OREF-funded research takes “small step forward” in improving patients’ lives

Cancer is a dreaded diagnosis for any patient. Though not always fatal, it can be debilitating. So, researchers like Kristy L. Weber, MD—a recipient of the Career Development Award presented by Zimmer and the Orthopaedic Research and Education Foundation (OREF)—are investigating ways to prevent complications from the disease.

Dr. Weber is focusing on how kidney cancer (renal cell carcinoma or RCC) grows within the bone. She hopes that her research will lead to new treatments for metastatic RCC.

“We’re not so bold as to be looking for a cure for RCC,” Dr. Weber says. “We are really just trying to make a small step forward in improving our patients’ lives. We’re trying to stop some of the suffering due to bone metastasis.”

From kidneys to the bone
RCC, unlike breast and prostate cancers, does not respond well to chemotherapy, radiation, or hormone treatments. According to Dr. Weber, once RCC is in the bone, no current treatments can reliably stop it. As RCC spreads into the bone, it can cause destructive holes that result in fractures; if it enters the spine, paralysis may result.

Orthopaedic surgeons can repair some of the damage and prevent future fractures by inserting prophylactic hardware in the bone, but Dr. Weber would like to find a way to prevent RCC from moving into the bone, or stop it from growing if it does.

“We’re looking for a way to help the bone specifically. Once RCC is spread in the bloodstream, it’s incurable,” she says, “so to treat it, we need to find a way to stop it from spreading from the kidney.”

First, however, Dr. Weber must learn how and why RCC metastasizes into the bone. With her patients’ permission, Dr. Weber has obtained tumor cells to create several RCC cell lines that she uses to test different drugs and to investigate the various molecular pathways the cells take when specific growth factors are added.

In addition to the cell line studies, when Dr. Weber performs surgery on a patient with metastatic RCC, she removes a slice of tissue and extracts the DNA or RNA, the building blocks of the cancer.

Through this research, Dr. Weber is trying to answer several questions—how do the cells respond to different drugs and different growth factors; what proteins do they secrete along the molecular pathway; how does RCC in the kidney differ from RCC in the bone, and what causes the difference?

“We try to figure out what had to happen for someone’s kidney cancer to move into his or her bone, and what growth factors are turned on in the bone versus in the kidney microenvironment,” she says.

Stopping cancer’s destruction
Dr. Weber is also studying bone metastasis from kidney cancer in an animal model. The cells from her patients are placed in a mouse’s tibia where they grow. Using a small, digital X-ray machine, she can view how much of the bone is destroyed.

She and her research team experiment, testing specific drugs or modifying the cells in some way, such as by blocking a certain growth factor receptor, to see if they can stop cancer growth and bone destruction.

“One drug doesn’t really cure anybody’s cancer anymore. Cancer cells are really smart, and if you block one pathway for growth, they will find a way around it,” says Dr. Weber. “So you’ve got to hit cancer with a few different agents at the same time. Just when we think we’ve made progress in one area, we find another whole area that’s more difficult to solve.”

Because the right drug probably hasn’t been developed yet, she also looks for natural methods of blocking cancer cell growth, such as antibodies or small molecule inhibitors.

“When we discover a successful biologic treatment in our mouse model, we can work that into actual treatment of patients in the clinic. We’re testing different ways to block growth factors, and if any of them look incredibly promising, then we’ll work with a company to develop the drugs that can reproduce the effect. If we can stop RCC from moving into or growing in the bone, we can prevent patients from breaking their bones and living in such misery,” she says.

Supporting research
Dr. Weber began her research with funding from an OREF/Zimmer Orthopaedic Career Development Award. “The OREF/Zimmer award was one of the first grants I received for the bone metastasis research, which has become the main focus of our laboratory. Without that support, we wouldn’t be going forward as we are,” she says.

Each year Zimmer supports six $50,000 awards through OREF. According to Ray Elliott, Zimmer board chair, “When we realized that young, practicing clinicians did not have the resources that are available to residents or veteran clinicians, we decided to help them through the OREF. Since then, we’ve granted to OREF more than $250,000 each year to help these younger surgeons pursue additional research, education, travel, or any legitimate endeavor to help them advance orthopaedic science or care.”

Dr. Weber also thinks supporting OREF is important to advance orthopaedic care. She joined the Shands Circle in 2004 and has given to the annual campaign at the Order of Merit level—$1,000 or more—since 2001.

“Without OREF funding, I probably wouldn’t be conducting any research today, because I wouldn’t have had the money to get the experiments off the ground,” she says. “We are now applying for funds from the National Institutes of Health and hope to receive additional support, but OREF helped me in the beginning.”

Dr. Weber also thinks that doctors who are not researchers, as well as the general public, should support OREF. “People who don’t have such an interest in research may understand what I’m trying to do for bone cancer patients and want to support OREF, too. Many of the current advances in orthopaedics are due to research performed using OREF funds,” she says.

The ongoing fight and continuing research
Her continuing research on growth factors recently earned Dr. Weber Kappa Delta’s Elizabeth Lanier Award. Dr. Weber found that a specific growth factor—TGF-b1—plays an important role in RCC bone metastasis and the bone destruction it causes. Although she has not yet determined whether TGF-b1 is primarily responsible for the extensive osteolysis associated with RCC bone metastasis, preliminary studies show that treating renal cell bone metastasis cells with TGF-b1 induces bone resorptive factors, showing that it is indirectly responsible for at least some bone loss.

To experiment further, Dr. Weber used TGF-b1 inhibitors in cell culture and a mouse model. “We saw decreased RCC growth in culture and decreased bone destruction in the mouse model,” she says.

Dr. Weber fears, however, that using TGF-b1 inhibitors to treat humans may have serious side effects, because TGF-b1 is present in many human tissues. “We would have to treat patients with kidney cancer for a lengthy period of time, allowing the effects of the medication to accumulate,” she explains.

TGF-b1 inhibitor drugs are in clinical trials for other forms of cancer, but Dr. Weber hopes to find another point along the path to prevent the metastasized kidney cancer cells from destroying bone.

“We are looking a bit downstream to see what factors TGF-b1 influences in the bone,” she says. “We plan to block one or more downstream factors instead, hopefully minimizing side effects while still obtaining the necessary protective effects on bone.”

For more information on supporting research through donations to the OREF, visit the foundation’s Web site, www.oref.org

Amy Kile is a public relations specialist with the OREF. She can be reached at kile@oref.org.