Faculty & Research
Richard F. Ambinder
|Rank||James B. Murphy Professor|
|School of Medicine Address||Room 389 CRB1|
1650 Orleans Street
Baltimore MD 21287
|Link to Lab Homepage|
Research Topic: Virology and human cancer; antiviral therapy; antitumor therapy; lymphoma pathogenesis and treatment
Epstein Barr virus is consistently found in association with a variety of tumors including African Burkitt's lymphoma, nasopharyngeal carcinoma, mixed cellularity Hodgkin's disease, post-transplant lymphoma and AIDS central nervous system lymphoma. KSHV (also known as HHV8) is consistently found in Kaposi’s sarcoma and primary effusion lymphoma. Our laboratory studies are aimed at better defining the role(s) of the virus in the pathogenesis of these tumors and the development of new strategies for diagnosis and treatment. For example, is there a way to utilize the presence of the virus to specifically target therapy? We have developed an approach that we refer to as Bortezomib Activated Viral Enzyme Targeted Radiotherapy”.
Radiation is one of the most effective anti-tumor therapies. In the early 1950’s it was shown that radioiodine would naturally concentrate in thyroid cancer cells just as it does in normal thyroid tissue. This led to what remains one of the best targeted therapies for cancer, radioiodine. 131I is administered, concentrates in cancer tissue and delivers targeted radiation that spares normal organs. Other approaches to thyroid cancer such as other chemotherapy agents are much less effective and much more toxic. Approaches to the selective delivery of radiation to tumor tissue by virtue of the ability to metabolically concentrate a radiopharmaceutical have not been an important focus of cancer research because tumor-specific metabolic pathways that would lead to highly selective concentration of a radioisotope have not been well characterized.
In the course of other studies of certain virus-related tumors, we realized that virus-encoded enzymes would concentrate certain nucleoside analogues. We studied FIAU and showed that cancer cells expressing the Epstein-Barr virus thymidine kinase would phosphorylate FIAU and following phosphorylation the drug would be trapped inside the cells. In a mouse xenograft model, we analyzed this effect in detail and demonstrated that if [131I]FIAU was used such tumors would regress. However, a barrier remained. This viral enzyme is not normally expressed in tumors even when the virus is present. We screened virtually all known FDA-licensed agents in search of an agent that might activate expression of the viral thymidine kinase. The search identified almost 200 such agents, but the most potent was bortezomib. Using bortezomib-induced enzyme targeted radiation therapy, we were able to induce tumor regression in human tumors transplanted into immunodeficient mice.
Ongoing studies include:
1. Investigation of the mechanism by which bortezomib induces expression of the viral enzyme. We have shown that using lentivirus vectors with inducible genes we can block the response to bortezomib. Detailed mapping of the relevant pathways are underway.
2. Investigation of the application to human tumors in the clinic.
a. We are working to evaluate the ability of bortezomib and some of the other chemotherapy agents identified to turn on viral kinases in tumors in patients as evidenced by PET scan using [124I]FIAU (an isotope that yields high resolution images and is safe but does not have therapeutic effect). This will involve an imaging trial in approximately 10 patients.
b. For patients who have such tumors and who have failed standard therapies, we will undertake a phase I/pilot trial with [131I]FIAU and bortezomib.
Lin L., Lee JY., Kaplan LD., Dezube BJ., Noy A., Krown SE, Levine AM, Yu Y, Hayward GS, Ambinder RF
., Effects of Chemotherapy in AIDS-Associated Non-Hodgkin’s Lymphoma on KSHV DNA in Blood. J Clin Oncol. 27: 2496-502, 2009.PubMed
Jones, R. J., Gocke, C. D., Kasamon, Y. L., Miller, C. B., Perkins, B., Barber, J. P., Vala, M. S., Gerber, J. M. Gellert, L. L., Siedner, M., Lemas, M. V., Brennan, S., Ambinder, R. F.
, Matsui, W. Circulating clonotypic B cells in classical Hodgkin's lymphoma. Blood .113:5920-6, 2009.PubMed
Kasamon, Y. L., Wahl, R. L., Ziessman, H. A., Blackford, A. L., Goodman, S. N., Fidyk, C. A., Rogers, K. M., Bolanos-Meade, J., Borowitz, M. J, Ambinder, R.F.
, Jones, R. J., Swinnen, L. J. Phase II study of risk-adapted therapy of newly diagnosed, aggressive non-Hodgkin lymphoma based on midtreatment FDG-PET scanning. Biol Blood Marrow Transplant. 15: 242-248, 2009.PubMed
Fu, D., Tanhehco Y., Chen J., Foss CA., Fos JF., Chong J, Hobbs RF., Fukayama M., Sgouros G., Kowalski, J., Pomper, MG., Ambinder, RF.
, Bortezomib-induced enzyme-targeted radiotherapy in herpesvirus-associated tumors. Nat Med. 14:1118-22, 2008.PubMed
Fu, D. X., Tanhehco, Y. C. Chen, J. Foss, C. A. Fox, J. J. Lemas, V.Chong, J. M., Ambinder, R.F.
,Pomper, M. G. Virus-associated tumor imaging by induction of viral gene expression Clin Cancer Res. 13: 1453-8, 2007.PubMed
Keegan TH, Glaser SL, Clarke CA, Dorfman RF, Mann RB, DiGiuseppe JA, Chang ET, Ambinder, RF
; Body Size, Physical Activity, and Risk of Hodgkin's Lymphoma in Women. Cancer Epidemiology Biomarkers & Prevention 15:1095-1101, 2006.PubMed
Keegan, TH. Glaser, SL. Clarke, CA. Gulley, ML. Craig, FE. Digiuseppe, J.A. Dorfman, RF. Mann, RB.; Ambinder, RF.
; Epstein Barr virus as a marker of survival after Hodgkin's lymphoma: a population based study. J Clin Oncol. 23: 7604 13, 2005.PubMed
; Lan L. Mononucleosis in the laboratory. J Infect Dis.192 : 1503 1504, 2005.PubMed
Glaser SL, Keegan THM, Clarke CA, Trinh M, Dorfman RF , Mann RB, DiGiuseppe JA, Ambinder RF
; Exposure to childhood infections and risk of Epstein-Barr virus-defined Hodgkin’s lymphoma in women. Int J Cancer 115 : 599-605, 2005.PubMed
Chan AT, Tao Q, Robertson KD, Flinn IW, Mann RB, Klencke B, Kwan WH, Leung TW, Johnson PJ, Ambinder RF
; Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors in patients. J Clin Oncol: 22: 1373-81, 2004.PubMed
Glaser SL, Clarke CA, Gulley ML, Craig FE, DiGiuseppe JA, Dorfman RF, Mann RB, Ambinder RF.
; Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area. Cancer, 98:300-309, 2003.Pubmed