Emory School of Medicine
Dr. Mamoru Shoji obtained his Medical Degree from the Hokkaido University, Japan, and completed internships at the US Naval Hospital, Yokosuka, Japan and the University of Pennsylvania in Philadelphia, residency in internal medicine at the Lahey Clinic, Boston, fellowship training in immunology at the Peter Bent Brigham and Robert Breck Brigham Hospitals (mentor, John R. David, MD), Harvard Medical School in Boston, in tumor immunology at the University of Minnesota (mentor, Charles F. Mckhann, MD from Massachusetts General Hospital) in Minneapolis, followed by fellowship in Hematology and Medical Oncology at Emory University (mentor, Charles M. Huguley, Jr, MD). Dr. Shoji and Dr. W. Ralph Vogler performed immunotherapy in patients with AML in remission using patients’ leukemic cells and BCG. Dr. Shoji postulated that cyclic AMP and cyclic GMP may be related to cell proliferation, and he studied cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase, protein kinase C and their inhibitors including alkyl-lysophospholipid in leukemia with Dr. J.F. Kuo, PhD in the Department of Pharmacology at Emory. Dr. Shoji then explored tissue factor (TF), vascular endothelial growth factor (VEGF) and angiogenesis in cancer with Dr. Frederick R. Rickles, MD, at the CDC and Dr. Peter P. Nawroth, MD, at the University of Heidelberg, Germany. Dr. Shoji found that TF is expressed in vascular endothelial cells (VECs) in all cancers, but not in normal VECs. Dr. Nawroth showed that curcumin inhibits TF by inhibiting transcription factors NF-kappa B and AP-1. Dr. Shoji aimed to develop the targeted delivery of curcumin to TF-expressing tumor and tumor VECs. In collaboration with Drs. Dennis C. Liotta, PhD, and James P. Snyder at the Department of Chemistry, Emory, a panel of chemicals was tested to determine the active structure of curcumin and over 100 curcumin analogs have been synthesized.
Dr. Shoji’s research goal is to cure drug-resistant glioblastoma multiforme, metastatic breast cancer to the lung, bone and brain, metastatic melanoma, metastatic prostate cancer, renal cancer, lung cancer and head and neck cancer. His approach is to deliver synthetic curcumin analogs (EF24, EF31 or UBS109) and paclitaxel (PTX) specifically to TF-expressing tumor vascular endothelial cells (VECs, the innermost layer of the blood vesels) and tumor itself. All tumors secrete VEGF, which attracts VECs to tumors and induces expression of TF (innate receptor of factor VIIa: fVIIa) on VECs, which is the target of Dr. Shoji’s drug delivery system. Malignant cancers also express TF due to activated transcription factors. Dr. Shoji has conjugated a drug to the inactivated fVIIa (innate ligand of TF) as a drug carrier in order to prevent blood clotting, given that cancer patients are in the hypercoagulable state due in part to TF-expressing cancer cells in circulation. FVIIa is modified to become an inactive enzyme in order to inhibit its initiation of clotting activity by coupling tri-peptides, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) to a histidine of the serine protease core, resulting in FFRck-fVIIa. However, FFRck-fVIIa retains the same binding affinity to TF as fVIIa. The drug conjugate (EF24-FFRck-fVIIa or PTX-FFRck-fVIIa) is endocytosed upon binding to TF and delivers the drug inside target cells. This drug conjugate targets and kills not only tumor VECs but also tumors simultaneously, whereas anti-VEGF antibody for example inhibits the attraction of VECs to tumors but does not kill tumors or VECs. TF is not expressed on normal VECs, but is present on the outer layers of the blood vessels. FVIIa usually does not contact with TF. Plasma fVIIa comes into contact with TF upon injury and initiates clotting to stop bleeding. Thus, TF on tumor VECs is the selective and universal target of this approach. VECs are normal cells and less likely to become drug-resistant. Therefore, the drug-conjugate can target tumor VECs to shut down tumors’ supply lines even when tumors become drug-resistant. Dr. Shoji and his associate Dr. Shijun Zhu, MD, PhD, are completing an efficacy study of the targeted delivery of PTX-FFRck-fVIIa and liposomes containing PTX in xenografts of human breast cancer lung metastasis. The therapy is significantly efficacious. Drs. Shoji and Brat, their collaborators Drs. Olson and Van Meir, Dr. J. Sarkaria, MD, at the Mayo Clinic and Dr.R. Bellamkonda, PhD, at GA Tech are working on treatment of glioblastoma multiforme using EF31-FFRck-fVIIa and liposomes containing UBS109. Dr. Shoji’s long time collaborators are Dennis C. Liotta, James P. Snyder, Aiming Sun, J. Maina Ndung, and Terry W. Moore at the Department of Chemistry and Dr. Frederick R. Rickles, MD, at the Departments of Medicine and Pediatrics of the George Washington University, Washington, DC.
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