Duke Cancer Institute Notes
Published: Feb. 18, 2008
Updated: Dec. 3, 2010
Just before Thanksgiving of 2006, Josh Sommer, a sophomore engineering student at Duke University, attended a lecture by Neil Spector, MD, a senior leader of the Duke Cancer Institute and director of Translational Research in Oncology. Little did Sommer or Spector know the impact that this chance encounter would create.
Six months prior to the seminar, Sommer had been diagnosed with chordoma, a rare bone cancer that can develop in the head or spine. Only about 300 new cases are diagnosed each year in the United States, and the average survival time is seven years. In May 2006 Sommer underwent surgery to remove the tumor.
After his diagnosis, Sommer went in search of information about his disease. Unfortunately, his searches often came up empty-handed. In Sommer’s Google search of the Web, only a few useful Web sites were found. He was forced to find other resources. Luckily, as a Duke student, Sommer had access to all of the university’s online subscriptions to medical journals, so he read every study he could find about the disease.
In his lecture that day, Spector discussed his research of the epidermal growth factor receptor. Gene amplification of the HER2 receptor, a member of the Epidermal growth factor receptor family, occurs in 25 percent of breast cancers where it predicts for a poor clinical outcome. Lapatinib, a highly selective inhibitor of the HER2 and EGFR receptors, is currently approved for the treatment of women with advanced stage HER2+ breast cancer that has progressed despite trastuzumab-based therapy.
Lapatinib, a drug recently approved for women with breast cancer, targets this receptor. Spector led the development of lapatinib while working at GlaxoSmithKline, prior to joining the Duke faculty. In the course of his research, Sommer had read that the same receptor may play a role in the development of chordoma. He approached Spector after the lecture and spoke with him about his diagnosis and about chordoma.
“Josh and his mother Simone are such an impressive team that it would have been impossible to say anything but ‘yes’ to helping them,” says Spector. Along with his mother Simone Sommer, MD, PhD, a Duke-trained physician, Josh started the Chordoma Foundation to accelerate the search for a cure and promote collaboration among researchers around the world.
“Much of my research has focused on breast cancer,” explains Spector. “But it’s not a big leap for me to begin studying chordoma. Two cancers that occur in two locations in the body may seem to be different but may be impacted by the same pathway and thus could require similar treatment.
“The key message,” says Spector, “is to look not just at the tumors, but also at the pathways.” Signaling pathways allow the cell to receive, process, and respond to information. Researchers work to determine which pathways may cause a tumor to form and then find treatments that target these pathways to thus block tumor formation.
Through his literature review, Sommer had also read about Michael Kelley, MD, a Duke physician-researcher who has been investigating chordoma for close to ten years and has a similar philosophy to Spector.
“I don’t refer to my research as chordoma research per se,” says Kelley, an associate professor of medicine at Duke and chief of hematology/oncology at the Durham VA hospital. “I’m researching the biology of disease.”
Sommer befriended Kelley and began working in his lab in October 2006. While he has a science background, Sommer had no experience with molecular biology, yet Kelley has patiently mentored Sommer.
Kelley’s laboratory is studying families with multiple cases of chordoma. Through classical genetics and candidate gene analysis, they are looking for mutated genes to determine why some family members have chordoma and others do not. Kelley’s lab is also examining the gene expression signatures of chordomas to find clues about which biochemical pathways are altered in chordoma.
“What we can learn from our study of a tumor that may affect only a few hundred people a year can likely be relevant to tumors that affect thousands or hundreds of thousands of people,” says Kelley.
“There has been an unbelievable level of enthusiasm and compassion shown by the faculty at Duke,” says Sommer. “I’m so happy that they’re including chordoma in their research interests and are helping me discover more about this awful disease.”
David Rizzieri, MD, director of the Hematologic Malignancy Program at Duke, also believes his work on rare diseases will help patients with other, more common tumors. Rizzieri and his colleagues are investigating rare cancers such as mantle cell lymphoma (3 to 5 percent of all non-Hodgkin lymphomas) and adult Burkitt lymphoma, which is even rarer at 2 percent. He recently led a national institutional study on an aggressive treatment for the condition under the auspices of the Cancer and Leukemia Group B (CALGB, a national clinical research group sponsored by the National Cancer Institute [NCI]).
The approach combines an aggressive regimen of multiple chemotherapy agents given in a compact schedule to overwhelm the cancer cells before they have a chance to develop resistance to the agents. The initial published results reveal over 50 perfecent of the patients remain well and in remission beyond five years with this approach. Rizzieri is leading the current CALGB strategy to minimize toxicity of the regiment using newer, improved supportive care agents.
Rizzieri also sees his research with rare cancers having broader ramifications. With blood cancers, doctors are constantly monitoring a patient’s blood to see how the treatment is working.
“With these multiple tumor samples routinely assessed, we are able to determine quickly if and how a treatment is working. The knowledge of a particular drug’s effectiveness for a rare tumor can provide a model to assess response that may be applicable to other types of tumors as well,” he says.
The federal government defines rare cancers as those with fewer than 40,000 cases a year in the United States. Cancers of the brain (18,000 cases a year) and ovaries (25,000 cases per year) fit in that category. However, there are many other much more rare cancers that have fewer than 1,000 cases diagnosed in the United States each year. What truly sets these cancers apart from other cancers are the barriers for researching and developing treatment options.
One of the biggest challenges associated with studying cancers that may only affect a few hundred or thousand is funding. Federal funding for cancer research has become increasingly more difficult to obtain. The budget for the NCI has been reduced by approximately $80 million over the last two years, and fewer than 20 percent of NCI grant applications to support cancer research were funded in 2006.
Those studies that are supported by the NCI often target more common cancers such as breast, lung, colorectal, and prostate cancers. It is very difficult for researchers to be awarded federal grants to study rare cancers, as acknowledged by Duke researchers including Spector and Kelley. Kelley believes that he is the only researcher in the country who has a grant to study chordoma.
Nevertheless, researchers have found creative ways to fund their work in rare cancers. Some have included those studies as part of their larger studies. Wei Chen, PhD, assistant professor of medicine at Duke, has been investigating the Hedgehog, WNT, and TGF beta pathways and how these pathways impact cancers such as breast and pancreatic. Chen has received grants to identify and study compounds that may block these pathways in several types of cancer and thus stop the progression of cancer.
“We’ve discovered that chordoma may be impacted by these pathways as well,” says Chen.
Pharmaceutical companies are also a major source of funding for many cancer research studies. However, for-profit corporations are motivated to fund the development of drugs that can treat many people in order to maximize profit.
“There is little seed money to test unproven concepts in rare cancers,” says Michael Morse, MD, associate professor of medicine at Duke.
But, says Morse, once you have some proof that you may have a good discovery, then the money may come in. “The key is you need that initial seed support. If you find evidence and have substantial findings, then you have a better chance of receiving pharmaceutical funding.”
In 1982 Congress passed the Orphan Drug Act to entice pharmaceutical companies to create drugs that will impact rare diseases -- and not just cancer. The act provides research funds, tax credits, and special legal protections to those involved in such research. More than 300 drugs have deemed “orphan” by the FDA in the 25 years including Gleevec, which is marketed for seven different types of rare cancers. However, even the financial and legal benefits that have emerged from the act are often not enough to persuade companies to invest in the development of these drugs.
Accrual of patients to clinical trials is another obstacle in the study of these rare cancers. Investigators often find it difficult to identify enough patients to participate in their studies since there are not many patients with these particular conditions. Rizzieri often works with the researchers at neighboring University of North Carolina and Wake Forest University to accrue patients for his studies. “It’s essential to partner with other hospitals when studying rare diseases,” he says.
Duke Cancer Institute has also formed partnerships around the world, in China and Singapore. “A cancer in the United States may only have a few hundred or a few thousand cases a year, but in China because of the large population, a cancer may have tens of thousands of cases,” says Chen. “It will be faster and easier to accrue patients for clinical trials when working with our partners in China.”
Some researchers studying rare diseases often join collaborative groups. Duke is a participant in the Sarcoma Alliance for Research Through Collaboration (SARC) which provides the infrastructure for collaboration between medical institutions from around the world for the development of new standards for sarcoma treatment, education, and prevention. Sarcoma is a term that describes about 50 different types of soft-tissue cancer and seven types of bone cancer. Only 10,000 or so patients are diagnosed each year with all sarcomas, including chordoma.
Rich Riedel, MD, assistant professor of medicine at Duke, is leading several new sarcoma studies. One of the studies is using gene expression profiling to better understand the biology of individual sarcoma subtypes. With this knowledge, he hopes to use current chemotherapies more effectively and identify key biologic pathways that may be targeted with novel therapies.
For patients diagnosed with rare types of cancer, it is often difficult to find physicians who have heard of or even treated that particular disease. Kenneth Rhinehardt, who lives in Marion, North Carolina, was diagnosed with a soft-tissue sarcoma near his hip.
Doctors initially thought it was osteoarthritis. Eventually they discovered the sarcoma. The first oncologist he visited wanted to remove his hip and leg.
Family and friends recommended that Rhinehardt go to Duke for a second opinion. In October 2006 Rhinehardt met with Brian Brigman, MD, an orthopaedic surgical oncologist and sarcoma specialist. Brigman told him he could remove the tumor and save the leg. A year after surgery, Rhinehardt’s cancer is gone and he feels good.
R. Edward Coleman, MD, professor of radiology, and Morse are studying two rare neuroendocrine tumors: pheochromocytoma and paraganglioma. They are conducting clinical trials for a radioactive targeted therapy agent known as iobenguane I 131. A phase I trial was completed in 2007 at Duke to determine the correct dose to administer to patients. Initial results of the trial showed that the patients’ tumors had shrunk.
A phase II trial of iobenguane I 131 recently opened. The initial positive results from the phase I trial have attracted patients from across the country to Duke to participate.
“Since we’ve already seen positive results, we are very anxious to conduct more trials of this treatment,” says Coleman.
Spector has also had success in early trials of lapatinib for patients with inflammatory breast cancer (IBC), which is diagnosed in about one percent of all breast cancers in the United States, but is much more deadly. Since IBC is so biologically different than other breasts cancers, patients with this disease are often excluded from clinical trials for new breast cancer therapies. But initial trials of the lapatinib among IBC patients are promising.
“The environment at Duke is very unusual,” says Spector. “There is a collaborative and entrepreneurial spirit here, and researchers are passionate about curing cancer -- all types of cancer. At most institutions, a student like Josh couldn’t walk into the offices of researchers, engage them in a fairly untapped area of research, and then see them working together and making progress in a matter of months.”
Sommer has already found several pathways that are likely to be involved in regulating the growth and survival of chordoma cells. Spector’s laboratory has also found similar pathways and has further identified some cancer drugs already approved for treating other tumors, that exert anti-tumor activity against chordoma cells lines in the laboratory. These drugs would need to be tested in clinical trials to see if they are effective in humans.
After working in Kelley’s lab for over a year, Josh is now pre-med and plans to become a physician-scientist like his mentors Kelley and Spector. Though Josh has found hope in his work at Duke, he knows that some day his chordoma might return.
“I am working as fast as I can to find a cure for my disease,” Sommer says. “The type of collaboration I see at Duke is really inspiring, and we need more of it. We also need more funding to have any real shot at finding a cure soon. We’re discovering that chordoma shares much in common with many other uncommon cancers, so I hope this work will lead to faster treatment development for all of us who have been affected by orphan cancers.”