Tiny Patients, Major Goals (Published 2013) (2022)


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By Gina Kolata

BOSTON — Here at Beth Israel Deaconess Medical Center, a black mouse lies on a miniature exam table, his tail dangling off the end. A plastic tube carries anesthetic to his nose and mouth. He is asleep.

Before he was born, the mouse was injected with two mutated genes often found in human prostate cancer. As he lies on the table, a technician is measuring his two-millimeter prostate tumor with a petite ultrasound machine — the very exam a man would undergo, only on a dollhouse scale.

“There’s the tumor,” says the technician, Bhavik Padmani, sliding a probe over the mouse as a bright white amoebalike shape comes into view.

The animal is in what is called a “mouse hospital,” a new way of using mice to study cancer. Although mice have been studied in regular labs for years, the results often have been disappointing. Usually, the cancers were implanted under their skin, not in the organs where they originated. And drugs that seemed to work in mice often proved useless in humans.

The mouse hospital at Beth Israel Deaconess and a few similar ones elsewhere are at the forefront of a new approach to studying human cancers. The mice are given genes that make them develop tumors in the same organs as humans, which means the researchers need scanners to watch the tumors’ growth inside the animals’ bodies. So the mouse hospitals have tiny ultrasound machines, CT and PET scanners, and magnetic resonance imaging machines with little stretchers to slide the mice into the machines. They also have mouse pharmacies to formulate medicines in mouse-size doses and mouse clinical laboratories specially designed to do analyses on minute drops of mouse blood and vanishingly small quantities of mouse urine. That lets them follow cancers’ growth and responses to treatments.

What’s more, with genetic advances in studies of human tumors, the researchers do not have to implant human cancer cells in all their complexity into mice to study the cancers; instead, they can give the mice just a few mutated genes that seem to drive a tumor.

They genetically alter the mice before they are born and then, with scanners, watch what happens as a cancer develops in the expected organ — the prostate, in this case. Then they can try out drugs designed to attack those gene mutations and the cancers they cause. The result, so far, has been astonishing. The mice with just a few cancer genes developed prostate cancer when they grew up. The cancer responded to the standard treatment — castration or, in the case of patients, chemical castration with a drug that shuts off testosterone production in the testes. Then, as often happens in men with advanced prostate cancer, the tumors in the mice started growing again, resistant to the castration treatment.

But because so few genes were involved in the mouse prostate cancer, the investigators, including Andrea Lunardi of Beth Israel Deaconess, could pinpoint the genetic roots of the treatment resistance. Researchers had studied prostate tumors before, asking how and why they grew resistant to treatment, but were stymied by the hundreds of mutations in cancer cells and unable to figure out which ones were important to the treatment resistance.

In retrospect, the solution seems obvious, said Dr. Pier Paolo Pandolfi, scientific director at Beth Israel Deaconess Medical Center. By making mice with only one or a few suspect mutations at a time, scientists cut through the chaotic genetic noise.

“The data were in front of our eyes, but we did not see them because the patients had many other things going on,” Dr. Pandolfi said.

New Developments inCancer Research

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Progress in the field. In recent years, advancementsin researchhave changed theway cancer is treated. Here are some recent updates:

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Uterine cancer. Cancer of the uterus is on the rise, especially among Black women.Experts say the cancer will eventually become the third most common type among women, and recent studies show that it is not only more likely to strike Black women, but also more likely to be deadly.

Blood tests. New blood tests that look for minuscule shards of DNA or proteinsto detect a variety of cancers have won praise from President Biden, who made them a priority of his Cancer Moonshot program. Supporters say the tests can find tumors when they are still small and curable, but a definitive study to determine whether the tests could prevent cancer deaths has yet to come.

Melanoma. A large study found that participants who ate high quantities of fish each week had a greater risk of developing melanoma, the most serious type of skin cancer. It is not clear what’s behind the surprising association between fish intake and melanoma, and the lead author of the study cautioned that the findings are not a reason to remove fish from a healthy diet.

Rectal cancer. A small trial that saw 18 rectal cancer patients taking the same drug, dostarlimab, appears to have produced an astonishing result: The cancer vanished in every single participant, undetectable by physical exam, endoscopy, PET scans or M.R.I. scans. Experts believe it to be the first time in history that a study has led to complete remission in every single cancer patient.

Breast cancer trial. A treatment with trastuzumab deruxtecan, a drug that targets cancer cells with laserlike precision, was found to be stunningly successfulat slowing tumor growth and extending life in clinical trial participants who had metastatic breast cancer.

The effect of weight loss. A new study found that people who lost significant amounts of weight through bariatric surgery had a 32 percent lower risk of developing cancerand a 48 percent lower risk of dying from cancer, compared with people who did not have the surgery. According to the study, the more weight people lost, the more their cancer risk fell.

Understanding the roots of the treatment resistance in mice, the investigators could try out rational ways to circumvent it in the animals, based on their genetic insights. It turned out to require more than one drug, which was not surprising.

The work is reported in Nature Genetics.

Many cancer researchers have suggested that the best way to treat cancer will be with more than one drug, blocking the cancer’s paths of escape. But the trouble was choosing which drug combinations to try.

“If we start randomly throwing every combination together, there are not enough patients on earth to test them,” said Dr. Lewis C. Cantley, director of the cancer center at Weill Cornell Medical College and NewYork-Presbyterian Hospital who worked with Dr. Pandolfi on the prostate cancer study. “We need a scientific rationale for picking a particular combination of drugs.”

The investigators just started one clinical trial to see if the mouse studies predict what will happen in patients, and are about to start another. And, they say, they could never have gotten this far without the mice with human cancer genes and the mouse hospital to study them.


Tiny Patients, Major Goals (Published 2013) (6)

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“It’s a very clever, innovative way to try to improve patient care,” said Dr. Scott Eggener, a director of the prostate cancer program at the University of Chicago, who was not involved with the research. “Now it is incumbent on them to show it works in humans.”

That, of course, is the goal of the two clinical trials. Each participant will be matched with collections of mouse proxies, with each group of mice engineered to carry different combinations of a few major human prostate cancer genes. The mice will develop tumors, just as the men did, and will receive the same treatments as the men. But since each mouse will have only one or a few of the critical cancer mutations, researchers will be able to see if a treatment is doing what it should and analyze the reason for resistance, if it develops. These trials will be the first to test treatments in mice and men simultaneously, Dr. Pandolfi said.

The patients will be men whose advanced cancer grew resistant to the standard treatment with chemical castration. To escape the drug, the cancers turn on genes that let them make their own testosterone. Some even make a more powerful version of the hormone, dihydrotestosterone.

“Surprisingly, over time, the prostate cancer cells become almost like mini-endocrine organs,” said Dr. Glenn J. Bubley, director of genitourinary medical oncology at Beth Israel Deaconess.

Cancer cells also have a way to survive even if their hormone supply is cut off. They inactivate genes that normally would make them commit suicide when deprived of the testosterone or its stronger cousin.

In the study that has just gotten started, men with advanced prostate cancer will get Zytiga, made by Janssen Biotech, which stops the tumors from making testosterone, along with an experimental drug made by Novartis that prevents the cancer cells from inactivating their suicide program — at least in the mice with the human prostate cancer genes.

The other study, beginning soon, will use a combination of drugs — Avodart, made by GlaxoSmithKline, to block dihydrotestosterone production, and another drug, embelin, a natural compound, to prevent cells from inactivating suicide genes.

Don De Grandis is patient No. 1 in the first study. He found out in October that he has prostate cancer when what he thought was a muscle pull in his back turned out to be bone pain from a cancer that had already spread to his bone marrow.

Mr. De Grandis, 58, a former warehouse worker from North Easton, Mass., was soon in excruciating pain, even with heavy doses of narcotics. The cancer was too advanced to cure, and the standard testosterone-blocking drug had stopped working.

He joined the study in March. Just a couple of weeks later, his wife, Kathleen, knew something was happening.

“He made me dinner,” she said. “It was very good — pasta with mushrooms, ground turkey and cheese. With a beautiful salad.” Until then, she said, he had been in too much pain and too tired to move much from his bed.

His physician, Dr. Bubley, noticed that Mr. De Grandis’s PSA levels, a measure of prostate cancer growth, had begun to fall.

Mr. De Grandis started using a cane instead of a walker and cut his narcotic dose in half. But, Dr. Bubley cautioned, this is an early-stage clinical trial, looking primarily for drug dosages and safety. There are many unknowns and no guarantees.

So far, some of the mouse proxies getting the same drugs as Mr. De Grandis are responding too, Dr. Bubley and the other researchers say. The cancer — and its response to treatment — progresses much faster in mice, so the animals may give a foretaste of what is to come in the men to whom they are matched.

Now the researchers will follow Mr. De Grandis and the mice that are responding to see how long the good effect lasts, and they will do a similar analysis of other men who are joining the study to see how well the mice mirror the men and whether the drug combination works for others as well.

Meanwhile, Mr. De Grandis said he was hoping for one more good year of life.

“I just want to spend more time with my family,” he said.

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