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$2 million grant funds Pitt dental school effort to prevent cancer’s spread to bone

November 03, 2014

by Jean Williams

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Armed with a five-year, $2 million grant from the National Cancer Institute, a University of Pittsburgh School of Dental Medicine team will explore the molecular mechanisms that enable certain cancers, particularly multiple myeloma, to metastasize to the bone.

Researchers aim to uncover a way to prevent the metastasis and to slow primary tumor growth.

Multiple myeloma is a cancer of plasma cells that begins in the bone marrow and progresses to bone erosion and deterioration. Even with treatment, the bone lesions rarely heal.

Reports of jaw pain or suspicious lesions to their dentists precedes diagnosis in some 30 percent of patients with the cancer, according to Dr. Hongjiao Ouyang, associate professor in the department of Restorative Dentistry/Comprehensive Care and Oral Biology and a member of the Center for Craniofacial Regeneration at Pitt School of Dental Medicine.

“This bone destruction is a significant cause of pain and mortality in this disease,” said Dr. Ouyang, an endodontist and bone biologist. “A better understanding of the molecular pathways that underlie this process could lead us to novel targets for treatment.”

The answers the team seeks may lie in bone marrow, where bone marrow stromal cells yield bone-forming osteoblasts, fat cells and other cells. In someone with multiple myeloma, BMSCs also produce growth factors and inflammatory proteins called osteoclasts, which are cells that break down bone, forming holes that do not heal. Osteoblasts, on the other hand, rebuild bone as part of normal metabolism.

The team is targeting a protein molecule in the BMSCs of multiple myeloma patients — X-box binding protein — that has been shown to regulate the production of inflammatory proteins in other tissues. In a lab experiment, the team determined that inducing healthy cells to produce XBP1s triggered changes in the bone microenvironment that support growth of multiple myeloma cells and osteoclast formation. Halting XBP1 production in multiple myeloma patients’ BMSCs stemmed the growth of multiple myeloma cells and osteoclast formation.

The project will seek to determine stromal XBP1’s molecular mechanisms and signaling in altering the bone microenvironment to favor multiple myeloma growth and bone destruction. As well, the project team will seek to determine pharmacologic and genetic strategies to repress stromal XBP1 and create a doorway to developing treatment options for multiple myeloma bone disease.

“This could be helpful, not only in treatment of multiple myeloma, but also in other cancers that spread to bone, such as breast, prostate and lung cancer since BMSCs play a similar role in supporting tumor cell growth in these neoplastic diseases as well,” Dr. Ouyang said. “I am delighted that our research will benefit not only dental patients but also those affected by many other diseases.”