Tissue banks help with research

By Suzie Siegel

A national group of physicians and scientists who study sarcoma has opened a biospecimen bank to help research.

Denise Reinke

SARC created the bank three years ago, and its staff and volunteers have talked to researchers about it, said SARC President Denise Reinke, a nurse practitioner who also has an MS and MBA. Because the number of sarcoma researchers is relatively small, she said, SARC has never made a public statement about the bank before.

“We’ve never really advertised it or announced that we’re open for business,” she said, but she welcomes researchers to contact SARC if they have a specific study in mind.

Dr. Robert Maki

SARC’s scientific leadership decides who receives tissue and serum samples, said Reinke from her office in Ann Arbor, Mich. Those leaders are divided into three committees: developmental therapeutics, concept review and clinical research. Robert Maki, MD, PhD, medical director of the sarcoma program at Mount Sinai Medical Center in New York, is the director of translational research.

“He moves among the committees; he’s the glue that holds them together,” Reinke said.

SARC stands for the Sarcoma Alliance for Research Through Collaboration. It is sometimes confused with the Sarcoma Alliance, founded in 1999 to provide information and support to anyone affected by sarcoma. Both are nonprofits.

SARC brings together physicians from different institutions to collaborate on clinical trials. It will celebrate its 10-year anniversary in November at the annual meeting of the Connective Tissue Oncology Society in New York, Reinke said.

“We have been able to work together to make a difference for sarcoma patients.”

SARC has run 20 clinical trials across the country, she said, and has collected thousands of biospecimens. “We’ve even got samples from the first trial.”

Tissue is saved frozen, in paraffin blocks and in unstained slides. Serum samples from blood draws are also frozen. Samples may come from different locations in the patient’s body and at different times. For example, in a trial of the drug Gleevec and dermatofibrosarcoma protuberans, surgeons took flash-frozen tissue before the patient got chemotherapy and afterward to gauge the drug’s effect. 

“We have 20 paired samples, and we’re now looking for money to analyze them," Reinke said.

Samples are stored at the biorepository at Nationwide Children’s Hospital in Columbus, Ohio, where SARC has bought space. Cooperative groups for other cancers save samples there, too, including the Children's Oncology Group and the Gynecologic Oncology Group. COG runs sarcoma clinical trials, as does GOG to a lesser extent.  

SARC doesn’t store all of its samples, Reinke said. “In our IGF1R trial, for example, we had 25,000 serum samples, and it costs money to keep them in a repository.” SARC’s scientific leadership decided they needed to keep only a third of the samples.

“It costs to collect, save and analyze samples,” she pointed out. A SPORE (Specialized Programs of Research Excellence) grant helps them pay some expenses.

“The samples are being collected with annotated information along the way," Reinke said. "Having annotated information is a critical component.” 

The information includes the patient’s age, treatment, the response to treatment, survival, the location of the tumor, when the sample was taken, and whether the sample came from the original tumor or a metastasis. The data comes from medical records, not the patients themselves.

“Sometimes patients don’t know all the details of their cases,” Reinke said.

Dr. Dafydd Thomas

Comprehensive sarcoma centers also save biospecimens, often tied to patient details, said Dafydd G. Thomas, PhD, MD, co-director of the University of Michigan's Molecular Pathology Research Laboratory and its cancer center's Tissue and Molecular Pathology Core in Ann Arbor.

"University hospitals like Stanford, Moffitt and UM are sitting on a gold mine of tissue. I have over a thousand sarcoma specimens sitting in my freezers, linked to clinical data," he said. "I take the viewpoint that I have joint ownership with the patient of the tissue and that I will not refuse a reasonable request for tissue samples. Unfortunately, I do not have grant money to do much with this resource."

He's more focused on breast-cancer research these days because he has grant money for it.

Dr. William Tap

“We have a large tissue bank here at Memorial," said William Tap, MD, section chief for sarcoma oncology at Memorial Sloan-Kettering Cancer Center in New York.

MSKCC researchers collaborate with colleagues at other institutions, he said, but they don’t send tissue just because someone asks for it. Tissue is very valuable. "Once the tissue is sent out, it's gone.”

The National Cancer Institute (NCI) has given MSKCC a SPORE grant for sarcoma. MSKCC, SARC and NCI representatives have met to discuss ways to share information and material, Reinke said.

“There are clearly initiatives focused on working together to effectively use samples,” she said.

A 2004 NCI report called for “establishing a centralized sarcoma tumor and tissue repository.” Dr. Tap said: “It’s still critical to have a centralized bank, with the resources to properly manage it and establish quality control."  

Cost is one of the challenges, Reinke said, as is the high demand for biospecimens. “Sometimes institutions don’t want to send them out because they don’t want to compromise their own institution’s ability to do research.”

What's the difference between a centralized bank and SARC's? The SARC bank contains samples only from its clinical trials, while a centralized (and larger) bank would also include tissue and serum from patients who did not participate in clinical trials.

Like SARC, a centralized bank would be run by people who had no vested interest in one institution or another. This differs from 

a university hospital that manages its bank for the benefit of its own faculty, which may or may not choose to share the resources.     

Some nonprofits also are collecting tissue samples, Reinke said. “In the future, we will look at patient-driven initiatives.”

For example, Leiomyosarcoma Direct Research and the National LMS Foundation are urging people to send samples to LMSdr Executive Director Sharon Anderson in San Francisco, who calls patients or their survivors to get medical histories. Anderson, an LMS survivor, is the tissue coordinator for the Leiomyosarcoma Paraffin Tissue Block Repository at Stanford University Medical Center.

She turns over anonymous information and paraffin blocks to Matt van de Rijn, MD, PhD. Both nonprofits also raise money for his research.

This work is crucial, Dr. van de Rijn said. “I can’t emphasize that too much.”

In an ongoing study, he and his colleagues determined that people with more macrophages in their tissue samples tended to do worse. “We had 147 patients where we knew the outcome, and we could correlate macrophages and how patients did. These findings have been confirmed three times.

“The macrophages encourage angiogenesis, which leads to a better blood supply for the tumors. Macrophages have another major function – they eat up bad things in your body. We’ve found that if you inhibit a protein, CD47, on the surface of LMS cells, that will change the macrophages so that they will eat the LMS cells.” 

The cases were almost equally split between LMS that started in the uterus and LMS that began elsewhere. In some cases, the LMS spread, and the bank received tissue from the metastases.

Dr. Matt van de Rijn in his lab.

It’s important to find something, such as macro- phages, that can help the medical community make a prognosis in LMS cases, Dr. van de Rijn said. More important, however, is finding a better way to treat patients.   

“I’ve never felt so close,” he said, to developing a new therapy, whether a small-molecule inhibitor or the use of antibodies.

John Brooks, MD, started the LMS bank at the University of Pennsylvania Hospital in Philadelphia, with the hope that it would be a central repository. (See my 2007 article.) Due to lack of resources, the tissue samples were later transferred to Dr. van de Rijn. He describes himself as the curator of the tissue, not its owner.

"You can help researchers all over the world" by sending tissue samples, says the LMSdr website. "The advantage of having a tissue bank is that researchers can go to one place & access enough tissue to conduct research. ... Bottom line, without a tissue bank, it is impossible for researchers to get enough samples to conduct any valuable research on LMS. No samples, no research, no cure!" The NLMSF uses similar wording.

The consent form says researchers whose proposals meet the criteria of Stanford's Institutional Review Board can receive tissue samples.

Dr. van de Rijn said his primary focus is his research, not managing a tissue bank for other researchers. But he added: “I’m all for collaboration. We need to collaborate.”

Indeed, he has worked with Dr. Thomas and many others. In the past, he said, he has sent LMS tissue to other researchers in the U.S. and abroad, but he has had few requests.

“There are very few people working on leiomyosarcoma, and not all of them can use paraffin-block samples.”

For example, Sarcoma Alliance board member Matthew Anderson, MD, PhD, studies uterine LMS at Baylor College of Medicine in Houston. He has gotten frozen tissue from Dr. Thomas and M.D. Anderson Cancer Center, also in Houston.