Joint Fellowship Training Program
Mentor:
Emily Shacter, Ph.D.
Organizational Affiliation and Position:
Chief, Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA
Email:
emily.shacter@fda.hhs.gov
Title of Research Program:
Chronic inflammation, apoptosis, and cancer chemotherapy
Research Project Summary:
Solid tumors such as breast cancer and lymphoma are often infiltrated by inflammatory phagocytes (neutrophils and macrophages) which can generate reactive oxygen species within the tumor tissue. The research in our laboratory attempts to elucidate: (1) molecular mechanisms of cell death caused by chemotherapy drugs in the presence of inflammatory oxidants and (2) the factors that control the clearance of dying tumor cells by macrophages. We have found that H2O2 inhibits both the ability of chemotherapy drugs to induce apoptosis in human lymphoma cells and the phagocytosis of the dying cells by macrophages. The research shows further that addition of antioxidants to the treatment regimen restores chemotherapy-induced apoptosis. These findings raise the possibility that co-administration of antioxidants may limit the negative, oxidant-related side effects of the drugs (e.g., cardiotoxicity from doxorubicin) while maintaining full tumor cell killing. This theory is supported by studies using a pre-clinical mouse model for breast cancer treatment. Other critical studies in the laboratory aim to characterize the molecular pathways through which oxidants directly kill tumor cells. The overall goal of the research is to find ways to improve cancer treatment by using our knowledge of basic biochemical and immunological mechanisms to develop novel therapeutic approaches for eliminating tumor cells.
Proposed project for IOTF Fellow:
The Fellow will have the opportunity to pursue one of several possible research projects in the laboratory based upon her/his particular interests, performing in vitro biochemical and cell biological studies on tumor cell death and clearance pathways and using a nude mouse model to study the effects of anti-oxidants on human breast cancer growth and treatment in vivo. The laboratory enjoys all of the benefits of being located on the NIH campus.
Regulatory Activity:
Our laboratory regulates a wide spectrum of novel and exciting therapeutic proteins, including proteins used to treat cancer, stimulate hematopoiesis or wound healing, and control coagulation. With appropriate mentoring, the Fellow will perform regulatory review of investigational new drug (IND) applications. This involves assessment of manufacturing processes and characterization of proteins to be used in clinical trials, working as part of an inter-disciplinary team to assess the potential efficacy and safety of the drugs, and communicating with product Sponsors.
Selected Relevant References:
- Shacter, E., Williams, J.A., Hinson, R.M., Sentürker, S., and Lee, Y.J. (2000) Oxidative stress reduces the efficacy of cancer chemotherapy drugs. Inhibition of lymphoma cell apoptosis and phagocytosis. BLOOD 96, 307-313
- Sentürker, S., Tschirret-Guth, R, Morrow, JD, Levine, RL, and Shacter, E. (2002) Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species. Arch. Biochem. Biophys. 397, 262-272
- Anderson, H.A., Maylock, C.A., Williams, J.A., Paweletz, C.P., Shu, H., and Shacter, E. (2003) Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nature Immunol. 4, 87-91
- Dwyer-Hoke, E., Maylock, C.A., and Shacter, E. (2005) Tumoricidal activities of desferrioxamine and doxorubicin. Role of iron. Free. Radic. Biol. Med. 39, 403-411
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