SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M Dadlani, GH, Harmon, WG, Simbre II, VC, Tisma-Dupanovic, S, and Lipshultz, SE . Cardiomyocyte injury to transplant: pediatric management. Current Opinion in Cardiology 18:91-7 (Review), 2003. Adams, MJ, Hardenbergh, PH, Constine, LS, and Lipshultz, SE . Radiation-associated cardiovascular disease. Critical Reviews in Oncology/ Hematology 45:55-75 (Review), 2003. BALAKRISHNA L. LOKESHWAR, PH.D. Associate Professor of Urology DESCRIPTION OF RESEARCH Dr. Lokeshwar’s research focuses on the mechanism of prostate cancer metastasis and its control by novel chemotherapeutic drugs. For the last several years, Dr. Lokeshwar’s laboratory has focused on extracellular matrix degradation and tumor metastasis. His laboratory has studied the regulation of a class of basement membrane matrix degrading enzymes called the matrix metalloproteinases (MMPs) in prostate cancer. Using cancer cell cultures established from human prostate tumor tissues obtained after prostatectomy, they showed that an imbalance exists between the levels of MMPs (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells. Based on this finding, they developed a hypothesis that a novel approach to control metastatic cancer is to correct the imbalance either by inhibition of secretion of MMPs or by increasing the extracellular levels of their endogenous inhibitor. Since several small synthetic inhibitors of MMPs exist, they tested the usefulness of the inhibitors using the criteria of oral bioavailability, systemic toxicity, and ability to target bone metastasis. In their search for a suitable inhibitor, Dr. Lokeshwar’s laboratory tested a series of synthetic tetracycline analogues, which were shown to possess a strong anti-collagenase activity with little or no antibiotic activity. Researchers tested eight different chemically modified tetracyclines (CMTs) and found one of them, 6-deoxy, 6- demethyl, 4-dedimethylamino tetracycline (CMT-3, COL-3, now termed Metastat R by CollaGenix Pharmaceuticals, Newtown, Pennsylvania), to be the most promising. Oral dosing with this analogue to rats and mice-bearing metastatic prostate tumors reduced tumor growth and metastasis, with no measurable systemic toxicity. Furthermore, prophylactic dosing of animals with the drug significantly reduced the incidence of tumor at the site of tumor cell injection. Their demonstration of a highly antimetastatic and antitumor activity of CMT-3 in a rat prostate tumor model led to its phase I clinical trial by the Developmental Therapeutics Program of the NCI (NCI-DTP). In the recently concluded human clinical phase I trial of CMT-3, the NCI-DTP recommended CMT-3 for phase II and phase III in patients with soft tissue sarcoma and advanced metastatic tumors. The University of Miami and the State University of New York at Stony Brook have jointly obtained a use patent on this drug. This finding also has generated a wide interest in the use of CMT-3 among many investigators within and outside the University of Miami, including a new patent issued to the University for the treatment of corneal ulceration in patients with meibomian gland disease, also called ocular rosacea. Dr. Lokeshwar’s current research focuses on identifying novel plant products that have been used as folk medicine and identifying novel combination therapies for advanced hormonerefractive prostate cancer. In a related development, COL-3 is undergoing a phase III clinical trial against HIVinduced Karposi’s sarcoma. Twenty centers nationwide are engaged in this trial, headed by Dr. Bruce DeZube of New England Deaconess Hospital, Boston. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 45
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M SELECTED PUBLICATIONS 2002 Dursun, D, Wang, M, Monroy, D, Li, DQ, Lokeshwar, BL , Stern, M, and Pflugfelder, SC. Experimentally induced dry eye produces ocular surface inflammation and epithelial disease. Advances in Experimental Medicine and Biology 506:647-55, 2002. Dursun, D, Wang, M, Monroy, D, Li, DQ, Lokeshwar, BL , Stern,ME, and Pflugfelder, SC. A mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology & Visual Science 43:632-38, 2002. Lokeshwar, BL , Selzer, MG, Zhu, BQ, Block, NL, and Golub, LM. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. International Journal of Cancer 98:297-309, 2002. Whitlatch, LW, Young, MV, Schwartz, GG, Flanagan, JN, Burnstein, KL, Lokeshwar, BL , Rich, ES, Holick, MF, and Chen, TC. 25- Hydroxyvitamin D-1alpha-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40, 2002. 2003 Chen, TC, Holick, MF, Lokeshwar, BL , Burnstein, KL, and Schwartz, GG. Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research 164:273-88, 2003. Dandekar, DS, Lokeshwar, VB, Cevallos- Arellano, E, Soloway, MS, and Lokeshwar, BL . An orally active Amazonian plant extract (BIRM) inhibits prostate cancer growth and metastasis. Cancer Chemotherapy and Pharmacology 52:59- 66, 2003. HIGHLIGHTS/DISCOVERIES • Demonstrated that an imbalance exists between the levels of MMPs (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells. • Identified a novel, chemically modified nonantimicrobial tetracycline (CMT-3) as an effective anti-metastatic drug with potential to treat prostate cancer metastatic to bone. The NCI has completed the phase I trial of this drug and is awaiting further trials. Other novel agents are being tested in Dr. Lokeshwar’s laboratory, not only for controlling cancer, but also other chronic diseases such as chronic ocular surface inflammation. Dr. Lokeshwar’s research has brought in one patent to the University of Miami jointly with the State University of New York at Stony Brook. Meanwhile, two patents are pending on the new application of his research findings. • Identified a potential application of CMT to treat the meibomian gland dysfunction that leads to the ocular rosacea. This was done in collaboration with Stephen C. Pflugfelder, M.D., Baylor College of Medicine, Houston, Texas. Li de, Q, Shang, TY, Kim, HS, Solomon, A, Lokeshwar, BL , and Pflugfelder, SC. Regulated expression of collagenases MMP-1, -8, and -13 and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells. Investigative Ophthalmology & Visual Science 44:2928-36, 2003. 46 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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