Robert Yarchoan, MD
Entry Id: TP-60

Overview
The HIV and AIDS Malignancy Branch (HAMB) in the Center for Cancer Research of the National Cancer Institute conducts translational research on AIDS-related malignancies and HIV infection. Investigators engage in basic laboratory research, preclinical studies, and clinical trials. The clinical trials are aimed at developing novel therapies for AIDS-related malignancies and HIV infection and on understanding the effects of therapies on disease pathogenesis.

Structure of the Clinical Training Program
This is a program primarily aimed at physicians who have completed their training in Internal Medicine (or Pediatrics) as well as their initial subspecialty clinical training in Oncology or Hematology and are interested in obtaining additional translational or clinical training in AIDS malignancies. Physicians in HAMB may choose to learn how to conduct high-quality, translational clinical studies. Current areas of focus in clinical research include: novel therapies for KSHV-related tumors, including Kaposi’s sarcoma and multicentric Castleman’s disease; studies of certain AIDS-related lymphomas; and novel approaches to anti-HIV therapy. Clinical trials involving patients with HIV-related lymphomas are currently being conducted in collaboration with other NCI investigators. Physicians in HAMB may also choose to participate in basic laboratory research. Areas of laboratory research interest in the Branch at present include: studies of the biochemistry of HIV protease; studies of the effect of HIV on target-cell gene expression; studies of the regulation of splicing in human papilloma virus and Kaposi's sarcoma-associated herpesvirus (KSHV), and studies of the role of KSHV in the pathogenesis of Kaposi's sarcoma and other KSHV-associated tumors.

Applicants interested in obtaining training in these areas may apply directly to the HIV and AIDS Malignancy Branch. It is anticipated that most physicians interested in participating in clinical research in the branch will have ACGME Accredited Board Certification in either Pediatrics or Internal Medicine plus relevant subspecialty training (usually, but not limited to, Oncology or Hematology). While this is not an absolute requirement, exceptions will be made only for candidates who have a strong academic background in relevant areas. Finally, physicians with a strong laboratory research background but without the above credentials may apply to individual laboratories in HAMB for training in laboratory research.

Applicants interested in both qualifying for subspecialty certification in Medical or Pediatric Oncology and in obtaining research training in AIDS or AIDS malignancies or AIDS may apply to those relevant programs in the National Cancer Institute. As noted in the descriptions of those programs, the Fellows have the option of spending their second and third years in various laboratories and branches of the National Cancer Institute, including the HAMB.

Physicians doing AIDS research in HAMB may be eligible for participation in the NIH loan repayment program for AIDS research.

The NIH Clinical Center provides a stimulating environment to learn translational research. Many significant advances in AIDS and AIDS malignancy research have been made at the NIH. There are numerous research seminars and lectures given on a daily basis throughout the NIH and open to the NIH community. Formal course work in the sciences is available through the NIH Foundation for the Advancement of Education of the Sciences.

• Robert Yarchoan, M.D. Research interests include development of therapy for Kaposi's sarcoma using anti-angiogenesis and other approaches, a study of the mechanisms by which KSHV causes Kaposi's sarcoma and other diseases, immunologic/vaccination approaches to the therapy of HIV infection, and studies of HIV protease. Along with Drs. Hiroaki Mitsuya and Samuel Broder, developed some of the initial anti-HIV drugs including didanosine and zalcitabine.
• Hiroaki Mitsuya, M.D., Ph.D. An immunologist and virologist who, along with Drs. Yarchoan and Samuel Broder, developed some of the early anti-HIV drugs and has a continued interest in drug resistance to HIv drugs and developing novel therapies.
• Zhi-Ming Zheng, M.D., Ph.D. A virologist with research interests focusing on the regulation of splicing in human papilloma virus and KSHV.
• Members of the Branch have long-standing collaborations with Giovanna Tosato, Denise Whitby, and Gene Shearer in the National Cancer Institute.

Examples of Papers and Chapters Authored by Program Faculty

• Little RF, Aleman K, Kumar P, Wyvill KM, Pluda JM, Read-Connole E, Wang V, Pittaluga S, Catanzaro AT, Steinberg SM, Yarchoan R. Phase II study of pegylated liposomal doxorubicin in combination with interleukin-12 for Kaposi’s sarcoma. Blood.  2007; FirstEdition.
• Koh Y, Matsumi S, Das D, Amano M, Davis DA, Li J, Laschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H. Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J. Biol. Chem.  2007; 282(39): 28709-28720.
• Majerciak V, Pripuzova N, McCoy JP, Gao S, Zheng Z. Targeted Disruption of KSHV ORF57 in the Viral Genome Is Detrimental for the Expression of ORF59, K8{alpha}, and K8.1 and the Production of Infectious Virus. J Virol.  81: 1062-1071, 2007.
• Davis DA, Singer KE, Reynolds IP, Haque M, Yarchoan R. Hypoxia enhances the phosphorylation and cytotoxicity of ganciclovir and zidovudine in KSHV-infected cells. Cancer Research.  2007; 67(14): 7003-10.
• Yarchoan, R. Clinical Implications of Basic Research: Key role for a viral lytic gene in Kaposi’s sarcoma. New Engl J. Med., 2006; 355(13): 1383-1385.
• Little RF, Pluda JM, Wyvill KM, Rodriguez-Chavez IR, Tosato G, Catanzaro AT, Steinberg SM, Yarchoan R. Activity of subcutaneous interleukin-12 in AIDS-related Kaposi’s sarcoma. Blood.  2006; 107(12): 4650-4657.
• Majerciak V, Yamanegi K, Zheng Z. Gene structure and expression of Kaposi's sarcoma-associated herpesvirus ORF56, 57, 58, and 59. J Virol.  80: 11968-11981, 2006.
• Yarchoan R, Tosato G, Little RF. Therapy Insight: AIDS-related malignancies - the influence of antiviral therapy on pathogenesis and management. Nature Clinical Practice Oncology. 2005; 2(8): 406-15.
• Tosato G, Little RF, Yarchoan R. EBV and KSHV-associated Malignancies. In: Young N, Gerson S, and High K, Eds., Clinical Hematology.  Elsevier Inc., Philadelphia, 2006; 610-624.
• Yarchoan R, Little RF. AIDS-related malignancies. In: DeVita VT Jr., Hellman S, and Rosenberg SA, Eds., Cancer: Principles and Practice of Oncology, 7th Edition.  Lippincott Williams and Wilkins, Philadelphia, 2005; 2247-2262.
• Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H. A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro. Antimicrob. Agents Chemother.  51: 2143-55, 2007.

For more information about the HIV and AIDS Malignancy Branch, please see http://ccr.cancer.gov/labs/lab.asp?labid=63.

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