M. Sue O'Dorisio, MD, PhD, with and Octreoscan of a tumor that will respond to therapy

M. Sue O’Dorisio, MD, PhD, with an Octreoscan of a tumor that will respond to therapy.

Targeting tumors

Radiotherapy saves children developmental delays

Treating an infant or child diagnosed with cancer can be an especially delicate affair. How do you attack tumor cells without damaging cells critical to development?

Chemotherapy plus radiation is the traditional treatment, but radiation hinders bone growth and contributes to other developmental delays. A physician with UI Children’s Hospital uses an approach that delivers radiation internally to precisely target certain tumors while sparing surrounding cells.

M. Sue O’Dorisio, MD, PhD, Distinguished Professor of Pediatrics in the UI Carver College of Medicine, discovered some childhood tumors have receptors for the hormone somatostatin. These cancers are neuroblastoma, a tumor of the peripheral nervous system and the most common cancer in children under 5; medulloblastoma; and neuroendocrine tumors, a rare cancer in children and adolescents.

After a tumor is identified on a CT or an MRI, a patient receives an intravenous injection of synthetic somatostatin radiolabeled for imaging. If the tumor lights up on a second scan–imaged with a special camera in a procedure called Octreoscan–the tumor has receptors for somatostatin and the patient then receives synthetic somatostatin tagged with a radioactive drug to kill the cancer cells.

"The advantage is that you know the tumor is going to take up the somatostatin look–alike peptide before you go in to give the child the treatment," O’Dorisio said.

Treatment occurs once every six weeks for three total doses. In Phase I trials only available at the UI, more than half of the children who received at least three doses of the therapy drug, radiolabeled octreotide, have responded with a decrease in tumor size of more than 50 percent; one-fourth of the children receiving at least three doses have had a decrease in tumor size of between 25 percent and 50 percent. There are no serious side effects.

"In the Phase I trial, because we are only allowed to give the drug to a patient whose tumor has grown during at least two other treatments, these tumors are quite large and very aggressive. A 50 percent response rate is remarkable," O’Dorisio said. "We are hopeful that when we can use this treatment right up front as first-line therapy, we will be treating smaller tumors at a time when they are less aggressive and even more responsive."

O’Dorisio and her colleagues in pediatrics, radiology, nuclear medicine and endocrinology are at the forefront of the UI’s clinical and translational science initiatives, using discoveries in the lab to develop treatments first delivered through clinical trials.

"Dr. O’Dorisio’s work is an outstanding example of how we are turning scientific research into new ways to treat cancer," said Gary Hunninghake, MD, director of the UI Institute for Clinical and Translational Science. "She and her collaborators are a major reason the UI received one of the first 24 Clinical and Translational Science Awards given by the National Institutes of Health."

About 20 children and young adults have undergone the radiolabeled octreotide treatment so far. The Phase I study was intended for children with neuroblastoma and medulloblastoma, but during the study researchers have discovered children and adolescents with pancreatic tumors also respond to the treatment. Because neuroendocrine tumors grow very slowly, they don’t respond to chemotherapy, and conventional radiation therapy is generally not used. However, neuroendocrine tumors are "uniquely loaded with somatostatin receptors," said Tom O’Dorisio, MD, UI professor of internal medicine and a researcher and staff physician at the Veterans Affairs (VA) Iowa City Health Care System.

"Neuroblastoma is more commonly diagnosed in any given year than neuroendocrine tumors, but because children with neuroendocrine tumors don’t progress as fast and therefore live longer, the number of children alive with neuroendocrine tumors is almost eight times the number of children who have neuroblastoma," Sue O’Dorisio said. "We’ve not only come up with a new therapy, but we’ve identified a group of children who have a unique tumor. It’s exciting to be able to offer them this treatment."

The UI research team is nearly ready to share Phase I results with the FDA. Phase II trials would expand the treatment to other sites.

Adults with neuroendocrine tumors, such as carcinoid, were treated with the radiotherapy in a study where the UI was the leading trial center in North America. The trial was headed by Tom O’Dorisio, Sue O’Dorisio and David Bushnell, MD, UI professor of radiology and chief of imaging at the VA. They found survival rates increased and symptoms improved for these adult patients, but the tumors didn’t always decrease, Bushnell said. Currently treatment for adults is available only in Europe.

After seeing the results with octreotide, Bushnell and Mark Madsen, PhD, UI professor of radiology, profesor of physics and astronomy, and director of the Clinical CT Research Core Facility, proposed pairing it with another anti–cancer agent, the radioisotope MIBG, to deliver more radiation to a tumor but further spare normal organs.

"MIBG doesn’t bind to the somatostatin receptor like octreotide does. Rather, MIBG insinuates itself into the metabolic processes inside a cell. Some cells may have more or less somatostatin receptors, some cells may have more or less of the MIBG, so you take advantage of that in putting the two drugs together," Bushnell said. He has been awarded a VA grant to test the combined therapy on adult neuroendocrine tumors, and he and Sue O’Dorisio have received a grant from the National Cancer Institute to test it in children with neuroblastoma as well.

Tom and Sue O’Dorisio

Surprises in the CELLS

When they discovered the somatostatin hormone in white blood cells in the mid–’70s, M. Sue O’Dorisio and Tom O’Dorisio repeated the lab test 20 times to diminish their disbelief.

"Nobody thought at that time that any non-innervated cells had hormones," said Sue O’Dorisio, MD, PhD, Distinguished Professor of Pediatrics in the UI Carver College of Medicine.

She was doing a pediatric hematology/oncology fellowship at Ohio State University. Tom O’Dorisio, MD, UI professor of internal medicine, was on an endocrine fellowship and was setting up one of the earliest assays for vasoactive intestinal peptide (VIP). For his negative control, Sue suggested he use leftover white blood cells from an immunological study she had going. They were shocked when the white blood cells tested positive for VIP.

"Every time we found the VIP, there seemed to be somatostatin," Tom said.

Some leukemias they tested were positive for the VIP and somatostatin, as were medulloblastoma and neuroblastoma. When they further examined these tumors, they found the receptor for somatostatin and VIP.

"The somatostatin hormone is so important, because every time it binds to its receptor it controls cell growth and hormone release," Tom said.

European researchers in the 1980s added a radioactive compound to synthetic somatostatin to image tumors. When the procedure arrived in the United States, the first Octreoscan–as the diagnostic scan is known–of a pediatric tumor was done at Ohio State. The O’Dorisios, who are both members of the Holden Comprehensive Cancer Center at the UI, came from Ohio to Iowa in 1999 and introduced the Octreoscan at the UI. Now, working with other Cancer Center investigators, they are testing these same hormones for use in targeted radiotherapy.

"Sue and Tom are pioneers, along with others in the world, in developing this understanding, concept and approach to recognizing the presence and importance–through therapy and diagnosis as well–of the somatostatin receptor in pediatric and adult neuroendocrine tumors," said David Bushnell, MD, UI professor of radiology and chief of imaging at the Veterans Affairs Iowa City Health Care System.