Skip to main content
SpringerLink
Log in

Targeted Therapy for Kaposi Sarcoma

  • Leading Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Kaposi sarcoma (KS) occurs as a result of Kaposi sarcoma-associated herpesvirus (KSHV) infection, typically in the context of one of several immunodeficient states. In the US, patients with KS may either be co-infected with HIV or receiving immunosuppressant therapy following solid-organ transplantation. Systemic treatment of KS has traditionally involved one of several chemotherapeutic agents administered either in combination or as single agents, which typically provide reasonable response rates and short-term control. However, recurrence of KS is common, and progression-free intervals are under 1 year. For these reasons, new therapies have been sought and with the elucidation of novel pathogenic mechanisms of KS infection, rational therapeutic targets have been identified. These include KSHV replication, restoration of immune competence, and signal transduction pathways utilized by KSHV in the propagation of KS. This review focuses on these emerging targets in the treatment of patients with KS and also highlights important clinicopathologic characteristics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I

Similar content being viewed by others

References

  1. Cesarman E, Chang Y, Moore PS, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995 May 4; 332(18): 1186–91

    Article  PubMed  CAS  Google Scholar 

  2. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 1994 Dec 16; 266(5192): 1865–9

    Article  PubMed  CAS  Google Scholar 

  3. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 1995 Aug 15; 86(4): 1276–80

    PubMed  CAS  Google Scholar 

  4. Aversa SM, Cattelan AM, Salvagno L, et al. Treatments of AIDS-related Kaposi’s sarcoma. Crit Rev Oncol Hematol 2005 Mar; 53(3): 253–65

    Article  PubMed  Google Scholar 

  5. Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, et al. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol 2007 Feb; 8(2): 167–76

    Article  PubMed  Google Scholar 

  6. Guttman-Yassky E, Dubnov J, Kra-Oz Z, et al. Classic Kaposi sarcoma: which KSHV-seropositive individuals are at risk? Cancer 2006 Jan 15; 106(2): 413–9

    Article  PubMed  Google Scholar 

  7. Mitxelena J, Gomez-Ullate P, Aguirre A, et al. Kaposi’s sarcoma in renal transplant patients: experience at the Cruces Hospital in Bilbao. Int J Dermatol 2003 Jan; 42(1): 18–22

    Article  PubMed  Google Scholar 

  8. Krown SE. Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol 2004 Feb 1; 22(3): 399–402

    Article  PubMed  Google Scholar 

  9. Moray G, Basaran O, Yagmurdur MC, et al. Immunosuppressive therapy and Kaposi’s sarcoma after kidney transplantation. Transplant Proc 2004 Jan-Feb; 36(1): 168–70

    Article  PubMed  CAS  Google Scholar 

  10. National Cancer Institute. SEER cancer statistics review 1975-2004 [online]. Available from URL: http://seer.cancer.gov/csr/1975_2004/results_merged/sect_10_kaposi_sarcoma.pdf [Accessed 2008 Feb 6]

  11. Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi’s sarcoma: results of a randomized phase III clinical trial. J Clin Oncol 1998 Jul; 16(7): 2445–51

    PubMed  CAS  Google Scholar 

  12. Stewart S, Jablonowski H, Goebel FD, et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi’s sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998 Feb; 16(2): 683–91

    PubMed  CAS  Google Scholar 

  13. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin Oncol 1996 Aug; 14(8): 2353–64

    PubMed  CAS  Google Scholar 

  14. Welles L, Saville MW, Lietzau J, et al. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 1998 Mar; 16(3): 1112–21

    PubMed  CAS  Google Scholar 

  15. Pantanowitz L, Dezube BJ, Pinkus GS, et al. Histological characterization of regression in acquired immunodeficiency syndrome-related Kaposi’s sarcoma. J Cutan Pathol 2004 Jan; 31(1): 26–34

    Article  PubMed  Google Scholar 

  16. Pantanowitz L, Fruh K, Marconi S, et al. Pathology of rituximab-induced Kaposi sarcoma flare. BMC Clin Pathol 2008; 8: 7

    Article  PubMed  Google Scholar 

  17. Krown SE, Metroka C, Wernz JC. Kaposi’s sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 1989; 7(9): 1201–7

    PubMed  CAS  Google Scholar 

  18. Ganem D. KSHV infection and the pathogenesis of Kaposi’s sarcoma. Annu Rev Pathol 2006; 1: 273–96

    Article  PubMed  CAS  Google Scholar 

  19. Casper C. Defining a role for antiviral drugs in the treatment of persons with HHV-8 infection. Herpes 2006 Aug; 13(2): 42–7

    PubMed  CAS  Google Scholar 

  20. Grundhoff A, Ganem D. Inefficient establishment of KSHV latency suggests an additional role for continued lytic replication in Kaposi sarcoma pathogenesis. J Clin Invest 2004 Jan; 113(1): 124–36

    PubMed  CAS  Google Scholar 

  21. Katano H, Sato Y, Kurata T, et al. Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi’s sarcoma, and multicentric Castleman’s disease. Virology 2000 Apr 10; 269(2): 335–44

    Article  PubMed  CAS  Google Scholar 

  22. Kedes DH, Ganem D. Sensitivity of Kaposi’s sarcoma-associated herpesvirus replication to antiviral drugs: implications for potential therapy. J Clin Invest 1997 May 1; 99(9): 2082–6

    Article  PubMed  CAS  Google Scholar 

  23. Casper C, Krantz EM, Corey L, et al. Valganciclovir for suppression of human herpesvirus-8 replication: a randomized, double-blind, placebo-controlled, crossover trial. J Infect Dis 2008 Jul 1; 198(1): 23–30

    Article  PubMed  CAS  Google Scholar 

  24. Glesby MJ, Hoover DR, Weng S, et al. Use of antiherpes drugs and the risk of Kaposi’s sarcoma: data from the Multicenter AIDS Cohort Study. J Infect Dis 1996 Jun; 173(6): 1477–80

    Article  PubMed  CAS  Google Scholar 

  25. Simonart T, Noel JC, De Dobbeleer G, et al. Treatment of classical Kaposi’s sarcoma with intralesional injections of cidofovir: report of a case. J Medical Virol 1998 Jul; 55(3): 215–8

    Article  CAS  Google Scholar 

  26. Little RF, Merced-Galindez F, Staskus K, et al. A pilot study of cidofovir in patients with Kaposi sarcoma. J Infect Dis 2003 Jan 1; 187(1): 149–53

    Article  PubMed  CAS  Google Scholar 

  27. Casper C, Nichols WG, Huang ML, et al. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 2004 Mar 1; 103(5): 1632–4

    Article  PubMed  CAS  Google Scholar 

  28. Braza JM, Sullivan RJ, Bhargava P, et al. Images in HIV/AIDS: pericardial primary effusion lymphoma. AIDS Read 2007 May; 17(5): 250–2

    PubMed  Google Scholar 

  29. Hocqueloux L, Agbalika F, Oksenhendler E, et al. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 2001 Jan 26; 15(2): 280–2

    Article  PubMed  CAS  Google Scholar 

  30. Shaw RN, Arbiser JL, Offermann MK. Valproic acid induces human herpesvirus 8 lytic gene expression in BCBL-1 cells. AIDS 2000 May 5; 14(7): 899–902

    Article  PubMed  CAS  Google Scholar 

  31. Klass CM, Krug LT, Pozharskaya VP, et al. The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production. Blood 2005 May 15; 105(10): 4028–34

    Article  PubMed  CAS  Google Scholar 

  32. Lechowitz M, Lee J, Dittmer D, et al. A pilot trial of valproic acid in patients with Kaposi’s sarcoma: a multi-center trial of the AIDS Malignancy Consortium [abstract no. 2279]. Blood 2007; 110 (ASH Annual Meeting Abstracts) [online]. Available from URL: http://abstracts.hematologylibrary.org/cgi/content/abstract/110/11/2279 [Accessed 2009 May 15]

  33. Sparano JA, Anand K, Desai J, et al. Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. J Acquir Immune Defic Syndr 1999 Aug 1; 21Suppl. 1: S18–22

    PubMed  CAS  Google Scholar 

  34. Aboulafia DM. Regression of acquired immunodeficiency syndrome-related pulmonary Kaposi’s sarcoma after highly active antiretroviral therapy. Mayo Clin Proc 1998 May; 73(5): 439–43

    Article  PubMed  CAS  Google Scholar 

  35. Casper C, Wald A. The use of antiviral drugs in the prevention and treatment of Kaposi sarcoma, multicentric Castleman disease and primary effusion lymphoma. Curr Top Microbiol Immunol 2007; 312: 289–307

    Article  PubMed  CAS  Google Scholar 

  36. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renaltransplant recipients. N Engl J Med 2005 Mar 31; 352(13): 1317–23

    Article  PubMed  CAS  Google Scholar 

  37. Sullivan R, Dezube BJ, Koon HB. Signal transduction targets in Kaposi’s sarcoma. Curr Opin Oncol 2006 Sep; 18(5): 456–62

    Article  PubMed  CAS  Google Scholar 

  38. Arvanitakis L, Geras-Raaka E, Varma A, et al. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997 Jan 23; 385(6614): 347–50

    Article  PubMed  CAS  Google Scholar 

  39. Bais C, Santomasso B, Coso O, et al. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998 Jan 1; 391(6662): 86–9

    Article  PubMed  CAS  Google Scholar 

  40. Dadke D, Fryer BH, Golemis EA, et al. Activation of p21-activated kinase 1-nuclear factor kappaB signaling by Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor during cellular transformation. Cancer Res 2003 Dec 15; 63(24): 8837–47

    PubMed  CAS  Google Scholar 

  41. Geras-Raaka E, Arvanitakis L, Bais C, et al. Inhibition of constitutive signaling of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. J Exp Med 1998 Mar 2; 187(5): 801–6

    Article  PubMed  CAS  Google Scholar 

  42. Montaner S, Sodhi A, Ramsdell AK, et al. The Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi’s sarcoma. Cancer Res 2006 Jan 1; 66(1): 168–74

    Article  PubMed  CAS  Google Scholar 

  43. Couty JP, Geras-Raaka E, Weksler BB, et al. Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. J Biol Chem 2001 Sep 7; 276(36): 33805–11

    Article  PubMed  CAS  Google Scholar 

  44. Sodhi A, Chaisuparat R, Hu J, et al. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 2006 Aug; 10(2): 133–43

    Article  PubMed  CAS  Google Scholar 

  45. Montaner S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi’s sarcoma. Cell Cycle 2007 Feb 1; 6(4): 438–43

    Article  PubMed  CAS  Google Scholar 

  46. AIDS Associated Malignancies Clinical Trials Consortium; National Cancer Institute. Sirolimus in treating patients with HIV-related Kaposi’s sarcoma [clinicaltrials.gov identifier no. NCT00450320; online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00450320?id=NCT00450320&rank=1 [Accessed 2009 Apr 16]

  47. Cho D, Signoretti S, Regan M, et al. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res 2007 Jan 15; 13 (2 Pt 2): 758s–763s

    Article  PubMed  CAS  Google Scholar 

  48. Skobe M, Brown LF, Tognazzi K, et al. Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi’s sarcoma. J Invest Dermatol 1999 Dec; 113(6): 1047–53

    Article  PubMed  CAS  Google Scholar 

  49. Marchio S, Primo L, Pagano M, et al. Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi’s sarcoma cells. J Biol Chem 1999 Sep 24; 274(39): 27617–22

    Article  PubMed  CAS  Google Scholar 

  50. Sodhi A, Montaner S, Patel V, et al. The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res 2000 Sep 1; 60(17): 4873–80

    PubMed  CAS  Google Scholar 

  51. Samaniego F, Young D, Grimes C, et al. Vascular endothelial growth factor and Kaposi’s sarcoma cells in human skin grafts. Cell Growth Differ 2002 Aug; 13(8): 387–95

    PubMed  CAS  Google Scholar 

  52. Ford PW, Hamden KE, Whitman AG, et al. Vascular endothelial growth factor augments human herpesvirus-8 (HHV-8/KSHV) infection. Cancer Biol Ther 2004 Sep; 3(9): 876–81

    Article  PubMed  CAS  Google Scholar 

  53. Bais C, Van Geelen A, Eroles P, et al. Kaposi’s sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR. Cancer Cell 2003 Feb; 3(2): 131–43

    Article  PubMed  CAS  Google Scholar 

  54. National Cancer Institute. Bevacizumab in treating patients with Kaposi’s sarcoma [clinicaltrials.gov identifier no. NCT00058136; online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00058136?id=nct00058136&rank=1 [Accessed 2009 Apr 16]

  55. Case Comprehensive Cancer Center; National Cancer Institute. Sunitinib malate in treating East African patients with Kaposi sarcoma [clinical trials.gov identifier no. NCT00521092; online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00521092?id=nct00521092&rank=1 [Accessed 2009 Apr 16]

  56. National Cancer Institute. Sorafenib in treating patients with Kaposi’s sarcoma [clinicaltrials.gov identifier no. NCT00304122; online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00304122?id=nct00304122&rank=1 [Accessed 2009 Apr 16]

  57. Yarchoan R, Pluda JM, Wyvill KM, et al. Treatment of AIDS-related Kaposi’s sarcoma with interleukin-12: rationale and preliminary evidence of clinical activity. Crit Rev Immunol 2007; 27(5): 401–14

    Article  PubMed  CAS  Google Scholar 

  58. Sgadari C, Angiolillo AL, Tosato G. Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 1996 May 1; 87(9): 3877–82

    PubMed  CAS  Google Scholar 

  59. Geras-Raaka E, Varma A, Ho H, et al. Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. J Exp Med 1998 Jul 20; 188(2): 405–8

    Article  PubMed  CAS  Google Scholar 

  60. Little RF, Pluda JM, Wyvill KM, et al. Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma. Blood 2006 Jun 15; 107(12): 4650–7

    Article  PubMed  CAS  Google Scholar 

  61. Little RF, Aleman K, Kumar P, et al. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood 2007 Dec 15; 110(13): 4165–71

    Article  PubMed  CAS  Google Scholar 

  62. Pistritto G, Ventura L, Mores N, et al. Regulation of PDGF-B and PDGF receptor expression in the pathogenesis of Kaposi’s sarcoma in AIDS. Antibiot Chemother 1994; 46: 73–87

    PubMed  CAS  Google Scholar 

  63. Sturzl M, Roth WK, Brockmeyer NH, et al. Expression of platelet-derived growth factor and its receptor in AIDS-related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor maintenance. Proc Natl Acad Sci U S A 1992 Aug 1; 89(15): 7046–50

    Article  PubMed  CAS  Google Scholar 

  64. Werner S, Hofschneider PH, Heldin CH, et al. Cultured Kaposi’s sarcoma-derived cells express functional PDGF A-type and B-type receptors. Exp Cell Res 1990 Mar; 187(1): 98–103

    Article  PubMed  CAS  Google Scholar 

  65. Roth WK, Werner S, Schirren CG, et al. Depletion of PDGF from serum inhibits growth of AIDS-related and sporadic Kaposi’s sarcoma cells in culture. Oncogene 1989 Apr; 4(4): 483–7

    PubMed  CAS  Google Scholar 

  66. Moses AV, Jarvis MA, Raggo C, et al. Kaposi’s sarcoma-associated herpes-virus-induced upregulation of the c-kit proto-oncogene, as identified by gene expression profiling, is essential for the transformation of endothelial cells. J Virol 2002 Aug; 76(16): 8383–99

    Article  PubMed  CAS  Google Scholar 

  67. Koon HB, Bubley GJ, Pantanowitz L, et al. Imatinib-induced regression of AIDS-related Kaposi’s sarcoma. J Clin Oncol 2005 Feb 10; 23(5): 982–9

    Article  PubMed  CAS  Google Scholar 

  68. Benelli R, Adatia R, Ensoli B, et al. Inhibition of AIDS-Kaposi’s sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. Oncol Res 1994; 6(6): 251–7

    PubMed  CAS  Google Scholar 

  69. Blankaert D, Simonart T, Van Vooren JP, et al. Constitutive release of metalloproteinase-9 (92-kd type IV collagenase) by Kaposi’s sarcoma cells. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1; 18(3): 203–9

    Article  PubMed  CAS  Google Scholar 

  70. Cianfrocca M, Cooley TP, Lee JY, et al. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS Malignancy Consortium study. J Clin Oncol 2002 Jan 1; 20(1): 153–9

    Article  PubMed  CAS  Google Scholar 

  71. Dezube BJ, Krown SE, Lee JY, et al. Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi’s sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol 2006 Mar 20; 24(9): 1389–94

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr Bruce Dezube is supported by the AIDS Malignancy Consortium/National Cancer Institute. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Ryan J. Sullivan &  Bruce J. Dezube

  2. Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts, USA

    Liron Pantanowitz

Authors
  1. Ryan J. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liron Pantanowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce J. Dezube
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce J. Dezube.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sullivan, R.J., Pantanowitz, L. & Dezube, B.J. Targeted Therapy for Kaposi Sarcoma. BioDrugs 23, 69–75 (2009). https://doi.org/10.2165/00063030-200923020-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200923020-00001

Keywords

Search

Navigation