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Izabela Podgorski, Ph.D. |
RESEARCH INTERESTS:
Recent clinical data suggest that more than 90% of patients who die from advanced refractory prostate cancer have clinical evidence of skeletal metastasis. Obesity and metabolic syndrome are major contributors to development of aggressive prostate cancer, with higher recurrence and higher mortality rates. Obese and overweight men have a three-fold higher risk of progression to metastatic disease compared to normal-weight men receiving the same treatment. With obesity and aging, there is a shift in bone marrow composition favoring the formation of fat cells (adipocytes). Adipocytes secrete endocrine and paracrine factors that strongly influence neighboring as well as distant cells. Marrow adipocytes also secrete inflammatory cytokines capable of recruiting macrophages and osteoclasts and contributing to dysregulated bone remodeling and accelerated tumor growth. There is a close interplay between inflammatory, osteolytic and tumor cell-driven events in the bone microenvironment. Our preliminary studies in mice deficient in cathepsin K (CTSK), protease involved in bone resorption, inflammation and obesity, demonstrate that specific bone marrow macrophage (BMM)-supplied proteases (e.g. CTSK) and inflammatory factors (e.g. CXCL1, CXCL2) collectively contribute to tumor colonization and growth in the skeleton. Bone marrow adipocytes are additional culprits that induce oxidative stress and affect macrophage response pathways. Our main research interests are to: identify molecular mechanisms underlying the association between obesity, inflammation and prostate cancer, and to develop an in vivo tractable model of obesity/inflammation-induced prostate cancer and use it as a tool for development of new therapies or novel applications of already existing drugs for prostate cancer.
Figure 1. Proposed model for the role of adipocyte- and macrophage-derived CTSK in obesity-induced bone resorption and homing of prostate tumors to the bone (From Podgorski et al, Biochem Soc. Trans, 2007)
Our current research encompasses three major projects:
A) We are examining how obesity/metabolic syndrome-driven inflammatory changes in the bone marrow impact aggressiveness of prostate bone tumors. We are searching to identify key adipocyte and macrophage response pathways that drive metastatic disease and to find genetic targets of macrophage inhibition in the bone tumor microenvironment. Our primary focus is on macrophage-derived proteases (i.e., CTSK, CTSS) and chemokines (i.e., CXCL1, CXCL2).
B) We are assessing how metabolic syndrome/inflammation-, insulin resistance- and oxidative stress-related factors differentially influence prostate cancer aggressiveness in African American and European American men. Specifically, using human blood samples from prostate cancer patients, we are exploring biochemical and genetic factors associated with racial differences in prostate cancer incidence, progression and risk of recurrence.
C) We are using novel, cMet/VEGFR2 targeted therapy for metastatic prostate cancer and a combination of imaging (PET, x-ray, optical imaging) and genomic approaches to identify bone- and tumor-specific molecular signatures that drive aggressive behavior of metastatic prostate tumors and determine their response to treatment. These studies are being initiated in a mouse model of bone metastasis and will extend to prostate cancer patients with metastatic disease.
EXAMPLES OF CURRENT MODELS UTILIZED IN OUR LABORATORY
Current Lab Personnel:
Mackenzie Herroon, M.A. – Research Assistant; mherroon@med.wayne.edu
Erandi Rajagurubandara, M.S. – Research Assistant; erajagur@med.wayne.edu
Aimalie Hardaway – Graduate Student (ahardawa@med.wayne.edu)
Selected Recent Publications:
1. Respondek, T., Garner, R., Herroon, M.K., Podgorski, I, Turro, C., and Kodanko, J. Light Activation of a Cysteine Protease Inhibitor: Caging of a Peptidomimetic Nitrile by Ru(bpy)
2. Journal of American Chemical Society 133(43):17164-12167, 2011.
2. Trivedi, E.R., Harney, A.S, Olive, M.B, Podgorski, I., Moin, K., Sloane, B.F., Barrett, A., Meade, T.J., Hoffman, B.M. Chiral Porphyrazines as Near-Infrared Optical Contrast Agents: Tumor Specific Accumulation In Vivo, PNAS, 107(4):1284-1288, 2010.
3. Podgorski, I, Linebaugh, B.E, Koblinski, J.E., Rudy, D., Olive, M.B. and Sloane, B.F. Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis Am. J. Pathol 175 (3): 1255-1269, 2009.
4. Podgorski, I. Future of Anticathepsin K Drugs: Dual Therapy for Skeletal Disease and Atherosclerosis? Future Medicinal Chemistry, 1 (1) 21-34, 2009.
5. Podgorski, I., Linebaugh, B.E, and Sloane, B.F. Cathepsin K in the Bone Microenvironment: Link Between Obesity and Prostate Cancer? Biochemical Society Transactions 35(4), 701-703, 2007.
