Issue: May 2006
May 01, 2006
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Kappa Delta’s Lanier award presented to renal cell carcinoma researchers

They found that blocking the growth factor signaling pathways in renal cell carcinoma bone metastasis could affect tumor growth.

Issue: May 2006
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CHICAGO — The Kappa Delta sorority recently recognized three researchers for nearly five years of work they put into studying the growth factor receptor signaling blockade involved in renal cell carcinoma as it metastasizes to bone. The sorority awarded the honor to orthopedic surgeon Kristy L. Weber, MD; researcher Michele Doucet, MS; and basic scientist Scott Kominsky, PhD, during the Orthopaedic Research Society’s Annual Meeting, held here.

 

Kristy L. Weber, MD [photo]
Kristy L. Weber

In accepting the award, Weber said she got involved and interested in this area of research at the M.D. Anderson Cancer Center, Houston, where she worked with many patients with renal cell carcinoma (RCC) bone metastasis. “Although it affects a small number of patients, the morbidity related to this disease and the mortality related to it is devastating,” she said.

RCC is typified by extreme pain, fractures or spinal compression problems. “It presents a challenge to the orthopedic surgeon/orthopedic oncologist. Its intense vascularity creates quite a problem.”

image
This AP radiograph of a patient shows a lytic lesion in her right ilium from metastatic renal cell carcinoma.

Stop the action

The team’s goal was to find new ways to stop the action of the growth factors related to this type of cancer, particularly epidermal growth factor receptor (EGF-R) and transforming growth factor-alpha (TGF-alpha), both of which have signaling pathways important to RCC bone metastasis.

Weber said there was a dire clinical need to find this out, since the lesions are “relatively resistant to the normal therapies, such as radiation or chemotherapy. And surprisingly, we know very little about the micro-interaction between the tumor cells and the bone microenvironment,” she said during her presentation.

photo
Kristy L. Weber, MD, chief, division of orthopedic oncology, Johns Hopkins University, received the Elizabeth Winston Lanier award. It is a research award given by the Kappa Delta sorority, a women-based organization. Weber is shown viewing slides of human renal cell carcinoma after it was injected into mouse tibia and grew into destructive lesions.

Courtesy of Kristy L. Weber

To begin studying this unexplored scientific area, the group needed to create an animal model, since none existed. They collected tumor metastasis cells from Weber’s patients, cultured and grew them. When they put the cultured cells in the tibia of a nude mouse, they grew. “They produced lytic destructive lesion similar to those we see in the human patients,” she explained.

The researchers used a more aggressive cell line cultured from the first group of cells for the majority of their work.

Epidermal growth factor

They started by tackling the EGF-R blockade, because other studies had identified its signaling pathway as being important to primary tumors. Among the areas they analyzed was growth factor expression, which they found to be very high in the cellular cascade related to RCC.

For example, when the researchers added EGF to their tumor cells, “we see a statistically significant increase in cell proliferation,” Weber said. However, when they added a novel inhibitor, protein tyrosine kinase inhibitor or PKI 166, they saw a dose-dependent decrease in cell proliferation.

The inhibitor is a small molecule and when given orally it affects the phosphorylation of the EGF-R, Weber said.

Stopping bone destruction

In the nude mice, the researchers also added the PKI 166 therapy with or without the anti-cancer drug Taxol (paclitaxel) to see what would happen. “At the end of 10 weeks of treatment, we saw statistically significant decrease in tumor growth” based on results of staining studies. “We also saw a significant decrease in bone destruction,” Weber said.

She showed radiographs that demonstrated the differences in bone destruction in the treatment groups.

The research team plans to continue its work in this area. “We’re looking at TGF-beta-regulated genes to try and find a more specific focus of bone destruction and also to minimize the side effects that might be obtained with using TGF-beta inhibitors in the clinic.”

Weber is chief of the division of orthopedic oncology at Johns Hopkins University, Baltimore.

For more information:
  • Weber KL, Doucet M, Kominsky S. Growth factor receptor signaling blockage in renal cell carcinoma bone metastasis. Presented at the Orthopaedic Research Society’s Annual Meeting. March 19-22. Chicago.