Project 5

Lymphoproliferative Disease and Lytic Bone Lesions in Tax Transgenic Mice

Principal Investigator: Lee Ratner, MD, Washington University
Co-Principal Investigator: Katherine Weilbaecher, MD, Washington University

Transgenic mice with HTLV-1 Tax expressed under the regulation of the granzyme B promoter develop a lymphoproliferative disorder of NK cells and lytic bone lesions. Tax is a potent transcriptional trans-activator, functioning through cellular transcription factors, including nuclear factor kappa B (NFkB). Tax transgenic tumors exhibit high levels of NFkB activity and NFkB inhibitors induce apoptosis of Tax transgenic tumor cells ex vivo.

The first aim of the study is to examine the effects of NFkB inhibitors on lymphoproliferative disease in the Tax transgenic mice. This will involve studies of a) double transgenic mice expressing both Tax and a stabilized form of the inhibitor of NFkB (I kB) or dominant negative forms of IKK alpha and beta, b) Tat transducible proteins linked to the stabilized form of I kB, c) or small molecule inhibitors of NFkB, such as LMD 341, which is currently in clinical trials in cancer patients. The second aim of the study will examine the molecular basis of bone metastases arising in the Tax transgenic mice. This will include studies of a) the temporal characteristics of lytic bone lesion development relative to tumor development, b) levels of M-CSF, RANKL, TFGbeta, TNF, IL1 in the lytic bone lesions and serum, c) soluble factors released by fresh or cultured Tax transgenic tumors that can activate osteoclasts in bone cultures, d) the role of the bone microenvironment in tumor growth, e) lytic bone lesions in Tax transgenic mice with knockout of RANKL or M-CSF and f) the effects of NFkB inhibitors used in aim 1 on lytic bone lesions.

These studies use Tax transgenic mice as a model system applicable to understanding the biology of many human malignancies. It is a unique animal model in which to explore the molecular basis of bone metastases. Moreover, it provides an opportunity to examine the efficacy of NFkB inhibitors as a form of cancer treatment.