Tag: biology

Scientists Discover a Better ALK Inhibitor to Treat Neuroblastoma

Originally published on Cornerstone, the CHOP Research Blog.

I edited this article based on a CHOP press release and an additional interview with the investigator.

Excerpt:

Pediatric cancer researchers at The Children’s Hospital of Philadelphia believe they have succeeded in their search for a powerful next-generation drug for neuroblastoma tumors with mutations in the anaplastic lymphoma kinase (ALK) gene associated with the cancer. Based on their preclinical findings, they are fast-tracking the launch of a clinical trial this year.

Usually appearing as a solid tumor in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy.

The search for better ALK inhibitors originated when, in 2008, CHOP pediatric oncologist Yael Mossé, MD, and colleagues identified ALK mutations as a driver of most cases of rare, inherited neuroblastoma. Subsequent research showed that abnormal ALK changes drive approximately 14 percent of high-risk forms of neuroblastoma.

Based on this knowledge, scientists including Dr. Mossé in the multicenter Children’s Oncology Group were able to repurpose crizotinib, an ALK inhibitor already approved to treat adults with lung cancer, in clinical trials of children with neuroblastoma. But they found that different mutations within the ALK gene in neuroblastoma responded differently to crizotinib, and a mutation labelled F1174L was resistant to the drug.

New Collaboration Uncovering a Mitochondrial Mystery

Originally published in Bench to Bedside, the CHOP Research monthly publication

I composed this original article based on an interview with the investigator.

Excerpt:

Mistakes happen. Inside every cell, the functions of life rely on the basic process of building proteins. But, about half the time, cells make errors when building proteins and have to recycle the pieces and start again. One important player in the cell’s recycling process, an enzyme called N-glycanase 1 (NGLY1), is at the center of a new, fundamental biological mystery that researchers at The Children’s Hospital of Philadelphia are setting out to solve.

Two young patients brought this mystery to the team’s attention. Both children arrived within a short time of each other with symptoms of suspected mitochondrial disease at CHOP’s Mitochondrial-Genetic Disease Clinic, which Marni Falk, MD, directs. Mitochondria are the organelles inside of cells that act as the cell’s energy generator, and diseases of mitochondria can have wide-ranging effects across every organ system and commonly include neurological and cardiac complications.

“There are a lot of areas of mitochondrial biology that are still not known at all,” said Dr. Falk, an attending physician at CHOP. “We’ve been so intrigued with this project because, every time we asked a question, three more questions followed.”

Dr. Falk and her team found that, instead of a primary mitochondrial disease, these two children had an extremely rare genetic disorder that was only recently identified, caused by an inherited deficiency in the protein-recycling enzyme, NGLY1. This was fundamentally weird. There was no evident logical reason for a disease of NGLY1 dysfunction to so closely resemble diseases of mitochondrial dysfunction because the proteins in mitochondria do not require NGLY1’s services, or so says conventional wisdom.

Possible ‘Central Hub’ Proteins Found in Cancer Cell Growth

Originally published on Cornerstone, the CHOP Research Blog.

I composed this original article based on an interview with the investigator.

Excerpt:

A study from researchers at The Children’s Hospital of Philadelphia may add new lines to the textbook description of how cancer cells divide uncontrollably and develop into tumors. Their study, published in Nature Communications, identifies and describes an epigenetic mechanism in cancer cells that amplifies the expression of many genes and could be a central hub in cancer cell growth. Unlike most molecular cancer discoveries that advance knowledge of the disease by dividing it into narrower subtypes, this finding could directly apply to multiple cancer types.

“We know the signaling pathway known as the Rb pathway is altered in pretty much every single tumor that you can find in clinical settings,” said Patrick Viatour, PharmD, PhD, the study’s senior author, an investigator at CHOP and assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Viatour’s research focuses on a family of proteins in the Rb pathway, called E2f transcription factors, that are an important part of the process of cell division — the cell cycle of reproduction that is carefully controlled in healthy cells but proceeds out of control when cancer cells proliferate. Transcription factors, including the E2f family of proteins, bind to specific target regions of DNA and help to either activate or deactivate expression of certain genes.

As a result of Rb pathway alteration, E2f factors are steadily turned on in cancer. In the study primarily using a mouse model of liver cancer, Dr. Viatour and his team found that E2f1 progressively accumulates as cancer progresses.

Drugs May Be What’s the Matter With White Matter in HIV

Originally published in Bench to Bedside, the CHOP Research monthly publication

I composed this original article based on an interview with the investigators.

Excerpt:

Some of the neurological and psychiatric complications associated with HIV may be side effects of the medications that control the virus, and not caused by the virus itself, according to a new study from researchers at The Children’s Hospital of Philadelphia and the University of Pennsylvania. Their pre-clinical findings were published in the Journal of Neuropathology and Experimental Neurology.

Certain antiretroviral drugs were associated with problems in developing myelin proteins in cell models and animal models, and the drugs were associated with reductions in white matter in autopsy brain samples from a cohort of individuals with HIV, reported the research team led by co-senior authors Judith Grinspan, PhD, research professor of Neurology at CHOP, and Kelly Jordan-Sciutto, PhD, chair and professor of Pathology at Penn’s School of Dental Medicine.

Both senior researchers emphasized that individuals with HIV should continue taking lifesaving antiretroviral drugs as prescribed. They hope their current and future findings can help researchers refine drug designs to reduce side effects, and help clinicians pursue prescribing practices that are risk-informed and tailored to the patient’s age and stage of brain development. These future changes could be particularly important for children with HIV whose brains are still developing.

On the Trail of a Cancer Predisposition Syndrome

Originally published in Bench to Bedside, the CHOP Research monthly publication

I composed this original article and complementary blog post based on interviews with the investigator and two parents of children with this syndrome.

Excerpt:

Inside the cells of a developing human embryo is a little piece of “Alice in Wonderland.” While most of our bodies’ genes are expressed from both our mothers’ and fathers’ chromosomes, there is a particular growth-regulating region of chromosome 11 where Dad’s genes make you grow bigger, and Mom’s genes make you small. As in Alice’s adventure, there is potential for some difficult situations to occur when that growth process is not handled with exacting care.

With new grants awarded by the St. Baldrick’s Foundation and the National Cancer Institute, attending physician and geneticist Jennifer M. Kalish, MD, PhD, at The Children’s Hospital of Philadelphia, is going down the rabbit hole to try to set things right. She aims to answer key questions about cancer while helping children with Beckwith-Wiedemann Syndrome (BWS), an overgrowth disorder that can result when epigenetic regulation of growth-regulating regions of chromosome 11 goes awry.

Five Fascinating Facets of Beckwith-Wiedemann Syndrome

Originally published on Cornerstone, the CHOP Research Blog

I composed this blog post as a complement to the above article about the new investigation into BWS.

Excerpt:

1. BWS is a mosaic condition. Some cells and organs or limbs grow unusually large in children with BWS, and some do not. Patterns of this overgrowth vary from child to child. This mosaicism happens because the changes in gene expression that cause BWS arise early when the developing human embryo has relatively few cells — and the changes occur in only some of them. Cells and organs descended from those dysregulated cells have unusual growth patterns, while cells and organs descended from normally developing cells continue to grow at normal rates. This results in a widely varying presentation of the syndrome in different children.

The mosaic nature of the condition makes it challenging to manage the elevated cancer risk that goes along with BWS. As Dr. Kalish noted, “I can see if a child’s arms are bigger. I cannot see what is going on in the liver or kidney.” Each child’s areas of overgrowth are variable, so all young children with BWS must undergo regular cancer screenings.

Cornering a Cancer-Connected Autoimmune Disease

Originally published in Bench to Bedside, the CHOP Research monthly publication

I composed this original article and related behind-the-science human interest blog post based on interviews with the investigators.

Excerpt:

It is certainly not good news for children to get a double whammy of both cancer and autoimmune disease. Unfortunately, for a small subset of children with neuroblastoma, a common childhood cancer of the peripheral nervous system, an extremely rare autoimmune disorder called OpsoclonusMyoclonus Ataxia Syndrome (OMAS) comes along for the ride. The overactive immune response is believed to be triggered by the cancer.

But there is a twist.

“Patients with neuroblastoma who have OMAS have better outcomes, in terms of their tumor, than patients with neuroblastoma who don’t have OMAS,” said Jessica Panzer, MD, PhD, a pediatric neurologist and attending physician at The Children’s Hospital of Philadelphia who is studying this disease.

That pattern leads Dr. Panzer and other researchers to wonder: Is it possible that OMAS is a case of the body’s immune system finding a successful defense against cancer (but taking it a little too far against healthy cells)? And could we learn safe ways to harness its ability to help more children with neuroblastoma, or even other cancers?

These are among many long-term questions on the distant horizon for researchers who study this little-understood autoimmune disease. First, they need to understand the basics.

Dancing Eyes Brought a Research Team Together

Originally published on Cornerstone, the CHOP Research Blog

I composed this story as a complement to the above article highlighting the science of this team’s collaboration.

Excerpt:

It started at the end of a long day. Jessica Panzer, MD, PhD, then just a few weeks into her pediatric neurology residency at The Children’s Hospital of Philadelphia, was about to go home. Instead, she was called to the emergency room to consult on a 3-year-old girl who could barely walk. What happened then opened up new questions in her budding research career.

Not long after that, Miriam Rosenberg, PhD, started on a convergent path when her own 19-month-old daughter got sick. The toddler first developed problems with excessive drooling and stumbling while she walked. Within a few months, she had a sudden onset of more severe symptoms — unable to walk, severe tremor, unable to feed herself. Dr. Rosenberg and her husband brought their child to the nearest hospital.

Young Investigator Seeks a Target for Targeted Neuroblastoma Therapy

Originally published on Cornerstone, the CHOP Research Blog

I composed this original blog post based on an interview with the investigator and took the accompanying photo.

Excerpt:

It is scary to learn your child has neuroblastoma, a tumor of the peripheral nervous system that is the most common cancer in infants. It is scarier still when you get test results that show your child is in the half of neuroblastoma patients whose cancer is very aggressive and high-risk. Doctors routinely test neuroblastoma tumor genes to see if there are multiple extra copies of the gene MYCN. Positive results come with that high-risk prognosis. Amplified MYCN occurs in about half of all high-risk neuroblastoma cases.

Currently, there is not a good answer for parents facing this scenario. Doctors have known about the association between amplified MYCN and poor neuroblastoma outcomes for more than 30 years, but that knowledge has not yet translated into improved, targeted treatments.

One researcher who is now trying to make the start of that translation is Robyn Sussman, PhD, a postdoctoral fellow at The Children’s Hospital of Philadelphia. Dr. Sussman has just received a two-year Young Investigator grant from the Alex’s Lemonade Stand Foundation (ALSF) to pursue this line of research. This week, she is joining 50 researchers from across the country at the third ALSF Young Investigator Summit to learn from and engage with leading researchers in pediatric oncology.