CSB Faculty
Babatunde O. Oyajobi, MBBS, PhD, MBA
Assistant Professor
University of Lagos, Nigeria, 1983
University of Sheffield, England, 1992
(210) 567-0909
OYAJOBI@UTHSCSA.EDU
Dr. Oyajobi joined the Department of Cellular & Structural Biology in September 2003. Before this, he did postdoctoral training at the University of Sheffield in England on an Arthritis & Rheumatism Council Fellowship, at the Hospital Lariboisière (Unitè 349, now Unitè 606) in Paris, France on an INSERM Fellowship and here at the Health Science Center in the Department of Medicine on Fellowships from the International Myeloma Foundation and the Multiple Myeloma Research Foundation. He is a past recipient of a John Haddad Young Investigator Award from the American Society for Bone and Mineral Research (2001) and a Minority Scholar Award in Cancer Research from the American Association of Cancer Research (AACR) (2005). He has also received an AACR Minority-Serving Institution Faculty Scholar Award each year since 2006. He serves regularly as an ad-hoc reviewer on the NIH/NCI-F Special Emphasis Panel (Manpower and Training). Dr Oyajobi teaches on, and directs the Human Gross Anatomy course for the Graduate School.
Research in our laboratory is focused on multiple myeloma, a cancer of antibody-producing terminally-differentiated B-cells (plasma cells) in which the primary site is the bone marrow cavity. Our studies aim to elucidate mechanisms mediating the osteolysis and bone deficit characteristic of myeloma. However, we are also interested in tumors with osteolytic/osteosclerotic metastases (breast cancer, prostate cancer, lung cancer, renal cell carcinoma) since the mechanisms underlying the associated bone disease are likely to be the same as in myeloma. We are currently refining existing mouse models of cancer-induced bone diseases as well as developing and characterizing new and better models. Our studies have a translational goal and involves identification of novel molecular targets for rational development of anti-cancer strategies and preclinical evaluation of novel anti-cancer agents. In this regard, we are investigating mechanisms mediating the anti-tumor and bone anabolic effects of compounds that inhibit the multi-meric proteasome. In particular, we are interested in bortezomib, (PS-341, Velcade™), the first-in -class proteasome inhibitor to be developed for clinical use. The FDA approved bortezomib for use in myeloma patients in 2003 after a fast-tracked process. Our group recently demonstrated that proteasome inhibitors (including bortezomib) stimulate new bone formation in vitro and in rodents (Garrett et al. 2003 J Clin Invest; Oyajobi et al. 2007 Br J Haematol).
Ongoing projects in our lab include:
(i) Role of NF-κB in myeloma cell growth and survival as well as myeloma tumor progression in vivo. In this project, we aim to define the contribution of the alternative (non-canonical) NF-κB signaling pathway (involving p100/p52) to myeloma.
Proteasome inhibitors, which are also potent inhibitors of NF-κB activation and the cell cycle, are increasingly being shown to be efficacious in myeloma therapy but they are non-specific. Therefore, we are evaluating the E3 ubiquitin ligase β-TrCP/FWD1 that recognizes components of NF-κB signaling as substrates for ubiquitin-mediated proteasomal degradation, as a possible more-selective molecular target in the murine 5TGM1 model of myeloma bone disease using classical 'gain of function' and 'loss of function' approaches. As part of this effort, in collaboration with Paul Hasty (Associate Professor, UTHSC Institute of Biotechnology), we are applying targeted transgenesis to mammalian somatic cells, in this instance malignant plasma (myeloma) cells. Understanding the mechanisms by which proteasome inhibition results in tumor cell death, inhibit osteoclastic bone resorption and concomitantly enhance new bone formation (see below) will help define novel molecular targets for the development of new therapies for treatment of myeloma bone disease.
(ii) Dickkopf 1 (Dkk1) and myeloma bone disease. The aim of this is to elucidate the role of Dkk1, a secreted antagonist of canonical Wnt signaling, in the pathogenesis and progression of myeloma bone disease. As part of these, studies, we are defining the role of Dkk1 in bone formation in postnatal and adult mice.
In addition to the profound osteolysis, myeloma is characterized by an inability of osteoblasts in the skeleton to respond appropriately to replace the bone lost. The detailed molecular mechanisms mediating this deficit in bone formation in myeloma patients remain unknown. None of the currently available chemotherapeutic agents correct this osteoblast dysfunction and reverse the bone loss. Recently several lines of evidence suggest that Dkk1 plays an important role in the osteoblast dysfunction and uncoupling of bone remodeling in myeloma. The role of Dkk1 in this regard and mechanisms by which its expression are regulated are largely unknown. We have recently found that bortezomib inhibits Dkk1 expression in cells from the myelomatous bone microenvironment. To facilitate studies into the mechanisms mediating dysregulation of osteoblast function in myeloma, we have characterized the changes in the skeleton in the murine 5TGM1 myeloma bone disease model and shown that these are indistinguishable from those seen in patients. Using this model and a novel transgenic mouse model overexpressing Dkk1, the studies we are undertaking will better define the role of Dkk1 in development of myeloma bone disease and advance our understanding of the mechanisms that are directly involved in the profound anti-tumor and bone anabolic effect of proteasome inhibition in myeloma. This should ultimately lead to development of specific targeted therapeutics to treat myeloma bone disease.
(iii) Application of "state-of-the-art" nuclear imaging modalities to monitor tumor dissemination and effects of tumor on the skeleton in murine models of cancer-induced bone diseases.
We are applying non-invasive, state-of-the-art nuclear imaging techniques to the 5TGM1 model of myeloma bone disease that should further facilitate rapid preclinical evaluation of novel anti-myeloma therapies. Together with collaborators in the Department of Radiology (Drs Philips and Goins), we have begun positron tomographic emission (PET) with 18F-NaF and single photon emission computed tomographic (SPECT/CT) with 99mTc-MDP to longitudinally track bone cell activity and skeletal changes respectively in the 5TGM1 myeloma model and the MDA-MB-231 experimental model of human breast cancer skeletal metastasis.
Work in our laboratory is supported by grants from the National Cancer Institute (NCI) and the Texas Higher Education Coordinating Board (Advanced Research Program).
Research Techniques:
Bone cell culture
Cell proliferation and cell viability assays
Bone histomorphometry
Promoter reporter assays
RNA interference
Whole body fluorescence imaging in live mice
Nuclear imaging in mice
PUBLICATIONS:
Edwards CM, Lwin ST, Fowler JA, Oyajobi BO, Zhuang J, Bates AL, Mundy GR. (2009)
Myeloma cells exhibit an increase in proteasome activity and an enhanced response to proteasome inhibition in the bone marrow microenvironment in vivo.
Am J Hematol. 2009 Feb 11;84(5):268-272.
Sung B, Murakami A, Oyajobi BO, Aggarwal BB. (2009) Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice. Cancer Res. 2009 Feb 15;69(4):1477-84.
Zhao M, Ko SY, Liu JH, Chen D, Zhang J, Wang B, Harris SE, Oyajobi BO, Mundy GR. (2009) Inhibition of microtubule assembly in osteoblasts stimulates bone morphogenetic protein 2 expression and bone formation through transcription factor Gli2. Mol Cell Biol. 2009 Mar;29(5):1291-305.
Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazon A, Azpilikueta A, Ochoa MC, Alfaro C, Solano S, Perez-Gracia JL, Oyajobi BO, Melero I. (2008) Therapeutic Antitumor Efficacy of Anti-CD137 Agonistic Monoclonal Antibody in Mouse Models of Myeloma.. Clin Cancer Res. 2008 Nov 1;14(21):6895-906.
Edwards CM, Edwards JR, Lwin ST, Esparza J, Oyajobi BO, McCluskey B, Munoz S, Grubbs B, Mundy GR. (2008) Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood. 2008 Mar 1;111(5):2833-42. Epub 2007 Dec 19.
Oyajobi BO, Garrett IR, Gupta A, Flores A, Esparza J, Munoz S, Zhao M, Mundy GR. (2007)
Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease.
Br J Haematol. Nov;139(3):434-8.
Oyajobi BO. (2007) Multiple myeloma/hypercalcemia. Arthritis Res Ther. 9 Suppl 1:S4.
Oyajobi BO, Munoz S, Kakonen R, Williams PJ, Gupta A, Wideman CL, Story B, Grubbs B, Armstrong A, Dougall WC, Garrett IR, Mundy GR. (2007) Detection of myeloma in skeleton of mice by whole-body optical fluorescence imaging. Mol Cancer Ther. Jun;6(6):1701-8. Epub 2007 May 31.
Book Chapter:
Oyajobi BO, GR Mundy. Pathophysiology of myeloma bone disease. In G Gahrton, BGM Durie, DS Samson (eds): Multiple Myeloma and Related Disorders (2nd edition), Part 2, Chapter 6. Arnold, London, pp 74-88 (2004).