Faculty
Kathy Weilbaecher.jpg

Katherine N. Weilbaecher, MD

Professor
Department of Medicine
Oncology Division
Molecular Oncology

Clinical Interests

  • Breast cancer

Research Interests

  • Skeletal metastasis
  • Beta 3 integrin
  • Osteoclast biology
  • Transcription factors
  • RANKL

Contact

  • 314-454-8858 (tel)
  • 314-454-7086 (fax)
  • Room 806, McDonnell Sciences Building (office)
  • Washington University School of Medicine
    Division of Oncology
    Campus Box 8069
    660 South Euclid Avenue
    St. Louis, MO 63110

Research

The skeleton is the organ most commonly affected by metastatic cancer in humans. Mechanisms by which skeletal metastases are established are unclear; however, osteoclast activation plays a critical role in the pathogenesis of bone metastases. Our laboratory focuses on the molecular mechanisms through which tumor cells metastasize to bone. We are specifically interested in characterizing ways in which host cells within the tumor microenvironment (including osteoclasts, osteoblasts, stromal cells, and immune cells) influence tumor growth. Bone-metastatic tumor cells are known to secrete molecules that affect the activity of these host cells. In turn, host-derived growth factors can further enhance tumor growth, known as 'the vicious cycle'. Understanding this will facilitate the identification and development of host-targeted therapeutics that will decrease tumor growth and tumor-associated bone disease.

Current projects in our laboratory include:

The role of the beta 3 integrin and its related molecules CD47, TSP1 and P2Y12 in skeletal metastases

The beta 3 integrin subunit (β3) has been implicated in the development of metastases because of its critical role in osteoclastic bone resorption (αvβ3), and its role in platelets in tumor cell homing (αIIbβ3). CD47, TSP1, and P2Y12 are activators of the αvβ3 integrin pathway. To examine the role of this pathway in normal and pathogenic bone remodeling, we utilize targeted knockout mice for each molecule and have established in vivo models of bone metastasis using osteolytic and osteoblastic tumor cell lines.

The role of the Tax oncogene in skeletal metastases

HTLV I associated Adult T cell leukemia (ATLL) is distinctive for its high rate of osteolytic skeletal metastases and hypercalcemia. Expression of HTLV-1 Tax oncogene, under the regulation of the granzyme B promoter, results in tumors which are associated with lytic bone lesions. We are characterizing Tax-tumor derived compounds, such as IFN-gamma, which deregulate osteoclast and osteoblast activity, resulting in bone pathology.

The role of the ARF tumor suppressor in regulating bone turnover and osteosarcoma development

We have shown that, in addition to its recognized actions as a tumor suppressor, ARF is critical to maintaining normal bone turnover. In Arf-/- mice, bone turnover is increased with a dominant enhancement of osteoblastic bone formation. Crossing Arf-/- mice with Tax-transgenic mice resulted in spontaneous, high penetrant osteosarcoma (the most common primary bone tumor). We are currently investigating mechanisms by which the high bone turnover state increases susceptibility of bone-resident tumors.

The role of the host microenvironment in multiple myeloma growth and bone disease

Multiple myeloma is a bone marrow-resident tumor of antibody-secreting plasma cells. Myeloma cells are known to produce a variety of factors that stimulate osteoclastic resorption and inhibit osteoblastic formation, resulting in severe bone pathology. We are testing novel pharmacological agents for their ability to inhibit myeloma growth and bone disease through direct effects on both tumor cells and host microenvironment cells.

Metastases Aspirin and APT102 in combination significantly decrease metastatic tumor burden in a murine tumor model.

From: Uluckan O, Eagleton MC, Floyd DH, Morgan EA, Hirbe AC, Kramer M, Dowland N, Prior JL, Piwnica-Worms D, Jeong SS, Chen R, Weilbaecher K
APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice.
J Cell Biochem 2008 Jul 1;104(4):1311-1323