UCSF Clinicians Get New Ammunition in Fight Against Childhood Cancers

By Steve Tokar

Steven DuBois, assistant professor of pediatrics, and Kate Matthay, professor of pediatrics and chief of the pediatric division, talk with nurse Kate Maniatis at UCSF Benioff Children's Hospital.

It’s a real challenge to treat a patient with relapsed cancer, because the cancer has outsmarted initial treatment and has become more resistant, says Steven DuBois, MD, assistant professor of pediatrics at UCSF’s School of Medicine and a specialist in childhood cancers.

Now, DuBois and his colleagues at the UCSF Helen Diller Family Comprehensive Cancer Center have access to a vastly expanded array of potential resources in their battle against childhood cancers.

The extra firepower comes from UCSF’s recent acceptance into the Children’s Oncology Group (COG) Phase 1 Consortium, an elite National Cancer Institute consortium of institutions selected to lead Phase 1 studies of potential pediatric cancer drugs. UCSF is one of only two COG Phase 1 institutions in California, and one of only 21 centers in the United States and Canada.

Phase I testing, the first step in a drug’s translation from the laboratory to possible approval by the Food and Drug Administration (FDA), is designed to assess safety and appropriate dosage in a specific population — in this case, children.

As in adult Phase I trials, the patients recruited for pediatric Phase I studies have typically not responded well to initial treatment or have had a recurrence of their cancer. Many have been told that they have no other therapeutic alternatives.

Thanks to the variety of experimental treatments available through COG, says DuBois, “we are now able to offer these patients a wider array of novel agents across the spectrum of childhood cancers, from leukemia to brain tumors to other types of solid cancers.”

Most of the agents are targeted molecular therapies, which are designed to short-circuit the biological pathways that cancers depend upon to grow. “If you can find the right molecular target that is driving the growth of a cancer and then block it, you can control the cancer,” says DuBois. Others are oncolytic viruses, which infect and then dissolve tumors.

DuBois recently concluded a Phase I pediatric study for sunitinib, an oral drug that blocks angiogenesis, the process of new blood vessel growth that is integral to the development of solid cancers.

Steven DuBois, MD, and Kate Matthay, MD

Steven DuBois, MD, and Kate Matthay, MD

The study successfully identified the safest dose for children. In addition, since not all children can swallow pills, DuBois and his team developed and tested a more child-friendly formulation, where the drug powder is sprinkled onto yogurt or apple sauce.

Such studies are “quite intensive,” DuBois says. Patients are monitored not only for toxic reactions, but for pharmacokinetics—how the drugs are metabolized by the body. “There are frequent visits to the outpatient PCRC for blood draws, which have to be done in a really precise, standardized way.

“We couldn’t do this type of work without the infrastructure and personnel of the Pediatric Clinical Research Center,” a unit of the Clinical Research Services program managed by UCSF’s Clinical and Translational Science Institute (CTSI).

Such clinical studies call for nursing care that is “totally specialized,” says Katherine Matthay, MD, professor of medicine and Mildred V. Strouss Endowed Chair in Translational Research in Pediatric Oncology at UCSF. For example, patients might need pharmacokinetics studies at very specific times after a drug is administered, as well as special lab studies for pharmacodynamics, “where we look at the effects of the drug on cancer cells and their molecular pathways,” Matthay says.

Blood samples are drawn by highly skilled nurses and rushed, sometimes in the middle of the night, to the CTSI core lab, where they are processed and stored. “These are not things that can be done on a regular pediatric oncology unit,” notes Matthay.

Side effects are a particular challenge. “Many of these inhibitors are oral medications, which don’t have the same obviously terrible side effects as intravenous chemotherapy, so we tend to think of them as benign,” says Matthay.

“But in Phase I therapy, we’re constantly running into unexpected or unusual side effects, and patients can die from them.” Parents, she says, “have to be willing to take that risk in enrolling their children in these trials. They usually are, because they have incurable cancers.”

“When we offer studies to patients, we’re offering them hope for more time,” says DuBois, who also notes that “some of the drugs that we’re testing now in children with relapsed cancer will become the future cornerstones of treatment for children with newly diagnosed cancer.”

“Ultimately, our participation in the COG Phase 1 Consortium will allow us to facilitate the translation of new drugs into the clinic from our rich pipeline of laboratories here at UCSF — and we can improve outcomes in pediatric oncology,” he says.

CTSI is a member of the National Institutes of Health-funded Clinical and Translational Science Awards network focusing on accelerating research to improve health. The Institute provides services for researchers at every stage, and promotes online collaboration and networking through UCSF Profiles.

Photos by Cindy Chew

Related Links:

UCSF’s Pediatric Oncology Phase 1 Program