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How does cancer start? Stanford cancer biologist Julien Sage, PhD, has spent much of his career tackling that fundamental question.

Sage is not alone in this pursuit, with many researchers at Stanford School of Medicine studying causes and treatments for a range of pediatric cancers and blood diseases: leukemia, retinoblastoma, osteosarcoma, and sickle cell anemia, among others.

Many Minds

According to Sage, cancer might initiate in the DNA of stem cells, which have the ability to transform into blood, liver, brain and other mature cells – a process called differentiation.

“Normal stem cells divide into differentiated cells that can be used to repair and maintain tissue,” explains Sage, associate professor of pediatric cancer biology and of genetics and a Tashia and John Morgridge Faculty Scholar in Pediatric Translational Medicine. “But in cancer, stem cells mutate and divide uncontrollably. Instead of making a normal tissue, the cells start making a tumor. We’re interested in understanding the fine balance between normal cell regeneration and abnormal cancer proliferation.”

Sage is studying the genes that cause retinoblastoma, the most common form of eye cancer in children. Nine out of 10 children diagnoses with the disease in the United States are cured, though the survival rate is much lower in developing countries.

Retinoblastoma is caused by mutations in the RB gene. Sage recently discovered that when the RB gene and its family members are inactivated, stem cells in the liver multiply rapidly and develop into a deadly tumor called hepatocellular carcinoma (HCC). But he also found that a specific signaling pathway called Notch can actually slow the tumor’s growth. In essence, the level of Notch activity can help predict the survival of HCC patients.

“Understanding the Notch pathway may lead to novel treatments for childhood tumors,” Sage explains.

Many Minds

Sage currently is examining tissue samples from eight patients who had a rare pediatric form of HCC called fibrolamellar carcinoma. He and colleagues at Stanford Genome Technology Center have begun the laborious task of comparing DNA in the tumor cells with DNA from healthy livers.

“We’re hoping to find out what kinds of mutations they have, how they start, and why they’re so rare,” Sage says. “That knowledge could help us understand the fundamental mechanisms that initiate other types of cancer in children as well.”

The fibrolamellar carcinoma study is a campus-wide, multidisciplinary effort that includes the liver transplant team at Packard Children’s, pathologists, DNA analysts, and many others.

“We want to do real-time sequencing and analysis fast enough that we can actually help the patient,” says Sage. “Right now that process takes six months or more. We can’t afford to make a mistake and misdiagnose a cancer.”

Personalized Medicine

This type of collaborative research distinguishes the Pediatric Cancer Biology program at Stanford. Under the direction of Michael Cleary, MD, the Lindhard Family Professor in Pediatric Cancer Biology, Sage and other researchers are developing targeted treatments tailored to individual patients – an approach known as personalized medicine.

Many Minds

Among this cadre of researchers is Matthew Porteus, MD, PhD, associate professor of pediatrics, who is developing a novel approach to gene therapy.

“The traditional approach is to use a genetically engineered virus to introduce a healthy version of a damaged gene into the patient’s DNA,” says Porteus. “That works for certain diseases, but the worrisome thing is that you can’t control where the virus enters the genome. It sometimes activates normal genes, causing the cell to become cancerous.”

Instead of using a virus, Porteus is exploring a cut-and-paste approach to gene therapy. The first step is to extract diseased stem cells from the patient. Next, he injects the cells’ DNA with engineered proteins that recognize the mutated gene, split it in half, and then correct the mutation and paste the healthy DNA back together. Porteus and his team are currently focused on repairing the gene that causes sickle cell anemia, but the technique could apply to other genetic diseases.

Recently, Porteus was named a Laurie Kraus Lacob Faculty Scholar. This five-year award supports personnel and projects in his lab. “Endowed support like the Lacob award is very important, because this kind of research cannot be done quickly,” he says. “It’s a long-term commitment that provides the time and resources we need to make tangible progress.”
Rebuilt Immune System

Stanford scientists are also investigating new ways to improve pediatric cancer therapies using progenitor cells – the intermediate stage between stem cells and mature cells.

Kenneth Weinberg, MD, is studying a recently discovered cell type called the commonlymphoid progenitor (CLP), the offspring of bone marrow cells. CLPs give rise to lymphocytes – white blood cells that fight infections – and may help boost the immunity of children who have undergone bone marrow transplants.

Many leukemia patients respond well to chemotherapy, which kills cancerous blood cells by destroying the bone marrow. Children who can’t tolerate high doses of chemotherapy are sometimes given bone marrow transplants afterwards to rebuild their immune system.

“The question is, how can we boost the new immune system so that it comes back faster and brings the cancer under control more quickly?” asks Weinberg, the Anne T. and Robert M. Bass Professor in Pediatric Cancer and Blood Diseases.

It typically takes six months to a year after a bone marrow transplant for a new immune system to develop. But studies conducted by Weinberg and his colleagues suggest that combining CLPs and the growth factor interleukin-7 could create a new immune system just three to six weeks after transplant.

“The more rapidly your immune system develops, the less likely your leukemia will recur,” Weinberg explains.

“Another problem with transplants and chemotherapy is that patients have a high risk of infections. In our lab, we’ve found that CLPs can basically prevent infections.”

Weinberg and his colleagues are planning a pilot study next year to test the effectiveness of CLPs in cancer patients. They hope to enroll two dozen children whose leukemia has recurred after chemotherapy. But clinical trials are very expensive, says Weinberg, and getting support from the National Institutes of Health (NIH), a traditional source of funding, has become extremely competitive.

“The clinical studies we do at Packard are among the first of their kind,” Weinberg says, “but the days when we could rely on NIH funding alone are long gone. We’re more and more dependent on philanthropy to provide continuity to our research.”

Finding the Achilles' Heel

Ewing sarcoma and osteosarcoma, the two most common types of bone cancer in children, have a 70 percent survival rate when detected early. Unfortunately, by the time many young patients come to Packard Children’s for diagnosis, the tumor has already spread.

“Those kids only have a 20 percent chance of survival,” says Alejandro Sweet-Cordero, MD, assistant professor of pediatric cancer biology. “We’re trying to understand the difference between a bone tumor that’s metastatic and one that’s not. The more we know about the biology of the tumor, the more likely it is that we can determine its Achilles’ Heel and prescribe a drug that blocks it.”

Ewing sarcoma and osteosarcoma are caused by DNA mutations that occur after a child is born. "But even though we understand the molecular cause of this disease, we don’t know why it happens in some people and not in others,” explains Sweet-Cordero, who is also a Tashia and John Morgridge Faculty Scholar in Pediatric Translational Medicine.

To help solve this genetic puzzle, Sweet-Cordero has turned to the high-throughput DNA sequencing facility at Stanford. “This technology can take a snapshot of a whole tumor and look at all the changes that are happening in all of the genes simultaneously,” he says. “It’s helping us identify genetic events in the tumor and correlate them with how the disease progresses or how the patient responds to therapy.”

Sweet-Cordero is also collaborating with colleagues at the Stanford Institute for Stem Cell Biology and Regenerative Medicine to determine if there is a specific cell type whose chromosomes are especially susceptible to specific genetic events that trigger cancer.

“It we can identify that cell type, there might be opportunities for better therapies,” he says. “That’s very exciting. We’re at the beginning of a revolution in the way we treat individual patients.”

100 Percent Cured

When Kathleen Sakamoto, MD, PhD, was in medical school 30 years ago, the prognosis for children with acute myeloid leukemia (AML) was grim.

“Back then, fewer than 20 percent of pediatric AML patients survived,” says Sakamoto. “Today, the overall survival rate is about 50 percent, which is still unacceptable. Our goal is to cure 100 percent of children with AML.”

A widely recognized expert on AML and other blood diseases, Sakamoto was recently appointed chief of the Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, and Cancer Biology at Stanford.

Each year, approximately 10 patients at Packard Children’s are treated for AML, an aggressive cancer that is relatively common – and often fatal – in adults but rare in children. AML causes bone marrow to produce large numbers of abnormal blood cells, which can invade the brain, spleen, and other organs.

The cause of AML is unknown, but Sakamoto and her colleagues have found an important clue. “We’ve been working to understand the signals that tell cells to divide, mature, or undergo programmed cell death,” she says. “About a decade ago, we identified a protein known as CREB, which is over-produced in bone marrow cells in patients with AML. CREB is a normal protein that helps the cell grow, but when you have too much of it, it causes too much growth and can become cancerous.”

Sakamoto’s goal is to develop a drug for kids with AML that inhibits the function of CREB without affecting normal cells. One compound has shown promising results, but getting it from the laboratory bench to the patient’s bedside will take more years of research and testing. For Sakamoto, being at Stanford has made that process far less daunting.

“We’re incredibly fortunate to have a preeminent children’s hospital, medical school, adult hospital, and university all on one campus in the heart of Silicon Valley, the biotech capital of the world,” she says. “This culture of technological innovation and cutting-edge science will lead to important medical advances for treating children with cancer.”

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