Stories about: Therapeutics

A metabolic treatment for pancreatic cancer?

nitrogen disposal is important to pancreatic cancer
Targeting an enzyme that helps dispose of excess nitrogen curbed malignant growth of pancreatic tumors in obese mice.

Pancreatic cancer has become the third leading cause of cancer mortality. Its incidence is rising in parallel with the rise in obesity, and it’s hard to treat: five-year survival still hovers at just 8 to 9 percent. A new study published online in Nature Communications finds early success with a completely new, metabolic approach: reducing tumors’ ability to get rid of excess nitrogen.

The researchers, led by Nada Kalaany, PhD, of Boston Children’s Hospital’s Division of Endocrinology and the Broad Institute of MIT and Harvard, provide evidence that targeting the enzyme arginase 2 (ARG2) can curb pancreatic tumor growth, especially in people who are obese.

“We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway,” says Kalaany.

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Novel therapeutic cocktail could restore fine motor skills after spinal cord injury and stroke

CST axons sprout from intact to injured side
Therapeutic mixture induces sprouting of axons from healthy (L) into the injured (R) side of the spinal cord.

Neuron cells have long finger-like structures, called axons, that extend outward to conduct impulses and transmit information to other neurons and muscle fibers. After spinal cord injury or stroke, axons originating in the brain’s cortex and along the spinal cord become damaged, disrupting motor skills. Now, reported today in Neuron, a team of scientists at Boston Children’s Hospital has developed a method to promote axon regrowth after injury.

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Mitigating blood vessel damage from heart attack, stroke

Mouse hearts showing the impact of a therapeutic protein fusion on blood vessel health
Imaging of mouse hearts reveals widespread tissue damage (light-colored areas) after heart attack. At far right, however, mice that were treated with an engineered, optimized ApoM protein containing S1P have better tissue recovery than untreated mice (left) and mice that were given an inactive “dud” ApoM treatment (center). Credit: Hla lab/Boston Children’s Hospital

The average human has 60,000 miles of blood vessels coursing through their body. There are a number of mechanisms the body uses to keep that vast vascular network healthy, including a tiny fat molecule, a lipid called S1P, that plays a particularly important role.

S1P receptors dot the surface of the endothelium, a layer of cells that line the inside of all the body’s blood cells. Together, these so-called endothelial cells form a barrier between the body’s circulating blood and surrounding tissue. When S1P molecules activate their receptors, it suppresses endothelial inflammation and generally helps regulate cardiovascular health.

Now, researchers led by Timothy Hla, PhD, from the Boston Children’s Hospital Vascular Biology Program, report a novel therapeutic fusion that could trigger increased S1P receptor activity and recover blood vessel health following the onset of hypertension, atherosclerosis, stroke, heart attack and other cardiovascular diseases.

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If I knew then what I know now: The need for infrastructure to enable precision medicine

precision medicine - closing the infrastructure loop
For precision medicine to happen, we need to be able to close the loop when genetic discoveries are made.

Catherine Brownstein, MPH, PhD, is scientific director of The Manton Center for Orphan Disease Research at Boston Children’s Hospital. Kelsey Graber, MSc, is a research assistant in the Developmental Neuropsychiatry Program. Joseph Gonzalez-Heydrich, MD, is director of the Developmental Neuropsychiatry Program at Boston Children’s Hospital.

Research implicating rare genetic variants in medical and psychiatric diseases is quickly accumulating. This expanding knowledge should be taken into account when making treatment decisions for patients carrying these variants — as well as other family members — even when that knowledge comes after the patient is tested. But all too often, medical institutions are unable to go back and update the information given to families. We need a better infrastructure to enable precision medicine.

This problem recently surfaced in our psychiatry practice. It came to our attention because of a young boy with mild coordination delays and learning disabilities. At age 6, he started experiencing daily hallucinations such as voices telling him to kill his classmates.

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Using ultrasound to trigger on-demand, site-specific pain relief

Ultrasound being applied to agitate injected liposomes, which then release nerve blocking medication that stops pain at the site
Ultrasound triggers the release of local anesthetics from injectable liposomes. Credit: Mary O’Reilly

According to the CDC, 91 people die from opioid overdoses every day in the U.S. Here in Massachusetts, the state has an opioid-related death rate that is more than twice the national average.

“Opioid abuse is a growing problem in healthcare,” says Daniel Kohane, MD, PhD, a senior associate in critical care medicine at Boston Children’s and professor of anesthesiology at Harvard Medical School.

Now, Kohane and other scientists who are developing triggerable drug delivery systems at Boston Children’s Hospital have found a new way to non-invasively relieve pain without opioids. Their novel system uses ultrasound to trigger the release of nerve-blocking agents — injected into specific sites of the body ahead of time — when and where pain relief is needed most. A paper describing the findings was published online today in Nature Biomedical Engineering.

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Nerve-growth agent could treat incontinence caused by spinal cord injury

Image of Rosalyn Adam, a urology researcher hoping to develop new treatments for incontinence, working in the laboratory
Rosalyn Adam is the director of urology research at Boston Children’s Hospital.

When the nerves between the brain and the spinal cord aren’t working properly, bladder control can suffer, resulting in a condition called neurogenic bladder. It’s a common complication of spinal cord injury; in fact, most people with spina bifida or spinal cord injury develop neurogenic bladders. Spontaneous activity of the smooth muscle in the wall of the bladder — called the detrusor muscle — commonly causes urine leakage and incontinence in people with neurogenic bladders.

“For children and adults, incontinence can be one of the most socially and psychologically detrimental complications of spinal cord injury,” says Rosalyn Adam, PhD, who is director of urology research at Boston Children’s Hospital. “The ultimate goal of our research is to return bladder control to the millions of Americans with neurogenic bladders.”

Now, Adam and a team of researchers think that they may have found a practical way to treat neurogenic detrusor overactivity by delivering medication directly into the bladder through self-catheterization, a practice that many people with neurogenic bladders already need to perform regularly.

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From mice to humans: Genetic syndromes may be key to finding autism treatment

Boy and a mouse eye-to-eye
(Aliaksei Lasevich/stock.adobe.com)

A beautiful, happy little girl, Emma is the apple of her parents’ eyes and adored by her older sister. The only aspect of her day that is different from any other 6-month-old’s is the medicine she receives twice a day as part of a clinical trial for tuberous sclerosis complex (TSC).

Emma’s mother was just 20 weeks pregnant when she first heard the words “tuberous sclerosis,” a rare genetic condition that causes tumors to grow in various organs of the body. Prenatal imaging showed multiple benign tumors in Emma’s heart.

Emma displays no symptoms of her disease, except for random “spikes” on her electroencephalogram (EEG) picked up by her doctors at Boston Children’s Hospital. The medication she is receiving is part of the Preventing Epilepsy Using Vigabatrin in Infants with TSC (PREVeNT) trial. Her mother desperately hopes it is the active antiepileptic drug, vigabatrin, rather than placebo.

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Severe flu infections linked to underlying genetic variation

Flu virusesThe Center for Disease Control estimates that influenza virus–related illnesses account for more than 200,000 U.S. hospitalizations and 12,000 deaths annually. Young children, the elderly and people with respiratory, cardiac and other chronic health conditions are at particularly high risk for being hospitalized for influenza-related complications. Until now, there has not been a clear reason to explain why some individuals become severely ill from flu and not others.

New findings published in Nature Medicine, however, might change that.

“We’ve identified a genetic variant that we believe may put people at risk of getting life-threatening influenza infections,” says Adrienne Randolph, MD, MSc, a senior associate in pediatric critical care medicine at the Boston Children’s Hospital.

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Newly-discovered epigenetic mechanism switches off genes regulating embryonic and placental development

Artwork depicting DNA and the code of genes

A biological process known as genomic imprinting helps control early mammalian development by turning genes on and off as the embryo and placenta grow. Errors in genomic imprinting can cause severe disorders and profound developmental defects that lead to lifelong health problems, yet the mechanisms behind these critical gene-regulating processes — and the glitches that cause them to go awry — have not been well understood.

Now, scientists at Harvard Medical School (HMS) and Boston Children’s Hospital have identified a mechanism that regulates the imprinting of multiple genes, including some of those critical to placental growth during early embryonic development in mice. The results were reported yesterday in Nature.

“A gene that is turned off by epigenetic modifications can be turned on much more easily than a gene that is mutated or missing can be fixed,” said Yi Zhang, PhD, a senior investigator in the Boston Children’s Program in Molecular and Cellular Medicine, a professor of pediatrics at HMS and a Howard Hughes Medical Institute investigator. “Our discovery sheds new light on a fundamental biological mechanism and can lay the groundwork for therapeutic advances.”

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CRISPR enables cancer immunotherapy drug discovery

Artwork depicting cancer cells with different genes deleted by CRISPR-Cas9, performed to identify novel cancer immunotherapy targets
These cancer cells (colored shapes) each have a different gene deleted through CRISPR-Cas9 technology. In a novel genetic screening approach, the T cells (red) destroy those cancer cells that have lost genes essential for evading immune attack, revealing potential drug targets for enhancing PD-1-checkpoint-based cancer immunotherapy. Credit: Haining Lab 

A novel screening method using CRISPR-Cas9 genome editing technology has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.

The method, developed by a team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, uses CRISPR-Cas9 to systematically delete thousands of tumor genes to test their function in a mouse model. In findings published today by Nature, researchers led by pediatric oncologist W. Nick Haining, BM, BCh report that deletion of one gene, Ptpn2, made tumor cells more susceptible to PD-1 checkpoint inhibitors. Other novel drug targets are likely around the corner.

PD-1 inhibition “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells. But for many patients, it’s not effective enough on its own.

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