Release date: 2018-06-08
Carole Godain remembers many details of the clinical trials he participated in nine years ago. She pressed the blue button to use the chemotherapy drug, and the green light proved that the drug was dripping into the blood vessel.
Everyone said that Godain's time is running out. She had colon cancer, the first treatment failed, and the last physical scan showed 27 tumors in her liver. Therefore, the French psychologist seized the opportunity to participate in a trial at the Paul Bruce Hospital in Villeyuuf. The study was designed to test whether administration at a particular time of day is more effective or reduces toxic side effects. Ideally, it can accomplish both tasks at the same time. “I am interested in increasing my chances of being cured,†Godain said.
Today, the 43-year-old Godain has no cancer. The oncologist Francis Lévi, who is in charge of its treatment, said that although such astonishing results are abnormal, new evidence should make people more interested in time therapy – rationally arranging treatment time, providing the most help and minimizing s damage.
For more than 40 years, scientists have delved into how the body's circadian rhythm (biological clock) affects the body's response to drugs, and thus changes the treatment of various diseases ranging from asthma to seizures. Studies have shown that today's best-selling drugs work better at specific times of the day. "When you administer, you always pay attention to the dose first, but we find that time is sometimes more important than the dose," Lévi said.
However, time therapy, sometimes referred to as time medicine, is still on the verge of clinical practice and drug development projects, and the reasons for this are diverse. Until about 10 years ago, scientists could not explain the molecular basis of these physiological effects, and the clinical data were inconsistent—for example, Lévi's early trials showed significant benefits for people with timed treatment, but later larger trials produced More mixing results. Most patients are not as lucky as Godain.
Axel Grothey, an oncologist at the Mayo Clinic in the United States, points out that the challenge of time therapy is twofold: “You need more reliable data and you need to prove that it is feasible.†This strategy is impractical for cancer treatment. of. Chemotherapy seats, like movies, must be booked in advance. "The seats at 4 pm are very popular because there are too many patients who need to start from that time," Grothey said.
Still, Lévi and others are optimistic. He believes that these efforts can help clarify inconsistencies in clinical trials and make time therapy more feasible. As the world's largest cancer research fund, the National Cancer Institute (NCI) also called for research on how the day and night process affects disease progression and response to treatment.
Watch the clock and other points
Last year, the propaganda of time therapy was improved. Just one week after the NCI workshop, the Nobel Prize in Physiology or Medicine was awarded to three scientists who elucidated the mechanisms that control the circadian rhythm.
The biological clock is an extraordinary system. The central timekeeper of the hypothalamus coordinates a peripheral clock network in almost every organ and tissue of the body, opening and closing a set of genes, including genes encoding drug molecular targets and enzymes that break down drugs.
These clock genes are especially important in cancer because they control cell cycle, cell proliferation, cell death, and DNA damage repair—all of which can be out of control in cancer.
Some but not all cancers have clocks, and researchers are trying to figure out their daily rhythms. Joshua Rubin, a neuro-oncologist at the University of Washington School of Medicine, and colleagues plan to launch a time-based clinical trial of malignant gliomas that examine how cancer develops over time.
Therefore, the researchers extracted cells from the patient's tumor and modified it to express luciferase when the clock gene was turned on. Then they made an observation. "It's so vibrant, the light is constantly lit and extinguished," Rubin said.
The team began treating the tumor cells with drugs at different times in the cell cycle and found that they were most sensitive to the oral drug temozolomide near the peak of the daily expression of the clock gene Bmal1. Scientists have concluded that if a patient takes a drug at the peak of Bmal1 expression, the effect may be better. Currently, his team is validating this hypothesis in a mouse model and in more than 20 patients, allowing them to take medication at different times of the day.
On the other hand, time therapy is exciting for some people, in part because of its simplicity. Jeremy Rich, a neuro-oncologist at the University of California, San Diego, said: "If we can help people reduce side effects, prolong life and improve quality of life by changing some of the timing, that's great." For example, steroid levels are Synchronized with the biological clock. Scientists discovered in the late 1960s that taking the synthetic corticosteroid methylprene cortisol, which is used to treat arthritis and asthma, was safer than taking it at other times. This is because the feedback pathway of the hypothalamus responsible for cortisol release is least likely to be suppressed in the morning.
Eric Holland, a neurosurgeon at the Fred Hutchinson Cancer Research Center, said these rhythms may also affect a patient's response to radiation therapy. Holland has demonstrated that corticosteroids reduce the efficacy of radiation therapy in humans and that the best time for radiation therapy is found in mice.
But the best time for different treatments seems to be different. This may explain why many studies that attempt to confirm the benefits of controlling dosing time have yielded ambiguous results. The Lévi team tested the efficacy of time therapy and conventional chemotherapy in 564 patients with metastatic colorectal cancer. The results showed that the survival time of the two groups was similar overall. However, when grouping patients by gender, the researchers found that the risk of early death was reduced by 25% for men and by 38% for women. Researchers say that during the day, men are most tolerant of an anticancer drug for four to seven hours earlier than women, and that cancer treatment can have more toxic side effects for women.
Age is also one of the factors that influence an individual's circadian rhythm. The circadian body clock tends to change during adolescence - prefers to sleep late, but will change back with age.
Tracking biological clock
Phyllis Zee, director of sleep medicine at Northwestern University's Feinberg School of Medicine, said that time therapy has great potential, but there is a need to find practical biomarkers to help clinicians confirm the best time for treatment. “These markers are the key to the application of time therapy,†she said. “We are not ready for the golden age of time therapy.â€
Lévi has been trying to figure out how to better track individual clocks. Before starting home time therapy, Godain wore a watch-like device to record her biological clock. Godain has a regular sleep-wake cycle, which Lévi believes may have a positive effect on her successful treatment.
Researchers are now using more sophisticated tools to identify circadian rhythm, including temperature sensors, blood samples, and saliva tests on the chest. A research team at the University of Pennsylvania is integrating data from wearables, smartphone apps, and physiological samples to define each person's "timing group" to determine the best predictors for optimizing time therapy.
In some ways, time therapy can represent an aspect of individualized treatment. Virginian Institute of Technology molecular biologist Carla Finkielstein said: "Incorporating the time dimension into the field of personalized medicine will bring about tremendous changes. Now we have a good molecular foundation. I hope this is a good start."
Time therapy also faces other real challenges. Cost and convenience are central factors in leading hospitals' decision-making in time therapy. Bart Staels, a molecular pharmacologist at the University of Lille, France, admits that it is unrealistic to limit heart surgery to a specific time of day.
David Ray, an endocrinologist at the University of Manchester in the UK, said there are several reasons why pharmaceutical companies are reluctant to take time therapy. Even if you don't consider time, it is difficult for patients to take the medicine. According to statistics, only about 50% of patients with chronic diseases follow treatment recommendations. More importantly, regulators may insist that more time-optimized drugs need to provide more warnings to warn of the risk of not taking drugs on time.
In any case, for the advocates of time therapy, the prospect of this approach is unprecedented. But given the unevenness of test results and the practical challenges in implementation, many scientists remain cautious.
Grothey said: "At the end of the day, we either need to completely rethink the time therapy, try to get more data to make it work, or admit that this is just a note in the history of oncology." He remembered when he entered the cancer field 20 years ago. People have been excited about time therapy, but that emotion is fleeting. He said: "At the time, many of us abandoned this method because it was too complicated, and at the time lacked the necessary technical means. However, it may be different now."
Source: Science Network
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