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Children’s Hospital Boston: Pioneers in cancer research

Angiogenesis in action

This micrograph of rat muscle shows the normal gridlike pattern of blood vessels (upper left) as contrasted to those growing toward a sarcoma tumor (dark area at right). New treatments targeting angiogenic vessels are extending the lives of cancer patients.

Since 1947, when Sidney Farber, MD, achieved the first remission of acute pediatric leukemia, Children’s Hospital Boston has blazed the trail leading to higher survival rates for childhood cancers. Sixty years later, more than 80 percent of children diagnosed with cancer will live to adulthood, due in large part to the collaboration of scientists and physicians on the frontiers of medicine at the world’s largest pediatric research center.

“The work in our laboratories influences the research at other hospitals as well as clinical medicine in oncology that benefits both children and adults,” says Bruce Zetter, PhD, chief scientific officer at Children’s and an institutional representative at DF/HCC. “Collaboration among researchers continues to be critically important for our institution.” To consolidate teams of experts from many different scientific fields, Children’s recently created six multidisciplinary programs that reflect its signature strengths. Highlighted here are a few of the discoveries emerging from CHB’s Vascular Biology, Stem Cell, and Neurobiology programs that may lead to better treatments in the clinic.

Challenging the wait-to-see approach

With the publication of his landmark paper on angiogenesis in 1971, Judah Folkman, MD, faced a skeptical scientific community. His revolutionary hypothesis—that tumors can grow only if they develop their own blood supply—even inspired scorn. But over the course of four decades, angiogenesis has become a mainstream field of investigation and clinical application. Today, Dana-Farber is conducting many clinical trials of new antiangiogenic agents, while 1.2 million patients take angiogenesis inhibitors by prescription to treat cancer and other diseases.

Folkman, now Director of the Vascular Biology Program at Children’s, continues down a revolutionary path. He and colleagues Giannoula Klement, MD, and Joseph Italiano, PhD, have shown that the angiogenesis regulatory proteins found so far—those that stimulate blood vessel growth and those that inhibit it—are sequestered in platelets, which collect these proteins from tumors. What’s more, platelets contain two sets of alpha granules: one that houses angiogenic stimulators like VEGF and PDGF and another that houses “a whole pharmacy of inhibitors: endostatin, angiostatin, thrombospondin,” says Folkman. “It was an unexpected finding,” he adds, which linked platelets with the process of angiogenesis.

Another major discovery in the Folkman lab found that when platelets die (after only a few days) they hand off the angiogenic proteins they’ve collected from the tumor to the next generation of platelets – like a parent bequeathing an estate. Opening the platelets reveals a record of the angiogenic proteins scavenged from the tumor, though this record does not reveal the type or location of the tumor. Folkman and his colleagues believe that this collection of proteins – called the platelet-angiogenesis proteome – might be useful as an early diagnostic biomarker of tumor recurrence.

To validate this hypothesis, investigators at BWH and DFCI are periodically measuring the angiogenesis proteome in patients with colon cancer and neuroblastoma –known to have high recurrence rates - to see whether the biomarker is rising. If no tumor is growing, explains Folkman, the angiogenic protein levels remain flat. If the hypothesis is validated, he adds, the next trial will seek to treat patients with non-toxic angiogenesis inhibitors if the biomarker is rising, indicating the presence of a microscopic tumor. “Why wait to see it before we treat it?” he asks.

Fishing for stem cells

Another pioneer at Children’s, Leonard Zon, MD, has earned an international reputation for his research in stem cell biology. As founder and director of the Stem Cell Program, he and colleagues are exploring ways to amplify blood stem cells, which could be used in bone marrow and cord transplants to treat leukemia or to replenish immune cells following chemotherapy. “We’re really trying to help the two-thirds of patients who do not have a donor match for a bone marrow transplant,” says Zon, patients whose only option is a cord transplant. “The problem is that a single cord doesn’t have enough stem cells to engraft in an adult,” he explains. That may soon change, however, thanks to experiments in the tiny zebrafish.

The zebrafish embryo, whose blood system is similar to that of humans, is an ideal organism for studying blood formation, says Zon. The transparent, rapidly developing embryos easily soak up chemicals, thereby allowing high-volume drug screening. As reported recently in the journal Nature, researchers in the program demonstrated for the first time that a chemical could increase stem cell production.

Investigators began by screening more than 2,500 chemicals in zebrafish embryos, searching for compounds that altered the expression of genes required for blood stem cell development. Of the 30 chemicals they found that amplified stem cells, about six or seven were prostaglandin precursors. “So we knew the prostaglandin pathway was certainly involved,” says Zon. Prostaglandin E2, in particular, was stable and significantly increased the number of stem cells. Researchers confirmed their observations in a mouse model, which demonstrated long-term engraftment. A clinical trial in collaboration with DF/HCC is planned for next year. “It’s very exciting and very fast,” remarks Zon, “from zebrafish screening to the clinic in about three to four years.”

A major avenue of research that may take a bit longer is the effort to convert embryonic stem cells (ESCs) to blood stem cells. Working with George Daley, MD, PhD, of Children’s and the Harvard Stem Cell Institute, Zon is exploring ways to create patient-specific ESCs and then coax them to become blood stem cells that could be infused into patients.

In search of kinder, gentler therapy

“Our current treatments for pediatric cancers do a variety of damage by bombarding cells,” says Scott Pomeroy, MD, PhD, neurologist-in-chief and chairman of the Department of Neurology at Children’s. “The new approach is to identify the mechanisms of development that drive tumor growth in the first place and to shut them down.” He and colleagues in the Neurobiology Program are searching for small molecule inhibitors that specifically target these mechanisms, while sparing the normal cells of the developing brain.

Using sophisticated genomic methods, Pomeroy is studying genetic mutations that promote the growth of two classes of pediatric brain cancers: embryonal (which arise during early development) and astrocytoma tumors (which arise in star-like cells). In one project, investigators are sequencing the human kinome – all the genes that encode kinases, the enzymes that act as on-off switches in regulating cell functions. Some mutations in kinase genes leave them turned on, explains Pomeroy, stimulating the tumor to grow uncontrollably. By comparing the sequence of normal kinase genes with that of kinase genes from tumor DNA, Pomeroy hopes to ferret out the mutated ones, which could then be turned off with small molecule drugs.

In other research, his lab discovered the first biomarker for medulloblastoma, the most common malignant brain tumor of childhood. High levels of expression of the TrkC gene in the tumor correlate with a good prognosis, says Pomeroy, a finding that could well affect treatment. “If we know which tumors have a better prognosis, we can treat those with less radiation and still keep them under control.” TrkC and several other genes are now being tested as prognostic biomarkers in validation studies in the United States and Europe through the Children’s Oncology Group.

Using gene expression profiling, Pomeroy’s lab was also the first to identify a subset of medulloblastoma tumors whose growth appears to be governed by upregulated genes in the Sonic hedgehog (SHH) pathway. “As investigators develop targeted SHH therapies,” explains Pomeroy, “these biomarkers of tumor growth could identify which types of tumors are likely to be most responsive.” He predicts that in the future, these biomarkers will help determine the type and intensity of treatment.

“We have made great strides in the treatment of pediatric cancers,” says Zetter, acknowledging the work of all the scientists and physicians at Children’s. “But we cannot rest until children no longer succumb to these diseases.”

—Lonnie Christiansen