Small interfering RNAs, or siRNAs, could be great targeted treatment tools for breast and other cancers. The problem is making sure they get packaged and delivered to where they need to go. (pscf11/Flickr)
Breast cancers whose cells carry the HER2 protein are pretty tough customers. They only account for about 20 percent of all breast cancers, but they are some of the most aggressive. While targeted drugs like trastuzumab (Herceptin) and lapatinib (Tykerb) have made these tumors easier to treat, those that resist these drugs, relapse or don’t have HER2 on their cells’ surfaces can still stymie oncologists.
A molecular phenomenon called RNA interference (RNAi)—in which small pieces of RNA silence the expression of individual genes—could provide an alternative solution for breast and other cancers.
Though it was first discovered in plants, researchers have known for about a decade that small interfering RNAs (siRNAs) are active in mammals like us, and are already working on ways to harness them for shutting down genes promoting cancer and other diseases.
The problem with siRNAs for treatment, however, is making sure they get exactly where they need to go. That’s a problem that Judy Lieberman, MD, PhD, has taken a big step toward solving. Full story »
What time is the right time to give a transfusion? Doctors at Boston Children's are turning a fresh eye on transfusion guidelines for children. (@alviseni/Flickr)
Cancer. Trauma. Sickle cell disease. Surgery. There are many reasons why a child might need a blood transfusion, but they all share a common theme: the need to replace blood or blood products (e.g., red blood cells, platelets) that have been lost or consumed, or make up for defects that keep the body from producing them in adequate amounts.
And though transfusions can be life saving, they come with risks, such as iron overload, inflammation or disease (a very low risk, thanks to improved screening tests). And blood products are expensive and scarce—another reason to be prudent about transfusions.
“There’s little science behind physicians’ current practices when deciding when to transfuse a patient,” says Jenifer Lightdale, MD, MPH, of Boston Children’s Hospital’s Division of Gastroenterology and Nutrition. “Many doctors use criteria their mentors passed down to them, which their mentors passed down to them, and so on. But ideally, the decision should be based on evidence, not tradition.” Full story »
Nestled in the pons (the red area above), the area that controls breathing, DIPG tumors have been impossible to biopsy and analyze for therapeutic insights. Until now. (MEXT Integrated Database Project/Wikimedia Commons)
Brain tumors can be very difficult to treat, but at least we know what to do about them. For years, a mix of surgery, radiation and chemotherapy has been used to treat brain tumors like medulloblastoma.
These treatments are fairly successful, but for a rare, almost always fatal tumor called diffuse intrinsic pontine glioma (DIPG), we haven’t had any success—in fact, we haven’t known where to start.
The problem has to do with where DIPGs are located: nestled among the nerves in a portion of the brain stem, the pons, that controls critical functions like our breathing, blood pressure and heart rate.
“For 40 years, we lacked the neurosurgical techniques to biopsy DIPGs safely,” say Mark Kieran, MD, PhD, director of the Brain Tumor Program at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). “In fact, one of the first lessons every oncologist is taught still is, ‘Don’t biopsy brain stem gliomas.’ The dogma was that the risk of severe or fatal damage was too great.” And because we couldn’t biopsy them, we couldn’t study them to learn what makes them tick.”
A lot can change in four decades. Techniques for operating on the brain have advanced considerably, as have the tools for probing tumors at the molecular level. So, looking to turn the dogma about DIPGs on its head, Kieran has launched a clinical trial that aims to use advanced surgical and diagnostic tools to target and individualize DIPG treatment. Full story »
Lewis Silverman, MD, thinks he may have a powerful new tool for treating children with relapsed acute lymphoblastic leukemia. (VashiDonsk/Wikimedia Commons)
The news that your child has cancer always comes as a shock, but for one cancer, acute lymphoblastic leukemia (ALL), parents can take comfort in the fact that doctors are really good at treating it. The cure rate for ALL has, over the last 40 years, climbed to nearly 90 percent.
Less comforting is the fact that some 10 to 20 percent of children who initially respond well to treatment suffer a relapse within five years. And right now, the drugs at our disposal aren’t very good at turning a relapse back into a remission.
“We have standard treatment regimens for newly diagnosed and relapsed ALL, both of which rely heavily on corticosteroids like prednisone and dexamethasone,” says Lewis Silverman, MD, director of the Pediatric Hematologic Malignancy Service at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). “But we know that leukemias with any level of steroid resistance are more likely to relapse. Anything we can do to overcome that resistance would let us help many children.”
Silverman has launched a clinical trial that will try a new strategy for tearing down ALL cells’ barriers against corticosteroids. Full story »
Measuring the total amount of DNA damage within a tumor’s cells could help doctors predict its vulnerability to drugs like cisplatin. (Haukeland universitetssjukehus/Flickr)
Drugs like cisplatin that break DNA are some of the strongest weapons we have against breast, ovarian and other cancers. The problem, common to every form of chemotherapy, is that cisplatin doesn’t work for everyone. Given the potential side effects that go along with the drug—including vomiting, hearing loss and muscle cramps, just to name a few—the decision to give it to a patient becomes something of a gamble: Does the benefit outweigh the risk?
There are tests that examine individual genes and which can give doctors a limited view as to which tumors might respond best to cisplatin. But a multicenter team co-led by Zoltan Szallasi, MD, of Boston Children’s Hospital’s Informatics Program (CHIP), thinks they may have a solution that looks beyond individual genes to see which tumors might succumb to cisplatin and other drugs like it. Full story »
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. Full story »
Manipulating the enzymes that turn genes on and off could help make the process of reprogramming cells into iPS cells a lot more efficient and safer.
There are several ways to reprogram skin cells into induced pluripotent stem (iPS) cells – cells that behave like embryonic stem cells, and which could help better understand the genetic basis of and develop new treatments for different diseases.
The major methods scientists use now include using viruses to deliver reprogramming genes or using RNAs to produce the necessary proteins without the genes. Different methods have different advantages and disadvantages, and some are more efficient than others.
What’s common across all of the methods is that they rely on four proteins to turn back the cellular clock – c-Myc, Klf4, Oct4, and Sox2. Less understood is whether enzymes that modify chromatin (the DNA-plus-protein package that constitutes our genome) play any role in the reprogramming process. These enzymes manage and control the cell’s epigenetic code – the layer of control that helps cells fine-tune gene expression by adding and removing small chemical tags to genes and proteins.
“During iPS reprogramming, a cell’s epigenetic code gets completely rewritten,” says George Q. Daley, director of the Stem Cell Transplantation Program at Children’s Hospital Boston. “But how the cell’s epigenetic enzymes influence the reprogramming process has been a mystery.” Full story »
Researchers and doctors dream of being able to artificially produce platelets (in the blood bag above) at clinically useful scales. A device that mimics the environments in which platelets mature could help them get there. (Toytoy/Wikimedia Commons)
The platelet – a crucial cog in our blood’s clotting machinery – is in high demand. Trauma, chemotherapy, and surgery patients often need platelet transfusions to keep their blood working properly. So too do people with genetic disorders like Wiskott-Aldrich syndrome that prevent them from producing enough platelets on their own and cause thrombocytopenia.
However, platelets are in short supply compared to other blood products, in part due to their short shelf life.
“Platelets only last in the body for about 10 days at a time,” explains Jonathan Thon, a fellow in the laboratory of Joe Italiano, a member of Children’s Vascular Biology Program. “In a blood bank, red blood cells can be stored in a refrigerator for 42 days, and plasma can be frozen for years. But platelets need to be stored at room temperature, and only for a short time for fear of bacterial contamination.” Which means that few platelets are available for those who need them – a situation that screams for a means of artificial platelet production. Full story »
In the vast majority of us, the Epstein-Barr virus (above) causes mild illness and never bothers us again. However, it can lay dormant in small numbers of B cells for years, waking up if the immune surveillance keeping it in check is broken and fueling lymphomas. (NCI)
Some 90 percent of us are exposed to the Epstein-Barr virus (EBV) at some point in our lives. While the immune system’s T cells rapidly clear most EBV-infected B cells, about one in a million infected cells escapes destruction. Within these cells, the virus enters a latent phase, kept in check by the watchful eye of so-called memory T cells.
This uneasy relationship usually holds steady for the rest of our lives, unless something suppresses the immune system – such as infection with HIV or use of anti-rejection drugs after a transplant – and breaks the surveillance. The virus can then reawaken and drive the development of certain B cell cancers.
How do our T cells keep their watch? Full story »
While a cell's chromosomes (red, in a dividing cell) may look like they sit in a tangled jumble, they are actually organized in precise 3D fashion, which in turn influences what happens when chromosomes break. (Lothar Schmermelleh/Wikimedia Commons)
We’ve known for decades that our chromosomes can break and reshuffle, especially in cancer cells. We also see this process, called translocation, in naïve B cells when they start to produce antibodies for the first time: the cell breaks, shuffles and recombines genes to decide which threat it will defend against.
But knowing these things happen doesn’t mean that we’ve understood the rules for how and why they happen. By combining two powerful methods of genomic mapping, a research team led by Frederick Alt, director of the Program in Cellular and Molecular (PCMM) Medicine at Children’s Hospital Boston and the Immune Disease Institute (IDI), has brought some of those rules into clearer focus. It turns out that the genome’s three-dimensional organization – where each of the genome’s thousands of genes lie spatially within the cell’s nucleus – holds great influence over where broken chromosome ends rejoin. Full story »
