Stories about: cancer

‘Nanobodies’ from alpacas could help bring CAR T-cell therapy to solid tumors

These alpacas produce the unusually small antibodies (nanobodies) used in a new form of CAR T-cell therapy
Like other alpacas, as well as camels and llamas, Bryson (left) and Sanchez produce unusually small antibodies that could have a role in cancer immunotherapy. (PHOTO COURTESY HIDDE PLOEGH / BOSTON CHILDREN’S HOSPITAL)

In 1989, two undergraduate students at the Free University of Brussels were asked to test frozen blood serum from camels, and stumbled on a previously unknown kind of antibody. It was a miniaturized version of a human antibody, made up only of two heavy protein chains, rather than two light and two heavy chains. As they eventually reported, the antibodies’ presence was confirmed not only in camels, but also in llamas and alpacas.

Fast forward 30 years. In the journal PNAS this week, researchers at Boston Children’s Hospital and MIT show that these mini-antibodies, shrunk further to create so-called nanobodies, may help solve a problem in the cancer field: making CAR T-cell therapies work in solid tumors.

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Dually-targeted liposomes curb triple-negative breast cancer, metastases in mice

dual targeting for triple-negative breast cancer
(IMAGE: ADOBE STOCK)

Some 15 to 20 percent of all breast cancers are triple-negative, meaning they lack receptors for estrogen, progesterone and human epidermal growth factor type 2. They have the worst prognosis of all breast cancers and very limited treatment options. Finding a treatment that distinguishes between cancer cells and normal cells has been especially challenging.

A novel precision medicine strategy described today in Science Advances offers an intriguing ray of hope. Researchers at Boston Children’s Hospital, with bioengineers at the City College of New York (CCNY), showed that dually-targeted, antibody-guided nanoparticles, loaded with an existing chemotherapy drug, markedly improved tumor targeting, decreased tumor and metastatic growth and dramatically improved survival in a mouse model of triple-negative breast cancer. There were no observable side effects.

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Blood stem cell transplants from any donor, without toxicity?

could stem cell transplants be made nontoxic?
(ADOBE STOCK)

Many blood disorders, immune disorders and metabolic disorders can be cured with a transplant of hematopoietic (blood-forming) stem cells, also known as bone marrow transplant. But patients must first receive high-dose, whole-body chemotherapy and/or radiation to deplete their own defective stem cells, providing space for the donor cells to engraft. These “conditioning” regimens are highly toxic: they wipe out the immune system, raising infection risk, and can cause anemia, infertility, other organ damage and cancers. And when the donor isn’t an exact match, patients’ immune systems must be suppressed for prolonged periods to prevent rejection.

As a result, most patients either don’t receive a transplant or must endure serious side effects. But if two new studies bear out in clinical trials, a far gentler conditioning treatment could enable stem-cell transplants for a much wider range of disorders, even possibly from unmatched donors.

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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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