Stories about: DF/CHCC

Rebooting Fanconi anemia cells: You have to fix the broken code first

David Williams wants to turn cells from Fanconi anemia (FA) patients into stem-like iPS cells. To do that, though, he needs to get the patients' cells to reboot properly. (_rockinfree/Flickr)

About a decade ago, David Williams, MD, set out to solve a problem. The chief of Dana-Farber/Children’s Hospital Cancer Center’s Hematology/Oncology division wanted to treat Fanconi anemia (FA)—a rare, inherited bone marrow failure disease—using gene therapy. In the process, he’d be able to replace patients’ faulty bone marrow cells with ones corrected for the genetic defect that causes FA.

There was one big problem though. “The main bar to attempting gene therapy in FA is that you need to be able to collect a certain number of blood stem cells from a patient in order to be able to give enough corrected cells back,” he says. “In our early clinical trials, we were unable to provide enough corrected stem cells to reverse the bone marrow failure we see in these patients.”

One way around the supply issue would be to create the necessary blood stem cells from FA patients’ own cells by first reprogramming skin cells into what are called induced pluripotent stem (iPS) cells. Using one of several methods, scientist can reboot mature skin cells into an immature, stem cell-like state—essentially turning the cells’ biological clocks back to a time when they could grow into anything the body might need.

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Unmasking brain tumors with gene therapy

Brain tumors like the diffuse, light gray one in this MRI do a remarkably good job of hiding from the immune system. A new treatment based on gene therapy could strip their camouflage away. (Filip Em/Wikimedia Commons)

If there’s anything that tumors are good at, it’s hiding themselves. Not from things like MRIs or CT scans, mind you, but from the immune system. Since a tumor grows from what were at one time normal, healthy cells it’s still “self,” still one of the tissues that makes you you.

“Tumor cells display very subtle differences that distinguish them from healthy cells, but by and large they look the same to your immune system,” says Mark Kieran, a pediatric neuro-oncologist at the Dana-Farber/Children’s Hospital Cancer Center and Children’s Hospital’s Vascular Biology Program. “The question is: How can we unmask tumors so that the immune system can do its job?”

Researchers have worked for years on cancer vaccines aimed at getting the immune system to wake up to the presence of a tumor and turn on it. With a Phase 1 safety trial , Kieran and his colleagues, including Children’s neurosurgical oncologist Lily Goumnerova, are evaluating a different strategy for patients with hard-to-treat brain tumors called malignant gliomas:  They’re giving the tumors a cold.

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Blood pressure, cancer and EETs: Too much of a good thing?

Medicine is a balancing act; how much of a drug is too much? A group of compounds called EETs provide a clear example of the possible dangers of giving patients too much of a good thing. (chris grabert/Flickr)

Usually when your doctor talks to you about lipids, he or she is talking about cholesterol (be it the good or bad kind). But cholesterol is only one kind of lipid. There are millions of these fatty molecules working in everyone’s body right now.

One family of lipids, known as EETs (or epoxyeicosatrienoic acids), is produced by the endothelial cells that line blood vessels, where they help control inflammation and the response to injury. Because EETs are also potent regulators of blood pressure, pharmaceutical companies are looking intently at compounds that raise bloodstream EET levels as a way of managing the cardiovascular aspects of more than 20 conditions, ranging from diabetes and stroke to kidney and eye diseases; some are currently in clinical trials.

There may be a catch, however: Some studies suggest that EETs promote angiogenesis, or blood vessel formation, and that the enzymes that process EETs have a relationship to cancer.

Dipak Panigrahy and Mark Kieran of Children’s Vascular Biology Program and the Dana-Farber/Children’s Hospital Cancer Center wanted to understand this relationship better: Could boosting EETs be dangerous?

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Is rapamycin the new aspirin?

rapamycin
Easter Island, home of rapamycin (Ndecam/Flickr)

I’ve heard it said that if aspirin had to go through today’s FDA approval process, it would never be approved for over-the-counter use because it just does so many things. Lately, it’s been hard to cover biomedical research at Children’s without stumbling on another drug that’s also FDA-approved and also seems to have multiple uses: rapamycin.

It’s a drug that targets a pathway fundamental to nearly every cell in the body, yet is seemingly good for nearly everything. But how can one drug touch on so many cells and tissues and organs and still be both effective and safe?

First found in the 1960s in soil bacteria collected on Easter Island (the drug’s name comes from the island’s native name, Rapa Nui), rapamycin is a naturally derived antibiotic, antifungal and immunosuppressant.

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Sickle cell disease and the thalassemias: The advantages of staying forever young

Flipping a single molecular switch could turn off the mutation that causes sickle cell diseae. Stuart Orkin has already done it in mice. (CDC PHIL)

What if we really could turn our bodies’ clocks back? In some cases, that could be a really good thing. Take sickle cell disease. A scourge of tens of thousands worldwide, it stems from a genetic defect in hemoglobin, the oxygen-carrying protein in red blood cells.

Normally, our bodies can produce two forms of hemoglobin: adult hemoglobin, the form susceptible to the sickle cell mutation; and fetal hemoglobin, which is largely produced during development and for a short time after birth. Our bodies finish making the switch from fetal to adult hemoglobin production by about four to six months old – the same time frame when children with the sickle cell mutation first start to show symptoms of the disease.

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Heart disease in childhood cancer survivors: Helping keep their hearts healthy

Survivors of childhood cancers may walk around with treatment-related heart damage for decades without knowing it. Ming Hui Chen wants to help these survivors keep their hearts healthy. (qthomasbower/Flickr)

Our success at treating children with cancer has steadily improved in the 40 years since President Nixon announced the War on Cancer. At the time, 3 in 10 children survived a diagnosis of cancer; now upwards of 8 in 10 do. The U.S. alone is home to an estimated 328,000 childhood cancer survivors today.

But as these survivors age, they can experience late effects, long-term medical complications of the very treatments that saved their lives. In fact, 30 years out, survivors are at more risk of dying from treatment-related illness than from cancer recurrence.

Perhaps the most insidious late effect – and the leading cause of non-cancer death at the 30-year mark – is cardiovascular disease.

Treatment-related heart damage can take decades to appear. This long latency means that a woman treated for cancer at age 6 could face a heart attack when she’s 36. And she might never see it coming. “A survivor can walk around for years with minimal symptoms while their cardiovascular disease silently progresses,” says Ming Hui Chen, an adult cardiologist at Children’s Hospital Boston.

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Cancer treatment and fertility: Acting now to have children later

While many childhood cancers are readily curable, those cures can come at a cost to future fertility. Sara Barton and Richard Yu want to help lower that cost. (Wikimedia Commons)

With over 75 percent of children diagnosed with cancer surviving into adulthood, more and more parents ask questions about the quality of life survivors can expect in the future, including: Will my child be able to have children down the road?

They’re right to be concerned. The therapies that are so effective at saving children’s lives can themselves cause a host of problems that don’t manifest until years later. These late effects of cancer treatment include particularly harsh impacts on fertility.

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Treatment abandonment in childhood cancer: Are we willing to face this challenge?

(Photo: The Advocacy Project/Flickr)

Though the diagnosis is overwhelming for patients and families to receive, many childhood cancers have become “curable diseases.” At major U.S. centers like mine, the Dana Farber/Children’s Hospital Cancer Center, research efforts now largely focus on survivorship, refining risk stratification, minimizing treatment toxicity and developing more effective salvage therapies upon relapse.

But the situation globally is quite different. The technologic and resource gap between our centers and centers in the developing world is widening. Only a fraction of the children diagnosed with cancer around the world have access to therapy, either curative or palliative.

Treatment abandonment is another significant barrier to cancer care in the developing world. The reasons aren’t only economic, but are complex and multifactorial, including limited education, fatalism surrounding a cancer diagnosis, magical thinking, mistrust of the health care system,

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Getting to the root of a hard-to-treat childhood leukemia

Giving chromosomes their structure and shape, strands of DNA, shown in gray, are coiled around histones, depicted as spheres. Scott Armstrong thinks that drugs that block a particular histone methylation pathway could be the key to treating a rare but devastating childhood leukemia. (Courtesy Eric Smith/DFCI)

In the 40 years of the war on cancer, there is probably no greater success story than that of childhood leukemias. Once nearly uniformly fatal, some forms of acute lymphoblastic (ALL) and acute myeloid (AML) leukemias can now be cured in 80 or even 90 percent of cases.

The prognosis for the remaining 10 to 20 percent is not as good, especially if the cancer involves a reshuffling or rearrangement of the mixed lineage leukemia (MLL) gene. “We still only achieve about 50 percent success in treating these MLL-rearranged leukemias,” according to Scott Armstrong, a pediatric oncologist at Children’s and Dana-Farber Cancer Institute. “We need to find better ways of caring for these patients.”

Armstrong and his colleagues may have just given patients with MLL-rearranged leukemias a leg up by finding and exploiting a core epigenetic vulnerability in this type of cancer.

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A new start for gene therapy for “bubble boy” disease: First U.S.-treated patient doing well

The first U.S.-treated patient with his parents. Photo: Patrick Bibbins

Until this month, Agustín Cáceres’s baptism was the only time his family could come close to him. Everyone had to wear masks, gloves and gowns.

After that, he went into isolation, along with his mother Marcela, who came out only for meals. His father Alberto, and his four-year-old brother Jeremías, kept to a separate bedroom. Jeremías had to stop attending nursery school, for fear he’d bring home an infection his baby brother might catch. When Agustín’s relatives came to help out, they had to change their clothes and wash their hands, and couldn’t enter Agustín’s room.

Agustín, born in Argentina, has a form of X-linked Severe Combined Immunodeficiency, or SCID-X1, better known as “bubble boy disease.”

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