cost to patients under the Affordable Care Act. People who are part of a program, as at Kaiser, where they're helped through the process and reminded annually, are more likely to get screened, her data shows.

Lung cancer screening can vary substantially by doctor and treatment facility, suggesting that some are better than others at prioritizing the screens.

In a recent study of the Veterans Health Administration from 2013 to 2021, researchers found that the facility where a patient received care accounted for 36% of the variation in screening rates and the doctor accounted for 19% of the difference – more than personal characteristics of the veteran.

New treatments have made significant advances against the disease, and early detection is the best predictor of long-term survival. Eighty percent of cancers detected with screening are at an early stage when it's potentially curable, she said, while 75% of cancers found without screening are at later stages with fewer treatment options. 

Lack of lung cancer screening is more about systems failing patients than patients failing to show up for tests, said Dr. Jacob Sands, a lung cancer specialist at the Dana-Farber Cancer Institute in Boston.

"Amongst the medical community, I think there's a history of blaming patients for bad stuff, as opposed to recognizing the flaws within our own system," he said. 

Lack of awareness also limits lung cancer screening, said Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital.

"When we go out in the community and we teach people about lung cancer screening, nobody's heard of it," he said. 

While mammogram appointments don't require prior approval from a primary care doctor, lung cancer screens usually do, Yang said, which is another barrier.

As with any screen, the low-dose CT scan can yield false positives, requiring further testing to prove the person doesn't have lung cancer. Nearly 13% of initial tests are false positives, with the person recommended for follow-up or more invasive testing. For repeat scans, the figure is closer to 5%

Thursday, November 10, 2022

COVID vaccination improves effectiveness of cancer treatment, study finds

 



Patients with nasopharyngeal cancer are often treated with drugs that activate their immune system against the tumor. Until now, it was feared that vaccination against Covid-19 could reduce the success of cancer treatment or cause severe side effects. A recent study by the Universities of Bonn and Shanxi in the People's Republic of China now gives the all-clear in this regard. According to the study, the cancer drugs actually worked better after vaccination with the Chinese vaccine SinoVac than in unvaccinated patients.

Many cancer cells are capable of subverting the body's immune response. They do this by pushing a kind of button on the immune cells, the PD-1 receptor. In this way, they effectively shut down these endogenous defense forces. Drugs can be used to block PD-1 receptors. This enables the immune system to fight the tumor more effectively.

Vaccination against Covid also stimulates the immune response, involving the PD-1 receptor. "It was feared that the vaccine would not be compatible with anti-PD-1 therapy," explains Dr. Jian Li of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at the University Hospital Bonn. "This risk is especially true for nasopharyngeal cancer, which, like the SARS Cov-2 virus, affects the upper respiratory tract."

Together with cooperation partners from the People's Republic of China, the bioinformatician has now investigated whether this concern is justified. More than 1,500 patients treated in 23 hospitals from all over China participated in the analysis. Such multi-center studies are considered to be particularly informative because the participants are very diverse and, moreover, the results are not distorted by regional characteristics.

Vaccinated patients responded better to cancer therapy

A subset of 373 affected individuals had been vaccinated with the Chinese Covid vaccine SinoVac. "Surprisingly, they responded significantly better to anti-PD-1 therapy than the unvaccinated patients," explains Prof. Dr. Christian Kurts, Director of IMMEI and member of the Transdisciplinary Research Area "Life & Health" and the Cluster of Excellence ImmunoSensation. "Furthermore, they did not experience severe side effects more often." The researchers cannot say why the treatment was more successful after vaccination. "We assume that vaccination activates certain immune cells, which then attack the tumor," says Prof. Dr. Qi Mei of Shanxi University Hospital. "We will now investigate this hypothesis further."

Nasopharyngeal cancer is quite rare in this country. In southern China and other countries in Southeast Asia, however, the disease is widespread. One of the suspected reasons for this is the frequent use of air conditioning in the hot and humid regions. Nutritional factors also appear to play an important role. In Taiwan, nasopharyngeal cancer is now considered one of the leading causes of death among young men.

Participating institutions and funding

In addition to the University of Bonn and the University Hospital, Shanxi Medical University and Tongji Medical College were involved in the work. The researchers also collaborated with a number of clinics throughout China. The study was funded by the Sino-German Center for Research Promotion (SGC), the DFG Cluster of Excellence ImmunoSensation², and the German Federal Ministry of Education and Research (BMBF).

Story Source:

Materials provided by University of Bonn. Note: Content may be edited for style and length.


Wednesday, November 9, 2022

Eating fiber alters the microbiome. It may boost cancer treatment, too.


 Cancer researchers think they have found an explanation for why some cancer drugs don’t always work. The answer — and a possible solution — may be found in the gut microbiome.

Even more stunning: scientists believe that giving patients a fiber-rich diet of fruits, vegetables, beans, nuts and whole grains to nourish the microbiome might improve the odds that the cancer treatment is effective.

A clinical trial testing the theory is currently underway at the University of Texas MD Anderson Cancer Center in Houston, the largest cancer center in the United States.

It includes participants like Hector Facton, a pediatrician in San Angelo who is undergoing immunotherapy treatments for Stage 4 melanoma.

“I’m eating triple the amount of fruits and vegetables that I used to eat,” Facton said. “I eat healthy, but not to the levels that I am now. A huge portion of my plate is always vegetables, lots of quinoa — anything I can find that has fiber in it.”

Scientists caution that this strategy of using a fiber-rich diet — or any diet for that matter — to boost immunotherapy remains unproven. But the research they are doing is shedding new light on how the gut microbiome affects our ability to fight disease.

“My patients who are starting treatment often ask if there’s something else they could be doing to enhance their chances of responding to immunotherapy,” said Jennifer McQuade, an assistant professor and physician scientist in melanoma medical oncology at MD Anderson. “We’re trying to test this diet with the same rigor that we use to test drugs.”


Scientists have long known that the microbiome is a crucial part of our immune systems. By some estimates, between 60 and 80 percent of the immune cells in our bodies reside in the gut.

But only recently did it become apparent that these microbes might affect cancer outcomes. Scientists at the University of Chicago discovered that mice with a strain of gut bacteria known as Bifidobacterium had a stronger immune response against melanoma tumors than mice who lacked the bacteria. They found that giving Bifidobacterium to the deficient mice slowed tumor growth. What’s more, combining the bacteria with an immunotherapy drug known as a checkpoint inhibitor nearly abolished the tumors.

Human studies showed that these checkpoint inhibitors were also more effective in cancer patients whose guts had more microbial diversity, as well as a greater abundance of several microbes, including Akkermansia muciniphila and Bifidobacterium longum. Patients with low levels of these and other microbes were less likely to respond to the treatment.

Some researchers are trying to overcome resistance to immunotherapy by doing fecal transplants. They take stool samples teeming with gut microbes from patients who responded to the drugs and transfer it via colonoscopy to another patient. In one recent trial, scientists gave fecal transplants to 15 people with advanced melanoma who didn’t respond to immunotherapy.

Based on their histories, the 15 patients had a less than 10 percent likelihood of responding to immunotherapy. But after undergoing stool transplants, six patients began responding to the drugs. Hassane Zarour, a cancer immunologist who led the study, called it “an encouraging proof of principle,” and said he is now recruiting melanoma and lung cancer patients for a larger study.

“We don’t want to say that the microbiome is the only mechanism,” said Zarour, the co-leader of the Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center. “But we have learned that the microbiome could definitely be responsible for the inability of some patients to respond.”

Zarour said the goal of his work is to figure out which gut microbes are involved and then package them into pills that patients could take to alter their microbiomes. “The endgame is not fecal transplants,” he added. “Giving patients a cocktail of probiotics might be the best option.”

Meanwhile at MD Anderson, McQuade and her colleague Jennifer Wargo, a cancer surgeon, explored a different route: why not change patients’ microbiomes by changing what they eat?

McQuade pointed out that some of the gut microbes that appear to improve how patients respond to immunotherapy are known to thrive on fiber. “These are bacteria that help us break down and utilize starch and fibers,” she said.

The team examined the diets of 128 melanoma patients and found that those who regularly ate large amounts of fiber from fruits, vegetables, and other plant foods had better outcomes on immunotherapy than patients who ate the least amount of fiber. Their findings, published in Science in December, showed that every five-gram increase in daily fiber intake was associated with a 30 percent lower risk of death or cancer progression.

In the new study, patients are given daily meals that include as much as 50 grams of daily fiber from foods like beans, lentils, farro, brown rice, fruits, and vegetables — about twice the recommended amount of 25 to 30 grams of fiber a day. By comparison, the average American eats roughly 15 grams a day. (A control group will eat a healthy diet that follows guidelines from the American Cancer Society.)

Facton in San Angelo was diagnosed in November 2021 with melanoma that had spread to his lymph nodes after his wife noticed a golf-ball sized lump on his back. He began immunotherapy and enrolled in the three-month diet trial.

“It was huge servings, like a plate heaping with broccoli or quinoa, or mixed vegetables,” he said. “It was an impressive amount — more than I have ever eaten in one serving.”

In January, he underwent surgery and learned the tumor was gone. “There was just a bunch of scar tissue there,” he said. “There was no cancer to be found.”

Facton is continuing immunotherapy for nine months, and he’s decided to continue his new way of eating. “I feel better, and I don’t see any downside to it,” he said. “It makes me a healthier person overall — and now, cancer free. What a huge bonus.”

Do you have a question about healthy eating? Email EatingLab@washpost.com and we may answer your question in a future column.

Colon cancer: Might dietary changes help starve tumors?

  Researchers studied the effects of a low protein diet on colon cancer growth. They found that a low protein diet reduces tumor growth and ...