Stories about: Therapeutics

‘Druggable’ cancer target found in pathway regulating organ size

Inactivating NUAK2 curbs cell proliferation in liver cancer
Reducing cancer proliferation: A small molecule that inactivates NUAK2, part of the Hippo/YAP pathway, reduces the number of cancerous cells in the mouse liver. (WEI-CHIEN YUAN/BOSTON CHILDREN’S HOSPITAL)

It’s known that cancer involves unchecked cell growth and that a pathway that regulates the size of organs, known as Hippo, is also involved in cancer. It’s further known that a major player in this pathway, YAP, drives many types of tumors. What’s been lacking is how to turn this knowledge into a practical cancer treatment. In a study published today in Nature Communications, researchers at Boston Children’s Hospital identify a target downstream of YAP, called NUAK2, and show that it can readily be inactivated with a small molecule.

“The Hippo pathway, and especially YAP, has been hard to target with drugs,” says senior study author Fernando Camargo, PhD, of Boston Children’s Stem Cell Research program. “This is the first demonstration of a ‘druggable’ molecule that could be targeted in any type of tumor driven by YAP.”

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From the ashes of a failed pain drug, potential treatments for autoimmunity and cancer

BH4 pathway - orchestra concept
ORCHESTRATING T-CELL RESPONSES: The BH4 pathway can be quieted with a small-molecule inhibitor to calm T-cell responses in autoimmune disease, or tuned up to activate T cells in cancer. (ILLUSTRATION: TIBOR KULCSAR/IMBA)

In 2013, renowned Boston Children’s Hospital pain researcher Clifford Woolf, MD, PhD, and Kai Johnsson, PhD, his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. Woolf had shown that tetrahydrobioptrin — a protein also known as BH4 — is a primary natural modulator of neuropathic and inflammatory pain sensitivity. Quartet was founded on the premise that inhibiting BH4 production could prevent the progression of acute pain to chronic pain in millions of patients, without threat of addiction or tolerance.

With solid human genetic data and chemical biology, plus $17 million in series A funding, Quartet looked primed for success. But in the summer of 2017, toxicology studies of the company’s lead candidate revealed neurologic side effects. Hope for the promising pain drug cratered, taking Quartet with it.

Now, however, a surprising discovery about BH4 will likely rekindle interest in the once-promising pathway and could have profound implications for treating autoimmunity and cancer. In yesterday’s Nature, Woolf and his team at Boston Children’s Hospital, together with immunologists from the Institute of Molecular Biotechnology (IMBA) in Vienna report that BH4 also functions as a kind of immunological thermostat in the body, raising and lowering the activity levels of T cells.

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Fishing for new leads in rare mucosal melanoma

Leonard Zon and Julien Ablain in the zebrafish facility
Leonard Zon and Julien Ablain are finding that zebrafish can tell us a lot about cancer. (PHOTO: SHANE HURLEY/BOSTON CHILDREN’S HOSPITAL)

Zebrafish are an emerging power tool in cancer research. They can be engineered to light up when certain genes turn on — capturing the moment when a cancer is initiated. Because they breed so quickly, they lend themselves to rapid, large-scale chemical screening studies, so can help identify tumor promoters and suppressors. Now, as a new study in Science demonstrates, zebrafish can also help scientists dissect the intricate molecular pathways that underlie many cancers, and could help guide treatment strategies — in this case, for mucosal melanoma.

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Could a simple injection fix spina bifida before birth?

Mesenchymal stem cells derived from amniotic fluid (FAUZA LAB / BOSTON CHILDREN’S HOSPITAL)

Ed. note: This is an update of a post that originally appeared in 2014.

The neural tube is supposed to close during the first month of prenatal development, forming the spinal cord and the brain. In children with spina bifida, it doesn’t close completely, leaving the nerves of the spinal cord exposed and subject to damage. The most common and serious form of spina bifida, myelomeningocele, sets a child up for lifelong disability, causing complications such as hydrocephalus, leg paralysis, and loss of bladder and bowel control.

A growing body of research from Boston Children’s Hospital, though still in animal models, suggests that spina bifida could be repaired at least partially early in pregnancy, through intrauterine injections of a baby’s own cells.

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Study sounds another warning about proton pump inhibitors

child crying while feeding oropharyngeal dysphagia
Toddlers with oropharyngeal dysphagia who were treated with a PPI had a nearly doubled hospitalization rate. (IMAGE: ADOBE STOCK)

A new study adds to growing concerns about a class of drugs frequently prescribed to suppress stomach acid in patients with gastroesophageal reflux disease (GERD). Previous research has linked the use of proton pump inhibitors (PPIs) to an increased risk of various pulmonary and gastrointestinal infections in both adults and children. Patients treated with PPIs are also at higher risk for upper respiratory infections, pneumonia and sepsis.

A new study, published last week in JAMA Otolaryngologysuggests that use of PPIs may also raise the risk of hospitalization of infants and children with oropharyngeal dysphagia, a common swallowing disorder. The study was led by Rachel Rosen, MD, MPH and Daniel Duncan, MD at Boston Children’s Hospital’s Aerodigestive Center.

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Earlier treatment may help reverse autism-like behavior in tuberous sclerosis

research in Purkinje cells may help complete the puzzle of autism
(IMAGE: PETER TSAI)

New research on autism has found, in a mouse model, that drug treatment at a young age can reverse social impairments. But the same intervention was not effective at an older age.

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Getting closer to cracking HIV’s envelope protein

missing segment of HIV envelope could be target for HIV vaccine
(IMAGE: ADOBE STOCK)

For 30 years, researchers have tried to develop an HIV vaccine that would stop the virus from gaining a foothold in the body — before it attaches to T cells and slowly weakens the immune system.

“It has been extremely challenging to induce effective antibody responses against HIV-1,” says Bing Chen, PhD, who researches HIV’s molecular mechanisms at Boston Children’s Hospital.

HIV offers just one target for a vaccine to mimic to trigger protective antibodies: the envelope protein on its surface. Scientists have been struggling to capture the complex protein’s precise structure — and specifically, its structure before the virus fuses with the T-cell membrane.

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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.

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Super suppressor: Boosting a gene that stifles tumor growth

Researchers have packaged a tumor suppressor into a therapeutic nanoparticle.
Researchers have packaged a tumor suppressor into a therapeutic nanoparticle. IMAGE: ISLAM, ET AL.

Most of the time, cancer cells do a combination of two things: they overexpress genes that drive tumor growth and they lose normal genes that typically suppress tumors. No two tumors are exactly alike, but some combination of these two effects is usually what results in cancer. Now, for the first time, researchers have shown that it’s possible to treat cancer by delivering a gene that naturally suppresses tumors.

Researchers from Boston Children’s Hospital, Brigham and Women’s Hospital and Memorial Sloan Kettering Cancer Center combined their cancer biology and nanomaterials expertise and developed a therapeutic capable of delivering a tumor suppressor gene known as PTEN, the loss of which can allow tumors to grow unchecked.

In several preclinical models, their PTENboosting therapeutic was able to inhibit tumor growth. Their findings were published yesterday in Nature Biomedical Engineering.

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Neurons from the brain amplify touch sensation. Could they be targeted to treat neuropathic pain?

neuropathic pain amplification circuit
CREDIT: ALBAN LATREMOLIERE/BOSTON CHILDREN’S HOSPITAL/JOHNS HOPKINS

Neuropathic pain is a hard-to-treat chronic pain condition caused by nervous system damage. For people affected, the lightest touch can be intensely painful. A study in today’s Nature may open up a new angle on treatment — and could help explain why mind-body techniques can sometimes help people manage their pain.

“We know that mental activities of the higher brain — cognition, memory, fear, anxiety — can cause you to feel more or less pain,” notes Clifford Woolf, MB, BCh, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “Now we’ve confirmed a physiological pathway that may be responsible for the extent of the pain. We have identified a volume control in the brain for pain — now we need to learn how to switch it off.”

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