Stories about: Dana-Farber Boston Children’s

After 80 years, genetic causes of Diamond-Blackfan anemia come into view

Vijay Sankaran, MD and a patient with Diamond-Blackfan anemia
Hematologist Vijay Sankaran with Jack Farwell (PHOTO: MICHAEL GODERRE / BOSTON CHILDREN’S HOSPITAL)

In 1938, Louis K. Diamond, MD, and Kenneth Blackfan, MD, at Boston Children’s Hospital described a severe congenital anemia that they termed “hypoplastic” (literally, “underdeveloped”) because of the bone marrow’s inability to produce mature, functioning red blood cells. Eighty years later, the multiple genetic origins of this highly rare disease, now known as Diamond-Blackfan anemia, or DBA, are finally coming into view.

The largest study to date, published recently in the American Journal of Human Genetics, raises as many questions as it answers. But in the meantime, it provides a genetic explanation for nearly 80 percent of patients.

Read Full Story | Leave a Comment

ctDNA: Bringing ‘liquid biopsies’ to pediatric solid tumors

Brian Crompton studies the use of ctDNA as an alternative way to biopsy pediatric solid tumors
Brian Crompton with Stephanie Meyer (left) and Kellsey Wuerthele (PHOTO: JOHN DEPUTY)

Our blood carries tiny amounts of DNA from broken-up cells. If we have cancer, some of that DNA comes from tumor cells. Studies performed with adult cancers have shown that this circulating tumor DNA (ctDNA) may offer crucial clues about tumor genetic mutations and how tumors respond to treatment.

Brian Crompton, MD, with colleagues at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and elsewhere, is now working to bring ctDNA “liquid biopsies” to pediatric solid tumors as well. The researchers hope that these blood tests will eventually improve early detection, choice of treatment and monitoring of young patients with these diseases without having to sample the tumor itself.

Read Full Story | Leave a Comment

In zebrafish, a way to find new cancer therapies, targeting tumor promoters

A new study suggests the power of zebrafish as tools for cancer drug discovery (PHOTO: KATHERINE C. COHEN)

The lab of Leonard Zon, MD, has long been interested in making blood stem cells in quantity for therapeutic purposes. To test for their presence in zebrafish, their go-to research model, they turned to the MYB gene, a marker of blood stem cells. To spot the cells, Joseph Mandelbaum, a PhD candidate in the lab, attached a fluorescent green tag to MYB that made it easily visible in transparent zebrafish embryos.

“It was a real workhorse line for us,” says Zon, who directs the Stem Cell Research Program at Boston Children’s Hospital.

In addition to being a marker of blood stem cells, MYB is an oncogene. About five years ago, Zon was having lunch at a cancer meeting and, serendipitously, sat next to Jeff Kaufman, who was also interested in MYB. Kaufman was excited to hear about Zon’s fluorescing MYB zebrafish, which can be studied at scale and are surprisingly similar to humans genetically.

“Have you ever heard of adenoid cystic carcinoma?” he asked Zon.

Read Full Story | Leave a Comment

Putting patients first in the translational research pipeline

During a follow-up visit, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.
During a follow-up visit at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.

This is part II of a two-part blog series recapping the 2018 BIO International Convention. Read part I: Forecasting the convergence of artificial intelligence and precision medicine.

The hope to improve people’s lives is what drives many members of industry and academia to bring new products and therapies to market. At the BIO International Convention last week in Boston, there was lots of discussion about how translational science intersects with patients’ needs and why the best therapeutic developmental pipelines are consistently putting patients first.

As a case in point, Mustafa Sahin, MD, PhD, of Boston Children’s discussed his work to improve testing and translation of new therapies for autism spectrum disorder (ASD). As a member of PACT (Preclinical Autism Consortium for Therapeutics) and director of Boston Children’s Translational Neuroscience Program, Sahin aims to bridge the gap between drug discovery and clinical translation.

“Our mission is to de-risk entry of new therapies in the ASD drug discovery and development space,” said Sahin, who is also a professor of neurology at Harvard Medical School.

One big challenge, says Sahin, is knowing how well — or how poorly — autism therapies are actually affecting people with ASD. Externally, ASD is recognized by its core symptoms of repetitive behaviors and social deficits.

Read Full Story | Leave a Comment

Solving the DIPG puzzle a single cell at a time

Image depicting the cellular makeup of DIPG/DMG tumors vs normal brain tissue development
Scientists have discovered that DIPG/DMG tumors are made up of H3K27M-mutated cell populations that contain many cells stuck in a stem-cell-like state, fueling tumor growth. Cells that can differentiate despite the H3K27M mutation could hold the key to unlocking a new therapy for DIPG/DMG.

For more than 15 years, pediatric neuro-oncologist Mariella Filbin, MD, PhD, has been on a scientific crusade to understand DIPG (diffuse intrinsic pontine glioma). She hopes to one day be able to cure a disease that has historically been thought of as an incurable type of childhood brain cancer.

“While I was in medical school, I met a young girl who was diagnosed with DIPG,” Filbin recalls. “When I heard that there was no treatment available, I couldn’t believe that was the case. It really made a huge impression on me and since then, I’ve dedicated all my research to fighting DIPG.”

Her mission brought her to Boston Children’s Hospital for her medical residency program and later, to do postdoctoral research at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Now, she’s starting her own research laboratory focused on DIPG — which has also been called diffuse midline glioma (DMG) in recent years — and continuing to treat children with brain tumors at the Dana-Farber/Boston Children’s pediatric brain tumor treatment center. She’s also a scientist affiliated with the Broad Institute Cancer Program.

This year, Filbin has made new impact in the field by leveraging the newest single-cell genetic sequencing technologies to analyze exactly how DIPG develops in the first place. Her latest research, published in Science, entailed profiling more than 3,300 individual brain cells from biopsies of six different patients.

Using what’s known as a single-cell RNA sequencing approach to interrogate the makeup of DIPG/DMG tumors, Filbin was able to identify a particularly problematic type of brain cell that acts forever young, constantly dividing over and over again in a manner similar to stem cells.

Read Full Story | Leave a Comment

A bold strategy to enhance CAR T-cell therapies, capable of targeting DIPG and other tough-to-treat cancers

CAR T-cell therapy uses a patient's own genetically modified T cells to attack cancer, as pictured here, where T cells surround a cancer cell.
T cells surround a cancer cell. Credit: National Institutes of Health

A Boston-based team of researchers, made up of scientists and pediatric oncologists, believe a better CAR T-cell therapy is on the horizon.

They say it could treat a range of cancers — including the notorious, universally-fatal childhood brain cancer known as diffuse intrinsic pontine glioma or DIPG — by targeting tumor cells in an exclusive manner that reduces life-threatening side effects (such as off-target toxicities and cytokine release syndrome). The team, led by Carl Novina, MD, PhD, and Mark Kieran, MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, calls their approach “small molecule CAR T-cell therapy.”

Their plan is to optimize the ability for CAR T-cell therapies, which use a patient’s genetically modified T cells to combat cancer, to more specifically kill tumor cells without setting off an immune response “storm” known as cytokine release syndrome. The key ingredient is a unique small molecule that greatly enhances the specificity of the tumor targeting component of the therapy.

Read Full Story | Leave a Comment

Failed cancer drug may extend life in children with progeria

child with progeria and damage to cell nucleus
Image: Wikimedia Commons. (Source: The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T. PLoS Biology Vol. 3/11/2005, e395 doi:10.1371/journal.pbio.0030395)

Hutchinson-Gilford Progeria Syndrome, better known as progeria, is a highly rare genetic disease of premature aging. It takes a cruel toll: Children begin losing body fat and hair, develop the thin, tight skin typical of elderly people and suffer from hearing loss, bone problems, hardening of the arteries, stiff joints and failure to grow. They die at an average age of 14½, typically from heart disease resembling that of old age.

An observational study published yesterday in the Journal of the American Medical Association suggests that a drug called lonafarnib, originally developed as a potential cancer treatment, can extend these children’s lives.

Read Full Story | Leave a Comment

Zeroing in on the fetal-to-adult hemoglobin switch and a new way to combat sickle cell disease

Normal red blood cell vs. sickle-shaped blood cell, which is found in sickle cell disease
Normal red blood cell vs. sickle-shaped blood cell.

It’s been known for more than 40 years that in rare individuals, lingering production of the fetal form of hemoglobin — the oxygen-transporting protein found in red blood cells — can reduce the severity of certain inherited blood disorders, most notably sickle cell disease and thalassemia. Typically, however, a protein called BCL11A switches off fetal hemoglobin production past infancy, but exactly how this happens has not been well understood until now.

In a new paper in Cell, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have revealed how BCL11A controls the switch in the body’s production of fetal hemoglobin to adult hemoglobin. It does so by binding to a DNA sequence — made up of the bases T-G-A-C-C-A — that lies just in front of the fetal hemoglobin genes.

Another approach to curing sickle cell disease is already being evaluated in a new clinical trial at Dana-Farber/Boston Children’s. The novel gene therapy restores fetal hemoglobin production by genetically suppressing BCL11A, which prevents it from blocking fetal hemoglobin production. Learn more.

“Genetically modifying this TGACCA segment could be another possible strategy to cure sickle cell disease by blocking BCL11A’s ability to bind to this DNA site and switch off fetal hemoglobin production,” says Stuart Orkin, MD, senior author on the study.

Read Full Story | Leave a Comment

A breakthrough in our understanding of how red blood cells develop

Artist's rendering of red blood cells
Red blood cells.

By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.

For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.

Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.

Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.

Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.

Read Full Story | Leave a Comment

News Note: Why is this eye cancer making headlines?

This illustrations shows a catheter is used during intra-arterial chemotherapy for retinoblastoma.
During intra-arterial chemotherapy for retinoblastoma, a catheter is placed into the common femoral artery and threaded through a child’s vasculature to access the blood vessel of the affected eye and deliver a concentrated dose of chemotherapy. Illustration: Dana-Farber/Boston Children’s.

Retinoblastoma is a rare cancer that originates in the retina, the tissue in the back of the eye that converts light into visual information that is interpreted by the brain.

One retinoblastoma symptom in particular is finding itself in the spotlight. With a rise in social media use in recent years, retinoblastoma has attracted media attention for being a type of cancer that can sometimes be detected through photographs. Across the internet, news stories like this one abound in which friends or relatives have alerted parents to the potential risk of eye cancer after noticing that a child’s pupil appears white instead of red — a symptom called leukocoria — on photos posted to social media.

Fortunately, with proper diagnosis and treatment, 95 percent of children diagnosed with retinoblastoma can be cured. What’s more, a catheter-based treatment approach is now sparing patients from some of the side effects that can be expected from more traditional therapies.

Read Full Story | Leave a Comment