Stories about: cancer

Deconstructed ‘death receptors’ suggest new ways to tackle cancer, autoimmune disease

death receptors apoptosis cancer autoimmune
The 3-D structure of the Fas death receptor’s transmembrane region, consisting of three tightly packed helices shown here from three angles. Cancer-causing mutations deform this structure, preventing “time to die” signals from passing through. (Fu Q; et al. Molecular Cell, Feb. 5, 2016).

Programmed cell death, or apoptosis, helps keep us healthy by ensuring that excess or potentially dangerous cells self-destruct. One way cells know it’s time to die is through signals received by so-called death receptors that stud cells’ surfaces. When these signals go awry, the result can be cancer (uncontrolled cell growth) or autoimmune disease (cells self-destructing too readily).

Researchers at Harvard Medical School (HMS) and the Program in Cellular and Molecular Medicine at Boston Children’s Hospital deconstructed a death receptor called Fas to learn more about its workings, using nuclear magnetic resonance (NMR) spectroscopy to reveal its structure.

They found that for immune cells to hear the “time to die” signal, a portion of Fas called the transmembrane region must coil into an intricate three-part formation, allowing the signal to pass into the cell. The NMR imaging also revealed that the amino acid proline is critical for the formation’s stability. Cancer-causing mutations in the transmembrane region (one of them affecting proline itself) deformed this delicate structure and prevented signals from passing through.

This better understanding of the Fas death receptor, published last week in Molecular Cell, could lead to new approaches that bypass Fas to encourage apoptosis in cancer or, conversely, inhibit Fas in autoimmune disease.

Read more on HMS’s news site.

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Science seen: Oral cancer up close

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Oral squamous cell carcinoma (OSCC), a kind of oral cancer, affects some 30,000 Americans annually. It spreads through the lymphatic system and often has already metastasized by the time it’s diagnosed. The top image here, from a recent study in the American Journal of Pathology, is a healthy mouse tongue; the bottom is the swollen tongue of a mouse with OSCC. The cancerous tongue is overloaded with lymphatic vessels, appearing in blue and white, which help the tumor spread to the regional lymph nodes. The Bielenberg lab in Boston Children’s Hospital’s Vascular Biology Program is studying ways of blocking the progression of this and other cancers by inhibiting their spread through the lymphatic system. (Image: Bielenberg laboratory/Kristin Johnson)

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The cell that caused melanoma: Cancer’s surprise origins, caught in action

It’s long been a mystery why some of our cells can have mutations associated with cancer, yet are not truly cancerous. Now researchers have, for the first time, watched a cancer spread from a single cell in a live animal, and found a critical step that turns a merely cancer-prone cell into a malignant one.

Their work, published today in Science, offers up a new set of therapeutic targets and could even help revive a theory first floated in the 1950s known as “field cancerization.”

“We found that the beginning of cancer occurs after activation of an oncogene or loss of a tumor suppressor, and involves a change that takes a single cell back to a stem cell state,” says Charles Kaufman, MD, PhD, a postdoctoral fellow in the Zon Laboratory at Boston Children’s Hospital and the paper’s first author.

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Fertility preservation for children with cancer: What are the options?

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More than 75 percent of children diagnosed with cancer are surviving into adulthood, leaving more and more parents to wonder: Will my child be able to have children down the road?

They’re right to be concerned. The cancer treatments that are so effective at saving children’s lives can themselves cause a host of problems that don’t manifest until years later. These late effects include particularly harsh impacts on fertility.

On our sister blog Notes, urologist Richard Yu, MD, PhD, of Boston Children’s Hospital and fertility specialist Elizabeth Ginsberg, MD, of Brigham and Women’s Hospital outline where the science of fertility preservation is going.

“It may take 15 or 20 years to develop the techniques to help a child who is 8 years old now,” notes Yu. “But if you don’t preserve something now, you run the risk of not being able to do anything for them later, which is where we are now with a large number of adults who survived childhood cancer.”

Read more about fertility preservation and childhood cancer on Notes.

 

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Siddhartha Mukherjee: Have we lost the fire to tackle childhood cancers?

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Siddhartha Mukherjee, MD, PhD, takes his audience on a tour of 60 years’ worth of successes in cancer. What does the future hold?

We’ve all heard the George Santayana quote, “Those who cannot remember the past are condemned to repeat it.” But there’s another way of thinking about the lessons that the past holds for the future: Those who do remember the past can recapture and harness earlier feelings of energy, urgency and possibility to overcome new problems, now and in the future.

That line of thinking threaded its way throughout the keynote address oncologist Siddhartha Mukherjee, MD, PhD, author of The Emperor of All Maladies, delivered today at Boston Children’s Hospital’s Global Pediatric Innovation Summit + Awards 2015.

In taking the audience on a tour through the last 60 years of advances in cancer biology, genomics and treatment, Mukherjee highlighted the central role pediatrics played as the starting point for the cancer successes we see today. How, he asked, did children come to play such a central role? What can we learn from the successes in the 1950s and ’60s, when pediatric cancer started to evolve from a death sentence to a treatable, even curable disease?

And how, he asked, can we recapture and harness the energy and urgency of that time today?

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Four emerging advances in childhood cancer

girl-in-jfcThe 20th century saw great strides in curing childhood cancer, thanks primarily to the discovery that broadly toxic chemotherapy agents could kill malignant cells. Once virtually incurable, pediatric cancer now has an overall long-term survival rate topping 80 percent.

In the 21st century, attention is turning to additional, less toxic developments in cancer therapy. Lisa Diller, MD, Chief Medical Officer of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, cites four coming changes:

  • Precision medicine treatments targeting specific genetic and epigenetic pathways
  • Immunotherapy drugs gaining FDA approval
  • Innovations to reduce treatment toxicity
  • A stronger focus on improving survival of childhood cancer globally.

Read more on the Dana-Farber/Boston Children’s website.

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Why does a new class of drugs work so well against melanoma?

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Anti-PD-1 antibodies may deliver a one-two punch in melanoma

Recent clinical trials for patients with advanced melanoma have found that a new class of drugs—anti-PD-1 antibodies—can elicit an unprecedented response rate. In the last year, the FDA gave accelerated approval to two anti-PD-1 antibodies, nivolumab and pembrolizumab, for patients with advanced melanoma (including Jimmy Carter) who are no longer responding to other drugs. And there’s growing evidence that this class of drugs may be effective in treating other forms of cancer.

Anti-PD-1 antibodies target a receptor on activated T cells, known as the programmed cell death 1 (PD-1) receptor. Tumor cells stimulate this inhibitory receptor to dodge immune attack, whereas anti-PD-1 antibodies block the same pathway, “waking up” the immune cells so they can attack the cancer. The drugs have been hailed as one of the first cancer immunotherapy success stories.

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Solving puzzles with Cigall Kadoch

Cigali Kadoch-Rubiks cube-croppedGrowing up in the San Francisco area, Cigall Kadoch, PhD, had a passion for puzzles. The daughter of a Moroccan-born, Israeli-raised father and a mother from Michigan who together developed an interior design business, Kadoch excelled in school and pretty much everything else. Above all, she loved to solve brain-teasers.

For Kadoch, the Rubik’s cube represents a love of puzzles, as well as the structure of the protein complexes she studies in her research at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber Chief of Staff Stephen Sallan, MD, describes her as “addicted to discovery.”

In high school, however, Kadoch came up against a problem that defied solution. Breast cancer took the life of a beloved family caretaker who had nurtured her interests in science and nature. She knew little about cancer except that it took lives far too early.

“I was deeply saddened and very frustrated at my lack of understanding of what had happened,” recalls Kadoch. “I thought to myself, cancer is a puzzle that isn’t solved, let alone even well-defined, and I want to try. As naïve a statement as that was, it was a defining moment—one which I never could have predicted would actually shape my life’s efforts.”

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Souped-up fish facility boosts drug discovery and testing

closeup of zebrafish-20150526_ZebraFishCeremony-60The care and feeding of more than 250,000 zebrafish just got better, thanks to a $4 million grant from the Massachusetts Life Sciences Center to upgrade Boston Children’s Hospital’s Karp Aquatics Facility. Aside from the fish, patients with cancer, blood diseases and more stand to benefit.

From a new crop of Boston-Children’s-patented spawning tanks to a robotic feeding system, the upgrade will help raise the large numbers of the striped tropical fish needed to rapidly identify and screen potential new therapeutics. It’s all part of the Children’s Center for Cell Therapy, established in 2013. We put on shoe covers and took a look behind the scenes. (Photos: Katherine Cohen)

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Timing is everything: Circadian rhythms, protein production and disease

Protein production by the clock: mouse over to learn more. (Illustration: Yana Payusova, used with permission.)

Second in a two-part series on circadian biology and disease. Read part 1.

We are oscillating beings. Life itself arose among the oscillations of the waves and the oscillations between darkness and light. The oscillations are carried in our heartbeats and in our circadian sleep patterns.

A new study in Cell shows how these oscillations reach all the way down into our cells and help mastermind the timing of protein production.

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