Theresa Guise
Professor
The University of Texas MD Anderson Cancer Center at Houston
Department of Internal Medicine - Endocrine Neoplasia and Hormonal Disorders
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).
The Guise lab has unique training opportunities in bone biology, bone metastases of
breast and thyroid cancer, muscle physiology, cognitive function and biomechanical
testing.
Education & Training
MD, University of Pittsburgh School of Medicine, 1985