Emerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: bidirectional translational science.
Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed.
Dezube
Bruce J
BJ
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. bdezube@bidmc.harvard.edu
Sullivan
Ryan
R
Koon
Henry B
HB
D017088:AIDS-Related Opportunistic Infections / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015497:HIV-1; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009389:Neovascularization, Pathologic; D014176:Protein Biosynthesis; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
D004791:Enzyme Inhibitors; C115448:G protein-coupled receptor, Human herpesvirus 8; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D019707:Receptors, Chemokine; D014764:Viral Proteins; D020782:Matrix Metalloproteinases