Robert  Yarchoan, M.D.
Robert Yarchoan, M.D.
Chief
Senior Investigator
Head, Retroviral Diseases Section
Director, Office of HIV and AIDS Malignancy, NCI

Center for Cancer Research
National Cancer Institute

Building 10, Room 6N106
Bethesda, MD 20892-1868
301-496-0328

Dr. Yarchoan has played a major role in developing the first successful drugs to treat HIV infection. More recently, his research is focused on the study of and development of treatment for HIV-associated malignancies, with a focus on those caused by Kaposi sarcoma-associated herpesvirus (KSHV). As Chief, Dr. Yarchoan oversees the Branch’s clinical/translational research program, which encompasses the development of novel therapies for HIV infection, the study of the viral causes of HIV-associated malignancies, and the development of novel therapies for HIV-associated malignancies.

Areas of Expertise
1) HIV-associated malignancies 2) Kaposi-sarcoma-associated herpesvirus (KSHV)/ human herpesvirus-8 (HHV-8) 3) HIV 4) Kaposi sarcoma 5) viral oncogenesis 6) hypoxia inducible factors

The research in the Retroviral Diseases Section includes a laboratory and clinical component, and there is substantial integration and cross-fertilization between these components.

Pathogenesis of Virus-Associated Tumors

One main area of research focus is the study of the pathogenesis of viral-associated tumors, especially those associated with Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). KSHV is the causal agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). We observed that KS preferentially develops in the feet and other areas of the body with a poor vascular supply. In studying this phenomenon, we discovered that KSHV is induced by hypoxia to undergo lytic replication and to produce factors with direct or indirect angiogenic activity. In further exploring this observation, we found that the genome of KSHV encodes for several hypoxia response elements (HRE) that respond to hypoxia-induced factor (HIF). We are currently exploring the differential upregulation of various KSHV genes by hypoxia and how this may influence the pathogenesis of KSHV-induced tumors. In an extension of this work, we are also exploring the differential upregulation of various cellular genes by two different HIFs, HIF-1 and HIF-2. We are also exploring how LANA interacts with HIF in affecting KSHV and cellular genes, and other factors that can upregulate certain KSHV genes. In particular, we are exploring how spliced X-box protein (XBP) can directly upregulate KSHV viral interleukin-6 (vIL-6); this may play an important role in the pathogenesis of MCD. In addition, we are exploring how KSHV latency-associated nuclear antigen (LANA) is affected by oxidative stress, and in particular its cleavage by cellular caspases.

We are also studying the pathogenesis of KSHV-associated MCD and related disorders. As part of of this effort, we are studying the cytokine dysregulation in MCD and its association with symptomatology.  We have also recently identified a new MCD-like syndrome caused by KSHV in which patients have inflammatory symptoms similar to those of MCD, have increase KSHV viral IL-6 levels, but do not have pathological findings of MCD. This syndrome, which we are calling KSHV-associated inflammatory cytokine syndrome (KICS), may account for otherwise unexplained fevers in certain patients with HIV and KSHV co-infection.

Development of Novel Therapies for AIDS-Related Malignancies and HIV Infection

Another main focus of our research is the development of novel therapies for HIV-related malignancies and HIV infection. This work is informed by the pathogenesis-associated work described above. One area of principal interest is Kaposi's sarcoma (KS). Our group is exploring approaches that are based on an understanding of the pathogenesis of this disease but that do not involve the use of cytotoxic chemotherapy. There is evidence that production of virally encoded and cellular angiogenesis-inducing factors by KSHV-infected cells is important in the pathogenesis of KS, and this makes antiangiogenesis approaches attractive to consider. Our group recently showed that bevacizumab (humanized anti-VEGF antibody) has activity in KS, and we are now studying the combination of this with liposomal doxorubicin and also pomalidomide, an analog of thalidomide. We recently initiated protocols to explore targeted therapy for KSHV-MCD and HIV-associated primary central nervous system lymphoma.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Microbiology and Infectious Diseases, Virology
Selected Recent Publications
  1. Uldrick TS, Polizzotto MN, Aleman KA, Wyvill KM, Marshall V, Whitby D, Wang V, Pittaluga S, O’Mahony D, Steinberg SM, Little RF, Yarchoan R.
    Blood. 124: 3544-52, 2014. [ Journal Article ]
  2. Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, Marshall V, Pittaluga S, O’Mahony D, Whitby D, Tosato G, Steuinberg SM, Little RF, Yarchoan R.
    Blood. 122(26): 4189-98, 2013. [ Journal Article ]
  3. Davis DA, Soule E, Davidoff K, Daniels S, Naiman N, Yarchoan R.
    Antimicrob. Agents Chemother. 56(7): 3620-8, 2012. [ Journal Article ]
  4. Uldrick TS, Wyvill KM, Kumar P, Bernstein W, O’Mahony DO, Polizzotto MN, Steinberg SM, Pittaluga S, Little RF, Yarchoan R.
    J. Clin. Oncol. 30(13): 1476-83, 2012. [ Journal Article ]
  5. Veeranna RP, Haque M, Davis DA, Yang M, Yarchoan R
    J. Virol. 86(2): 1097-1108, 2012. [ Journal Article ]

Dr. Robert Yarchoan received his B.A. from Amherst College with a major in biophysics and his M.D. from the University of Pennsylvania. He trained in internal medicine at the University of Minnesota and Immunology in the Metabolism Branch, NCI. He then joined the laboratory of Dr. Samuel Broder, where he played a major role in the development of the first effective therapies for HIV infection, including zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC). In particular, he led the first clinical trials of these drugs, was a co-inventor of didanosine and zalcitabine as AIDS therapies, and led initial studies of combination anti-HIV therapy. He was a Section Chief in the Medicine Branch from 1991 to 1996 and was named chief of the newly formed HIV and AIDS Malignancy Branch in 1996. Since that time, he has focused much of his research on AIDS-related malignancies, especially tumors caused by Kaposi's sarcoma-associated herpesvirus (KSHV).

Among other honors, he has been awarded the Assistant Secretary for Health Award and the U.S. Public Health Service Outstanding Service Medal, has been inducted as a Fellow of the American Association for the Advancement of Science (AAAS), and is a member of the American Society for Clinical Investigation. In December, 2006, he was a recipient of the first NIH World AIDS Day Award, and in November, 2007, he received the NCI HIV/AIDS Research Excellence Award along with Drs. Samuel Broder, Robert C. Gallo, and Hiroaki Mitsuya. In May, 2013, he received an honorary degree from Amherst College, and in May 2014, he was awarded the Abbott Award in Clinical and Diagnostic Immunology by the American Society for Microbiology.

In December 2007, Dr. Yarchoan also was appointed as the first Director of the NCI Office of HIV and AIDS Malignancy (OHAM). This office, which is in the Office of the Director, NCI, coordinates and prioritizes the HIV/AIDS and AIDS malignancy research portfolio throughout the NCI.

Position Number of Positions Contact E-mail Contact Name Contact Phone
Senior Clinician 1

huquej@mail.nih.gov

Janice Huque, Executive Secretary n/a
Name Position
Karen O. Aleman R.N. Clinical Research Nurse
Holda Awah Anagho Postbaccalaureate Fellow
David A. Davis Ph.D. Staff Scientist
Prabha Shrestha Ph.D. Postdoctoral Fellow (CRTA)
Shewit Tekeste Ph.D. Postdoctoral Fellow (CRTA)
Thomas S. Uldrick M.D. Staff Clinician
Coralie Viollet-Djelassi M.Sc. Predoctoral Fellow
Victoria Wang M.D. Research Biologist
Kathleen Wyvill R.N. Senior Clinical Research Nurse

Summary

Dr. Yarchoan has played a major role in developing the first successful drugs to treat HIV infection. More recently, his research is focused on the study of and development of treatment for HIV-associated malignancies, with a focus on those caused by Kaposi sarcoma-associated herpesvirus (KSHV). As Chief, Dr. Yarchoan oversees the Branch’s clinical/translational research program, which encompasses the development of novel therapies for HIV infection, the study of the viral causes of HIV-associated malignancies, and the development of novel therapies for HIV-associated malignancies.

Areas of Expertise
1) HIV-associated malignancies 2) Kaposi-sarcoma-associated herpesvirus (KSHV)/ human herpesvirus-8 (HHV-8) 3) HIV 4) Kaposi sarcoma 5) viral oncogenesis 6) hypoxia inducible factors

Clinical Trials

Research

The research in the Retroviral Diseases Section includes a laboratory and clinical component, and there is substantial integration and cross-fertilization between these components.

Pathogenesis of Virus-Associated Tumors

One main area of research focus is the study of the pathogenesis of viral-associated tumors, especially those associated with Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). KSHV is the causal agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). We observed that KS preferentially develops in the feet and other areas of the body with a poor vascular supply. In studying this phenomenon, we discovered that KSHV is induced by hypoxia to undergo lytic replication and to produce factors with direct or indirect angiogenic activity. In further exploring this observation, we found that the genome of KSHV encodes for several hypoxia response elements (HRE) that respond to hypoxia-induced factor (HIF). We are currently exploring the differential upregulation of various KSHV genes by hypoxia and how this may influence the pathogenesis of KSHV-induced tumors. In an extension of this work, we are also exploring the differential upregulation of various cellular genes by two different HIFs, HIF-1 and HIF-2. We are also exploring how LANA interacts with HIF in affecting KSHV and cellular genes, and other factors that can upregulate certain KSHV genes. In particular, we are exploring how spliced X-box protein (XBP) can directly upregulate KSHV viral interleukin-6 (vIL-6); this may play an important role in the pathogenesis of MCD. In addition, we are exploring how KSHV latency-associated nuclear antigen (LANA) is affected by oxidative stress, and in particular its cleavage by cellular caspases.

We are also studying the pathogenesis of KSHV-associated MCD and related disorders. As part of of this effort, we are studying the cytokine dysregulation in MCD and its association with symptomatology.  We have also recently identified a new MCD-like syndrome caused by KSHV in which patients have inflammatory symptoms similar to those of MCD, have increase KSHV viral IL-6 levels, but do not have pathological findings of MCD. This syndrome, which we are calling KSHV-associated inflammatory cytokine syndrome (KICS), may account for otherwise unexplained fevers in certain patients with HIV and KSHV co-infection.

Development of Novel Therapies for AIDS-Related Malignancies and HIV Infection

Another main focus of our research is the development of novel therapies for HIV-related malignancies and HIV infection. This work is informed by the pathogenesis-associated work described above. One area of principal interest is Kaposi's sarcoma (KS). Our group is exploring approaches that are based on an understanding of the pathogenesis of this disease but that do not involve the use of cytotoxic chemotherapy. There is evidence that production of virally encoded and cellular angiogenesis-inducing factors by KSHV-infected cells is important in the pathogenesis of KS, and this makes antiangiogenesis approaches attractive to consider. Our group recently showed that bevacizumab (humanized anti-VEGF antibody) has activity in KS, and we are now studying the combination of this with liposomal doxorubicin and also pomalidomide, an analog of thalidomide. We recently initiated protocols to explore targeted therapy for KSHV-MCD and HIV-associated primary central nervous system lymphoma.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Microbiology and Infectious Diseases, Virology

Publications

Selected Recent Publications
  1. Uldrick TS, Polizzotto MN, Aleman KA, Wyvill KM, Marshall V, Whitby D, Wang V, Pittaluga S, O’Mahony D, Steinberg SM, Little RF, Yarchoan R.
    Blood. 124: 3544-52, 2014. [ Journal Article ]
  2. Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, Marshall V, Pittaluga S, O’Mahony D, Whitby D, Tosato G, Steuinberg SM, Little RF, Yarchoan R.
    Blood. 122(26): 4189-98, 2013. [ Journal Article ]
  3. Davis DA, Soule E, Davidoff K, Daniels S, Naiman N, Yarchoan R.
    Antimicrob. Agents Chemother. 56(7): 3620-8, 2012. [ Journal Article ]
  4. Uldrick TS, Wyvill KM, Kumar P, Bernstein W, O’Mahony DO, Polizzotto MN, Steinberg SM, Pittaluga S, Little RF, Yarchoan R.
    J. Clin. Oncol. 30(13): 1476-83, 2012. [ Journal Article ]
  5. Veeranna RP, Haque M, Davis DA, Yang M, Yarchoan R
    J. Virol. 86(2): 1097-1108, 2012. [ Journal Article ]

Biography

Dr. Robert Yarchoan received his B.A. from Amherst College with a major in biophysics and his M.D. from the University of Pennsylvania. He trained in internal medicine at the University of Minnesota and Immunology in the Metabolism Branch, NCI. He then joined the laboratory of Dr. Samuel Broder, where he played a major role in the development of the first effective therapies for HIV infection, including zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC). In particular, he led the first clinical trials of these drugs, was a co-inventor of didanosine and zalcitabine as AIDS therapies, and led initial studies of combination anti-HIV therapy. He was a Section Chief in the Medicine Branch from 1991 to 1996 and was named chief of the newly formed HIV and AIDS Malignancy Branch in 1996. Since that time, he has focused much of his research on AIDS-related malignancies, especially tumors caused by Kaposi's sarcoma-associated herpesvirus (KSHV).

Among other honors, he has been awarded the Assistant Secretary for Health Award and the U.S. Public Health Service Outstanding Service Medal, has been inducted as a Fellow of the American Association for the Advancement of Science (AAAS), and is a member of the American Society for Clinical Investigation. In December, 2006, he was a recipient of the first NIH World AIDS Day Award, and in November, 2007, he received the NCI HIV/AIDS Research Excellence Award along with Drs. Samuel Broder, Robert C. Gallo, and Hiroaki Mitsuya. In May, 2013, he received an honorary degree from Amherst College, and in May 2014, he was awarded the Abbott Award in Clinical and Diagnostic Immunology by the American Society for Microbiology.

In December 2007, Dr. Yarchoan also was appointed as the first Director of the NCI Office of HIV and AIDS Malignancy (OHAM). This office, which is in the Office of the Director, NCI, coordinates and prioritizes the HIV/AIDS and AIDS malignancy research portfolio throughout the NCI.

Positions

Position Number of Positions Contact E-mail Contact Name Contact Phone
Senior Clinician 1

huquej@mail.nih.gov

Janice Huque, Executive Secretary n/a

Team

Name Position
Karen O. Aleman R.N. Clinical Research Nurse
Holda Awah Anagho Postbaccalaureate Fellow
David A. Davis Ph.D. Staff Scientist
Prabha Shrestha Ph.D. Postdoctoral Fellow (CRTA)
Shewit Tekeste Ph.D. Postdoctoral Fellow (CRTA)
Thomas S. Uldrick M.D. Staff Clinician
Coralie Viollet-Djelassi M.Sc. Predoctoral Fellow
Victoria Wang M.D. Research Biologist
Kathleen Wyvill R.N. Senior Clinical Research Nurse