Stories about: cancer

Overriding resistance to epigenetic inhibitors in neuroblastoma: Targeting PI3K

(IMAGE COURTESY NATIONAL CANCER INSTITUTE)

Children’s cancers pose unique challenges. They’re not caused by the same kinds of genetic mutations that cause adult cancers, and only a minority of their mutations can be targeted with drugs. In a recent study, Kimberly Stegmaier, MD, at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and her colleagues systematically deleted every gene in the genome in a number of childhood cancers. This led them to previously unknown — and targetable — genes that help drive tumor growth.

But Stegmaier is also interested in epigenetic regulators — proteins that help control the regulation of genes and contribute to many pediatric cancers. They’re a hot subject of research: Child cancers tend to arise in developing tissues, and epigenetic regulators are active during early development. Clinical trials are starting to test drugs that inhibit epigenetic cancer-promoting factors.

There’s a problem, though: Cancers often become resistant to targeted inhibitors, including epigenetic inhibitors. So, again using genome-wide approaches, Stegmaier set out to find ways to overcome this resistance.

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CRISPR-Cas9 screen opens new targets for Ewing sarcoma, other childhood cancers

Ewing sarcoma research by Kimberly Stegmaier, MD
The TP53 pathway normally helps pull the plug on cancerous cells. While the pathway is intact in most pediatric cancers, research finds that drugs targeting the pathway can curb tumor cell proliferation in Ewing sarcoma. Photo: Kimberly Stegmaier, MD (SAM OGDEN / DANA-FARBER CANCER INSTITUTE)

While the genetic mutations driving adult cancers can sometimes be targeted with drugs, most pediatric cancers lack good targets. That’s because their driving genetic alterations often create fusion proteins that aren’t easy for drugs to attack.

“This is one reason why it is notoriously hard to make targeted drugs against childhood cancers — their cancer-promoting proteins often lack good pockets for drugs to bind to,” says Kimberly Stegmaier, MD.

However, that’s beginning to change.

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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.

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Proposed cancer treatment may boost lung cancer stem cells, study warns

Epigenetic enzymes and lung cancer: Treating adenocarcinoma with G9a histone methyltransferase inhibitors leads to an increase in tumor cells with stem-like properties. In contrast, inhibiting histone demethylase prevents tumor growth. (SAMUEL ROWBOTHAM/BOSTON CHILDREN’S HOSPITAL)

Epigenetic therapies — targeting enzymes that alter what genes are turned on or off in a cell — are of growing interest in oncology as a way to make cancers less aggressive or less malignant. But now, at least one epigenetic therapy that had looked promising for lung cancer appears to boost the cancer stem cells that are believed to drive tumors. A study published today in Nature Communications also identifies a strategy that reduces these stem cells, curbing lung cancer in mice.

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‘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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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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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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Typing medulloblastoma: From RNA to proteomics and phospho-proteomics

medulloblastoma proteomics study
Medulloblastoma (CREDIT: ARMED FORCES INSTITUTE OF PATHOLOGY/WIKIMEDIA)

Medulloblastoma is one of the most common pediatric brain tumors, accounting for nearly 10 percent of cases. It occurs in the cerebellum, a complex part of the brain that controls balance, coordination and motor function and regulates verbal expression and emotional modulation. While overall survival rates are high, current therapies can be toxic and cause secondary cancers. Developing alternative therapeutics is a priority for the field.

As early as the 1990s, the lab of Scott Pomeroy, MD, PhD, neurologist-in-chief at Boston Children’s Hospital, discovered molecules in medulloblastoma tumors that could predict response to therapies. In 2010, Pomeroy and colleagues uncovered four distinct molecular subtypes of medulloblastoma.

The World Health Organization updated the brain tumor classification scheme in 2016 to include these molecular and genetic features. In the new scheme, tumor subtypes with a good molecular prognosis receive less radiation and chemotherapy. But the creation of targeted therapeutics has remained a challenge, since some of the genetic pathways implicated in these subtypes are found in non-cancerous cells.

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Why are males more prone to bladder cancer than females?

A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females.
A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females. IMAGE: ADOBE STOCK

New research helps explain why men are three to five times more likely to develop bladder cancer than women.

Using mouse models and human patient data, Boston Children’s Hospital researchers in the urology department, Xue Sean Li, PhD, and Satoshi Kaneko, PhD, found that inherent genomic differences contribute to the contrast in bladder cancer rate between males and females.

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