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.
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 Advancesoffers 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.
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
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. …
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.
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. …
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. …
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.” …
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. …