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Diabetes drug metformin corrects mitochondrial metabolism in familial cancer disorder
November 21, 2016
Individuals with Li-Fraumeni syndrome are at an increased risk for a number of cancers, including breast and bone cancer. Li-Fraumeni syndrome is an inherited cancer disorder caused by mutations in the tumor suppressing protein p53, which are also linked to increases mitochondrial metabolism. It is not clear whether targeting these metabolic changes can effectively reduce the risk of cancer associated with p53 mutations.
In this issue of the JCI, research led by Paul Hwang at the National Heart, Lung, and Blood Institute discovered that treatment with the commonly-prescribed diabetes medication metformin treatment blocked increases in mitochondrial metabolism in a mouse model of Li-Fraumeni syndrome, leading to a lower rate of tumor formation and increased survival time.
Furthermore, in a pilot study involving Li-Fraumeni patients, metformin treatment produced a similar inhibition of mitochondrial metabolism and activated of anti-proliferation signaling.
The finding that this FDA-approved drug can ameliorate abnormal mitochondrial metabolism suggests that it may be a potential strategy for tumor prevention in Li-Fraumeni syndrome.
More information: Ping-yuan Wang et al, Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome, Journal of Clinical Investigation (2016). DOI: 10.1172/JCI88668
Journal reference: Journal of Clinical Investigation
Provided by: JCI Journals
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Local cancer survivor using his experience to help those who are currently battling gets quite the surprise
KANSAS CITY, Mo. — A cancer survivor uses laughter to help fellow patients get through treatment, and recently those patients brought him to tears with a big thank you.
Dan Dickinson is a cancer survivor who is helping make life more bearable for patients at the KU Cancer Center as he sits for hours at a time listening and giving them support. Dickinson has also designed funny T-shirts to lift their spirits.
To recognize Dickinson for his kind ways, Ray Lindsay nominated him for FOX 4’s Pay-It-Forward award.
“We’re here to recognize Dan Dickinson for all of his time and all of his heart and passion that he shows all these patients who are going through hard times,” Lindsay said. “Just offers a lot of comfort, a lot of care and compassion, and he listens to you.”
Lindsay says Dickinson brings a lot of hope to patients’ situations.
“On behalf of all the patients in here tough time, all of our lives so much better and our experience that much better,” Lindsay said to Dickinson just before presenting him with the $300 as part of the award. “Your heart and passion, and your sympathy, your willingness to come here and just offer your heart and your tears and your ears to all of these people who are going through a difficult time.”
Dickinson was humbled by the award. Watch his reaction in the video above.
“It’s a hard time, so just to be able to sit with people who are going through the very same thing and just help them talk it through,” Dickinson said. “Sometimes you don’t have answers, sometimes all you can do is listen.”
FOX 4 loves your ideas for our future Pay-It-Forward stories. To nominate someone who’s not a relative, click on this link.
Dr. Victor MarchioneVictor Marchione, MD received his Bachelor of…
Dr. Richard M. Foxx, M.D.Dr. Foxx volunteered for the U.S. Army and served as…
Dr. Craig MintzerDr. Craig Mintzer currently serves as team…
Dr. Alwyn WongDr. Alwyn Wong has been involved in the…
About Bel Marra
On any matter relating to your health or well-being, please check with an appropriate health professional. No statement herein is to be construed as a diagnosis, treatment, preventative, or cure for any disease, disorder or abnormal physical state. The statements herein have not been evaluated by the Foods and Drugs Administration or Health Canada. Dr. Marchione and the doctors on the Bel Marra Health Editorial Team are compensated by Bel Marra Health for their work in creating content, consulting along with formulating and endorsing products.
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By Laurie McGinleyNovember 21 at 12:48 PM
Former president Jimmy Carter, who disclosed in 2015 that he had advanced melanoma, was treated with surgery, radiation and an immunotherapy drug. In December, he said his cancer had disappeared. (Elise Amendola/Associated Press)
This post has been updated.
The idea of using the body’s immune system to fight cancer has been around for more than a century, but dramatic breakthroughs have occurred only in the past half-dozen years.
“That’s when the tsunami came,” says Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunology at Johns Hopkins University. Advances are spawning hundreds of clinical trials nationwide, plus generating intense interest from patients, physicians and investors. Yet researchers say the treatments, for now, help only a minority of patients. And they remember the past anti-cancer efforts that fizzled after initially showing promise — which explains why they say daunting hurdles and years of perseverance are still ahead.
Here’s a primer about the new treatments and how they work:
What is cancer immunotherapy?
Immunotherapy is a significantly different approach from conventional treatments such as chemotherapy or radiation. The latter attack the malignancy itself, while immunotherapy aims to empower the immune system to kill it.
Because of the immune system’s unique power, says the nonprofit Cancer Research Institute, this therapy could prove a formidable weapon against many kinds of cancer and offer long-term protection with reduced side effects.
Which immunotherapies are sparking excitement?
Two types of immunotherapy are drawing most of the interest: checkpoint inhibitors, which remove “brakes” from the immune system, allowing it to see and go after cancer; and CAR T-cell therapy, which involves a more personalized attack.
“Checkpoint” inhibitors are designed to block the ability of certain proteins to weaken the response of the immune system so it can’t recognize and go after abnormal cells. In normal times, such checkpoint proteins keep the immune system from being too aggressive and damaging the body. But cancer sometimes hijacks them and uses them to suppress the immune system’s response to disease.
The Food and Drug Administration has cleared four checkpoint inhibitors for adults: Yervoy, also known as ipilimumab; Keytruda, or pembrolizumab; Opdivo, or nivolumab, and Tecentriq, or atezolizumab. The drugs are approved for malignancies including melanoma and Hodgkin lymphoma, as well as lung, kidney and bladder cancer. The treatments also are being tested in a wide range of other cancers.
Former president Jimmy Carter was treated with Keytruda, surgery and radiation for advanced melanoma last year. He announced in December that all signs of his cancer had disappeared.
In CAR T-cell therapy, T cells — a key part of the immune system — are removed from a patient, genetically modified in the lab to target a specific cancer and infused back into the person. This treatment, available only in clinical trials, is being tested mainly for leukemia and lymphoma. The FDA is likely to approve the first CAR T-cell treatment next year or in 2018.
Of these two immunotherapy approaches, most of the interest is focused on checkpoint inhibitors. That’s because they are off-the-shelf treatments that are much easier to administer than CAR T-cell therapy, which is customized to every patient, said Crystal Mackall, a former National Cancer Institute researcher who’s now leading immunotherapy trials for Stanford University School of Medicine.
What are the latest developments?
Some of the biggest news involves the use of Keytruda in lung cancer, which kills almost 160,000 Americans a year. In an international trial invoving the most common type of the disease, the drug outperformed chemotherapy for patients with high levels of a protein, called PD-L1, on their cancer cells.
At one year, for example, 70 percent of the patients in the Keytruda group were alive, compared with 54 percent of the chemo group, researchers said in October. The Keytruda group also experienced significantly fewer side effects. Based on the trial, the FDA approved the drug as a first-line treatment for patients with non-small-cell lung cancer and a high level of the protein. That was the first time that an immunotherapy drug got the green light as an initial treatment for lung cancer.
“It’s a significant breakthrough,” said Neal Ready, an oncologist at the Duke Cancer Institute. “We’re starting to see people with advanced lung cancer who are alive at a year or two years or three years.”
What are some of the main challenges in immunotherapy?
Among the biggest challenges are increasing the response rate among patients and turning initial responses into long-lasting remissions. CAR T-cell therapy often produces a high remission rate in blood-disorder trials, but a significant percentage of patients relapse.
Checkpoint inhibitors induce responses — a tumor is shrunk or stabilized — in an average of just about 20 percent of patients, said oncologist Elizabeth Jaffee, the deputy director of the Sidney Kimmel Comprehensive Cancer Center at Hopkins. The percentage is higher in some cancers, and researchers need to understand why, for example, the treatment benefits patients with melanoma but not pancreatic cancer. They think the key to improving effectiveness will be the development of combination treatments, as happened with AIDS. Jaffee points out that the tide was turned against that disease only after researchers figured out how to use a “cocktail” of medications to keep people with HIV from contracting AIDS.
Nationwide, hundreds of combination trials are underway. They involve the use of two or more checkpoint inhibitors, a checkpoint inhibitor with CAR T-cell therapy or an immunotherapy plus such standard treatments as radiation and chemotherapy. But combining these treatments can increase safety risks.
Jill O’Donnell-Tormey, chief executive of the Cancer Research Institute, said researchers also are trying to understand tumors’ “micro-environments,” which contain cells and other elements that appear to sometimes suppress the immune system’s response to cancer. She made her remarks at a conference earlier this year in New York that was sponsored by the institute, along with the American Association for Cancer Research and two European groups.
What are immunotherapy’s downsides?
By revving up the immune system, immunotherapy can cause sometimes serious damage to healthy tissue and organs. Researchers are working on ways to limit or even reverse the potential toxicity, but much work needs to be done.
CAR T-cell therapy poses two types of safety risks. Almost all patients get sick with flu-like symptoms, including high fever and pain, a week or so after the treatment; some end up in intensive care. The treatment also can cause brain swelling that can be fatal.
Yet standard treatments have major side effects as well. Chemotherapy and radiation, when used for children with leukemia, can cause long-term problems such as secondary cancers, infertility and heart damage. In many ways, researchers say, immunotherapy is less toxic over the long term.
Immunotherapy can carry higher price tags. For example, Merck’s checkpoint inhibitor, Keytruda, costs about $150,000 a year. Once CAR T-cell therapies are approved by the FDA, they may cost hundreds of thousands of dollars a year, according to some analysts. If the treatments are used as directed by the agency, chances are good that insurance will pay for at least some of that.
Does immunotherapy work for children?
Immunotherapy in kids is a mixed picture.
Checkpoint inhibitors are only now being tested extensively in children, so it will take time to see how well they work. But very early-stage studies suggest that they may not be as effective as in adults. One theory holds that these drugs work better in cancers with many mutations — and pediatric cancers tend to have many fewer mutations.
CAR T-cell treatment, on the other hand, is being widely tested in children and has shown impressive effectiveness against the most common childhood leukemia, called acute lymphoblastic leukemia.
How do I find immunotherapy treatments?
Talk first to your doctor, who should be able to help you find appropriate medication or clinical trials for unapproved treatment. Trials sponsored by the National Cancer Institute can be found at trials.cancer.gov. Studies also are listed on the website ClinicalTrials.gov –though that doesn’t signify government endorsement or approval. Another resource is the Cancer Research Institute’s Clinical Trial Finder.
It is with a heavy heart that we report this news: Your heart tissue can sometimes start turning to bone.
During a heart attack, blood flow gets blocked and cells die as they are deprived of oxygen, SciShow explains. Sometimes the heart tries to heal itself following the episode and ends up making mineral deposits, like calcium, that harden the heart, preventing it from properly conducting electrical signals — “and your heart can’t keep that smooth, steady beat,” host Michael Aranda says.
Researchers are still trying to understand how this process works so they can prevent it and treat it.
While the heart is a dangerous place for mineral deposits, it’s not the only part of the body where this sort of process can occur. Harvard Health Publications notes that calcium can build up in soft tissues like the breast. In most women, breast calcium deposits are benign and do not come with any symptoms — “you become aware of them only when mammography reveals white spots or flecks of various shapes and sizes.” In some cases, however, the calcium is associated with breast cancer. Sometimes they are caused by injury, when fat cells die through trauma, infection, radiation or a cyst and release fatty acids “that combine with calcium to form deposits,” Harvard says. Other places calcification can occur is in brain-related arteries in the neck and spine, which may be a risk factor for stroke, and in the tendons, which can then become inflamed, cause pain and limit movement.
When heart tissue turns to bone after a heart attack, there could be serious health consequences. Image courtesy of Pixabay, public domain
Kidney stones are also the result of mineral deposits and buildup. Those compacted minerals and salts then travel down the urinary tract from the kidneys to the bladder, causing sharp pain, blood in the urine, nausea and frequent urination, among other symptoms. Calcium is a common mineral in kidney stones. Harvard explains that “people prone to kidney stones excrete about one-third more of their calcium intake in urine than people who don’t have kidney stones.”
Sharon Jones symbolized endurance.
The endurance of an old-fashioned style as music changed around it. The endurance of ambition despite the record industry’s neglect. And the endurance of a body that withstood disease until Friday, when Jones died of pancreatic cancer at age 60.
Described by a bandmate on her debut album as “110 pounds of soul excitement,” Jones sang funk-fueled R&B the way it used to be sung, back in the era of Tina Turner and Betty Wright and especially the late James Brown, with whom Jones shared a hometown of Augusta, Ga.
Her hand-played music – which she made in close collaboration with her New York-based backing band, the Dap-Kings – was willfully retro, showing little interest in the genre’s sonic and thematic evolution since the early 1970s. Yet her powerful voice and her natural exuberance attracted an audience outside the vintage-soul cognoscenti.
A few years ago she and the Dap-Kings performed on a float in the Macy’s Thanksgiving Day Parade – hardly a record nerd’s paradise – and their 2014 album “Give the People What They Want” was nominated for a Grammy Award.
The recognition came after decades of dismissal by label executives who said Jones was “too short, too fat, too black and too old,” as she put it with characteristic frankness in a recent documentary about her life, “Miss Sharon Jones!”
And in her music you could hear how that rejection had toughened her. The Dap-Kings’ sound is hard and lean, built on taut grooves set at quick tempos; Jones’ singing was direct and to the point, mostly free of vocal ornamentation.
Where many R&B singers try to summon the feeling of a moment being savored, Jones – who supported herself pre-Dap-Kings as a prison guard and as a member of a wedding band – offered forward momentum. You wouldn’t call it optimism, exactly, but a conviction that one’s troubles could be outlasted.
More than boudoir fantasies, she was drawn to lyrics about survival, as in “Longer and Stronger,” which was featured prominently in “Miss Sharon Jones!”:
Longer and stronger, that’s how I live
The more I get, the more I got to give
Fifty years of soul gone by, and 50 more to come
You think you’ve seen something, but Lord I’ve just begun
In other songs she described injustice with familiarity but zero self-pity. “Money don’t follow sweat/ Money don’t follow brains,” she sang in “People Don’t Get What They Deserve.”
Along with her gritty, no-nonsense vocals, Jones’ hard-nosed worldview made the singer an object of fascination – some might say a fetish object – to younger artists eager to absorb some of her weathered credibility.
One of Amy Winehouse’s producers, Mark Ronson, famously enlisted the Dap-Kings to accompany Winehouse on her smash 2006 album “Back to Black.” And Michael Buble, the polished neo-Rat Pack crooner, sang a duet with Jones in 2009.
Remarkably, that transfer of energy from Jones to her admirers never reversed flow; she didn’t start to make her music smoother or more modern after working with pop stars whose paths to success had been far straighter than hers.
Perhaps things would’ve gone differently if she hadn’t been diagnosed with cancer in 2013, a development that stalled her career at a most unwelcome moment. Had she not gotten sick, maybe Jones would’ve given hip-hop a try, as Wright has in recent years by singing on tracks by rappers such as Rick Ross.
But it’s hard to imagine. During a brief remission of her cancer, Jones went back on the road with the Dap-Kings, playing shows that made it clear how devoted she still was to her chosen style. And last year she released a Christmas album that paired favorites like “Silent Night” with an original called “Ain’t No Chimneys in the Projects.”
She also retained the instinct of a hard-working wedding singer. Before the cancer returned, Jones and the Dap-Kings were booked for a New Year’s Eve show next month in Long Beach.
Her steadfastness will be missed that night and beyond.