Could the Microbiome be the Key to Ending Chemotherapy-Induced Pain?

gut-microbiome.jpg

Most of us have experienced the odd sensation of “pins and needles” in our hands or feet. While annoying and painful, the sensation usually goes away quickly.

But for many people with peripheral neuropathy, a disorder involving increased sensitivity of nerves outside of the brain and spinal cord, this experience may linger for months to years.

“It’s a horrible condition,” said Shiqian Shen, MD, clinical investigator in the Massachusetts General Hospital Center for Translational Pain Research and director of the Mass General TelePain Program. “You literally want to shake off your leg, but you can’t.”

Unfortunately, a third of cancer patients who receive chemotherapy encounter this as a side effect, a condition known as chemotherapy-induced peripheral neuropathy (CIPN). This neuropathy is a result of nerve damage or impairment of the nervous system and often is chronic. If the pain is severe enough, chemotherapy dosages must be lowered, which causes the treatment to be less effective.

With the survival rates for many cancers increasing due to the improved understanding of genetic mutations, targeted therapies and immunotherapy, CIPN has become a major challenge and can hurt a survivor’s quality of life.

Dr. Shen and Jianren Mao, MD, PhD, chief of the Mass General Pain Management Center and vice chair for research in the Department of Anesthesia, Critical Care and Pain Medicine, are leading a research team in exploring why patients undergoing chemotherapy develop CIPN.

There is strong evidence that the gut, which carries about 10 trillion bacteria, has a major impact on the central nervous system. Previous research in the field has also shown that gut microbiota plays a critical role in the tumor-killing effect of many chemotherapeutics drugs. In a recent study published in Nature Neuroscience, the researchers questioned whether an immune response that results from interactions between chemotherapy drugs and the bacteria in the microbiome also plays a role in developing CIPN.

The researchers exposed two sets of mice, one with a normal microbiome and one that had their microbiome essentially eliminated through antibiotic treatments or genetic engineering, to oxaliplatin—a chemotherapy drug used to treat colon or rectal cancer and that is known to cause CIPN. The normal mice manifested symptoms of CIPN while those without a microbiome did not. Therefore, a microbiome is necessary for CIPN symptoms to manifest.

Next, the team dug into why the microbiome influences the onset of CIPN.

The researchers determined that the mice who experienced CIPN had higher levels of two proteins involved in inflammation (IL-6 and TNFalpha) in the dorsal root ganglia (DRG). This inflammatory response in the DRG leads to an increase in neuron sensitivity, which is what causes the neuropathy pain and tingling in a person’s extremities.

The team found further evidence that suggests a reaction between the chemotherapy agent and bacteria in the microbiome, releases lipopolysaccharides (LPS), a molecule found in bacteria on the gut lining, into the bloodstream. LPS then appears to cause a chain reaction that increases the levels of the two inflammatory proteins in the DRG.

“We found there’s a concurrent response—one initiated by the chemotherapy agent, and one by the inflammatory response,” said Shen. “They work hand in hand to promote the pain.”

However, there is a dilemma to sort out. Previous research has found that chemotherapy treatments such as oxaliplatin and cyclophosphamide are dependent on the gut microbiome. Meaning chemotherapy does not work well without help from a normal microbiome, but having it runs the risk of developing CIPN.

“Our research has revealed that you cannot get rid of the gut microbiome entirely to prevent side-effects because your therapeutic effect is also linked to the same presence,” says Shen.

The researchers are conducting follow-up studies to see if the same results are found in humans, and to see whether the same phenomenon exists in other type of neuropathic pain.

Potential in the Clinic

Since eliminating a cancer patient’s microbiome will essentially render chemotherapy treatment ineffective, more research will need to be done to see if investigators can determine if and how an individual’s microbiome composition affects their likelihood of developing CIPN. If they can identify favorable bacteria profiles, clinicians may be able to reduce the risk of developing CIPN by prescribing probiotics or fecal transplants in advance of starting chemotherapy. On the flipside, knowing the optimal microbiome profile that reduces risk of CIPN for every chemotherapy agent may help oncologists select the ideal chemotherapy drug for each patient.

Liquid Biopsies Give Clues on When and Why Cancer Treatments Lose their Efficacy

With the advent of targeted cancer therapies and immunotherapy, and with new CAR-T therapies on the way, more cancer patients are living with their disease. However, many cancer patients find that their therapies have limitations and are faced with the potential of disease progression. Often, those who initially respond to a course of treatment eventually develop a resistance to these medications, forcing oncologists to switch therapeutic course.

Currently, one of the ways to know when a treatment stops working is by taking a biopsy of the tumor. These surgical procedures are invasive and costly, and because they can only be done sporadically, valuable treatment time can be lost. Additionally, some cancer patients may be too physically fragile for surgery.

Researchers have been looking for a safe, fast, less expensive and more accurate way to identify early signs of treatment resistance, while also searching for new insights into the genetic changes that occur within tumor cells to drive this resistance. This way, new therapy plans can be considered sooner, giving the patient a better chance for their best possible outcome.

A new diagnostic blood test known as a liquid biopsy has shown early promise in addressing these needs. Now researchers, including a team from the Mass General Cancer Center, are providing confirmatory data that may help to move liquid biopsies into clinical practice. These data were presented at the ESMO 19th World Congress on Gastrointestinal Cancer.

How do liquid biopsies work?

A liquid biopsy is a diagnostic test that detects circulating tumor DNA (ctDNA), which is genetic material released by dying tumor cells that flows through the bloodstream. These tests are less invasive than a tissue biopsy and therefore can be given with greater frequency.

Regularly monitoring ctDNA levels in a patient’s bloodstream can provide early notice when a treatment is no longer working. It could also offer a more complete picture of the genetic changes in tumor cells that are driving the resistance to treatment, which could guide new treatment courses.

Liquid biopsies and gastrointestinal cancer study

Mass General Cancer Center investigators followed nearly 40 patients with various forms of gastrointestinal cancers who had experienced initial success with targeted therapies, but then began to show signs of treatment resistance. Liquid biopsies were taken when the patients’ disease started to progress to analyze the levels and genetic profile of ctDNA in their bloodstream. Researchers identified one or more mutations or mechanisms that contributed to treatment resistance in 31 of the 40 patients. Fourteen of these patients had multiple mutations that contributed to resistance.

In patients who had both solid tissue biopsies and the liquid biopsies, the researchers found that in two-thirds of the cases, the liquid biopsies revealed the presence of more genetic mutations than tissue biopsies alone.

“Identifying what specific mutations are responsible for treatment resistance is very important in helping clinicians choosing what treatment path a patient should try next, whether it be another drug or perhaps radiation,” said study investigator Aparna Parikh, MD, from the Mass General Cancer Center.

“We have shown this approach is feasible across many different GI cancers,” she noted. “The next step is to study how best to use this new technology in daily practice. It’s important for clinicians to understand its utility as well as its limitations.”

Research Teams at Mass General Explore Ways to Limit Alcohol-Induced Damage to the Liver and Better Understand Alcoholism’s Effect on the Brain

Hofbraeukeller_5906_2

Summer is almost upon us, which for many people means more outdoor time, cookouts, and for some—more drinking. While moderate alcohol consumption may have some health benefits, drinking too much can take a toll on our body. Researchers from Massachusetts General Hospital are investigating the long-term effects of excessive drinking on liver and brain function to find ways to reduce its impact on our health.

Enzyme treatment reduces alcohol-induced liver damage

Excessive drinking of alcohol can damage our liver in various ways. One way is through drinking more alcohol than the liver can process. And another is by making the gut’s intestinal membrane more permeable, which allows toxins to enter the blood stream and damage the liver.

Researchers in the lab of Richard Hodin, MD, in the Mass General Department of Surgery, reported in a new study that supplemental doses of an enzyme called intestinal alkaline phosphatase (IAP), which is known to stop bacterial toxins from entering the bloodstream through the gut, may also reduce liver damage from excess drinking.

In mouse models of binge drinking and chronic alcohol consumption, the research team found that feeding the mice a supplement of IAP reduced the amount of fat accumulation and inflammation in the liver and lessened signs of liver damage.

The enzyme appears to work in two ways. The first is by reducing the toxic effects of the lipopolysaccharide(LPS) molecule, which kills several important bacteria in the microbiome and can damage the liver if it passes through the intestinal membrane. The second is by reducing alcohol-induced membrane permeability in the intestine, which limits the overall amount of LPS that passes through the intestine. To be effective, the enzyme had to be administered before or at the same time as the alcohol. Administration after the fact had no effect. Human research is now being planned to confirm these results, and researchers plan to investigate other molecules that may have a role in liver inflammation.

“Liver damage is one of the most devastating effects of excess alcohol consumption, and so blocking this process could save millions of lives lost to alcohol-related liver diseases such as cirrhosis and liver cancer,” says Hodin, the study’s senior author. Read more here.

Imaging study reveals structural difference in brains of male and female alcoholics

It is known that alcoholic men and women have different psychological and behavioral profiles. Female alcoholics tend to have higher levels of anxiety, while male alcoholics tend to become more antisocial. But how do men and women’s brain structures that comprise the reward system that responds to alcohol compare? A collaborative study by researchers at Mass General and Boston University was the first to take a look.

The brain’s reward system includes the amygdala, which controls the fight or flight instinct, and the hippocampus, which controls long-term memory and emotional response.  The system is known to be involved in the development of substance abuse disorders like alcoholism.

In a study of 60 men and women with a history of alcoholism, along with a control group of non-alcoholics, researchers from the BU School of Medicine and the 3D Imaging Service and the Center for Morphometric Analysis in the Martinos Center for Biomedical Imaging at Mass General found that women with alcoholism tend to have a larger reward system than women without alcoholism—4.4 percent larger. It also confirmed previous studies that showed men with alcoholism tend to have smaller reward structures than those without—4.1 percent smaller.

It is not yet known if the differences in reward system size preceded the development of alcoholism or were a result of the disease. The results also suggest that alcohol works in different ways on the male and female brain, and that gender-specific approaches to treatment for alcoholism may be more effective than a one-size-fits-all approach. Learn more here.