Zhiwei Hu MD, PhD
Cancer Immunotherapy; Photodynamic Therapy; Tumor Angiogenesis; Cancer Stem Cell; Tumor Immunology; Natural Killer Cells
Current ProjectsOur research projects are supported by the Swebilius/Yale Cancer Center Translational Cancer Research Award, the Susan Komen Award from the Susan G. Komen for the Cure Foundation, Biomedical Research Grant from the Connecticut Department of Public Health and the Exceptional Project Grant from Breast Cancer Alliance in Greenwich, CT, in addition to collaboration grants from the National Institutes of Health.
Our research interest is to develop and translate novel therapeutics for eradication of pathological angiogenesis-involved diseases and to better understand the relationship between cancer cell/cancer stem cell and tumor angiogenesis. Pathological angiogenesis, the formation of new capillary vessels in diseased tissues from existing blood vessels, is involved in development of several diseases, notably cancer, macular degeneration (wet-form), rheumatoid arthritis, and diabetic retinopathy. In the case of cancer it was found that the receptor Tissue Factor (TF), a normal cell surface receptor, is expressed on tumor vascular endothelial cells, but not on normal vascular endothelial cells. TF is also over-expressed on many types of solid cancer cells as well as leukemia cells. Therefore TF can be used as a common target on both tumor cells and tumor vascular endothelial cells for development of novel cancer therapies. Moreover, TF has other physiological and pathological roles. A well-established role of TF is to initiate the blood coagulation process through extrinsic pathway upon binding of its natural ligand factor VII (fVII) and formation of fVII/TF complex. There are also evidences to indicate another role of TF in initiating intracellular signal pathways. These pathways could be involved in tumor angiogenesis, tumor metastasis, and embryonic vascular development.
Extensive Research Description
To target TF for cancer immunotherapy, I constructed a novel immunoconjugate molecule,called an Icon(fVII/IgG1 Fc), when I worked asvisiting scholar/postdoctoral associate (1998-2000), associateresearch scientist (2000-2002) and research scientist (2002-2007) in Dr. Alan Garen laboratory in the Department of Molecular Biophysics and Biochemistry of Yale School of Medicine. We tested the efficacy and safety of Icon-targeted immunotherapyof cancer in several mouse models of primary and metastatic mouse and human cancer, including melanoma, prostate, breast, head and neckand endometrial cancer. The results of these extensive tests demonstrated that the Icon mediated eradication of injected primary tumor and uninjected disseminated tumors without associated toxicity. Recently wedeveloped another novel targeted therapeutics, i.e., targeted photodynamictherapy (PDT), for treatment of cancer and the wet form of macular degeneration. Conventional or nontargeted PDT is a treatment for cancer involving three keycomponents: a photosensitizer, light, and tissue oxygen. It is also an approved treatment for wet macular degeneration. Due to the poor selectivity of photosensitizer, nontargeted PDT could cause severe side effects, which significantly limits its application.Here we improve photosensitizers’ selectivity by conjugating photosensitizers with fVII proteins, which can bring the photosensitizers specifically to tumor neovasculature and tumor cells that express TF. Our results showed that targeted PDT indeed not only improved the poor selectivity but also enhanced the efficacy of PDT for treatment of cancer. This neovascular-targeted PDT has therapeutic potential particularly for chemoresistant cancers. Like any other solid tumors, chemoresistant tumors also have pathological tumor blood vesselsthat could be the target for these TF-targeted therapies.