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Grant helps researchers unravel role of glucose, fats in bone cancer

Michael Schug • 11/27/18

INDIANAPOLIS—A $1.2 million Department of Defense grant has been awarded to an Indiana University School of Medicine physician whose research explores a cascade of events that decreases quality of life and treatment responses for patients with metastatic bone cancer.

Theresa Guise, MD, hopes to understand the role of the tumor-bone microenvironment on glucose metabolism and the role that a high-fat diet plays in the process. Her work is supported by the U.S. Army Medical Research Acquisition Activity through award W81XWH-18-1-0678.

An endocrinologist, Guise is the Jerry and Peggy Throgmartin Professor of Oncology and professor of medicine at IU School of Medicine and a co-leader of the Tumor Microenvironment and Metastasis research program at the Indiana University Melvin and Bren Simon Cancer Center.

“One of the reasons we are studying high-fat diets in mice is to mimic our population in Indiana,” Guise said. “It is known that once cancer is in the bone, it causes bone destruction and the risk of fracture is increased. Diabetes also increases the risk for bone fractures. Our recent data show that bone destruction in the setting of a high-fat diet can induce diabetes. We believe this high glucose load can further impair bone quality, leading to a downward spiral.”

The questions she wants to answer are:

  • How does this occur and what are the specific mechanisms by which cancer-induced bone destruction disrupts glucose metabolism in the setting of a high-fat diet?
  • Does this fuel tumor growth in bone?
  • Does it further increase the risk of fractures?
  • How can we intervene?

“The initial aim of the study involves older mice who have breast cancer that has spread to the bone. Our research will evaluate their insulin secretion, glucose tolerance, bone loss, muscle function and cancer progression when they are fed either a high-fat or a low-fat diet,” Guise explained. “If the mice lose bone, do they develop diabetes? Can this be prevented by a low-fat diet or by blocking bone loss? This is important because patients with high blood sugar do not respond as well to cancer therapy which further increases the high risk for bone fractures.”

In another phase of the research, Guise will consider different means to stabilize glucose metabolism in obese mice with metastatic bone cancer to prevent the metabolic changes that result in diabetes.

Data from the first two arms of the study will be applied to information obtained from people with breast cancer that has spread into the bone to validate the similarities in the “molecular cascade” that places patients at higher risk for fractures during treatment.

“All three arms of the study will also determine how much fat gets into the bone, blood and other organs and if blocking a specific protein called TGF-beta will interfere with the molecular cascade that causes patients to develop diabetes. TGF-beta is released from the bone during the process of bone breakdown from cancer or cancer treatment. Ideally, the next step will be clinical studies in humans with breast cancer,” Guise said.

Bone may appear to be just a hard tissue that provides structural support for tendons and muscles, but, in fact, it is a dynamic tissue in a state of constant change. Bone normally undergoes a remodeling process where bone-breakdown cells called osteoclasts removes dead bone, and bone-forming cells called osteoblasts replace this with new bone. Guise has spent her career trying to figure out how cancer disrupts this normal process of bone remodeling to cause fragile bones, fracture and pain. Her lab has had many successes including defining the role of a growth factor called transforming growth factor-beta (TGF-beta) in tumor-induced bone destruction, muscle weakness and now diabetes.