Theresa Guise

Metabolic complications of cancer and cancer treatment-induced bone destruction: Role of TGFβ-mediated oxidation 1) Research Accomplishments: The Guise laboratory described the molecular mechanisms of bone metastases, the role of TGFβ in the tumor-bone microenvironment and cancer treatment-induced bone loss to promote tumor growth as well as to mediate systemic effects on skeletal muscle to cause weakness. Alterations in the bone microenvironment, such as with osteolysis due to cancer and cancer treatment, cause muscle weakness via the novel pathway by which bone-derived TGFβ induces oxidation of skeletal muscle ryanodine receptor (RyR)1 via NADPH oxidase 4 (Nox4) to cause calcium (Ca2+) leak. These are the first studies to show 1) the unique aspects of the bone microenvironment to regulate target organs at distant sites, such as muscle, when normal bone remodeling is disrupted by cancer and cancer treatment and that 2) muscle dysfunction can occur without the loss of muscle mass. New drugs which stabilize the RyR1-calstabin1 complex, drugs called rycals, improve muscle weakness in the mouse models of bone metastases and cancer treatment-induced bone loss (7,8). A clinical trial to study bone-derived TGFβ in aromatase inhibitor-induced musculoskeletal toxicity is underway in breast cancer patients, with interventions of low intensity vibration (LIV)(9) and later, rycals. The effects of bone destruction are systemic and we hypothesize that cancer and cancer treatment-induced bone destruction will impact other target organs to increase morbidity and mortality: 1) pancreatic islets and glucose metabolism; 2) brain and cognitive function and 3) heart and cardiac function. These clinically relevant studies will identify new targets to treat consequences of pathologic bone destruction due to cancer and cancer treatment. (Key words: Bone loss, bone metastases, muscle function, cardiac function, cognitive function).