DAB389EGF fusion protein therapy of refractory glioblastoma multiforme.
Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.
Cohen
Kimberley A
KA
Department of Medicine and Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Liu
TieFu
T
Bissonette
Reid
R
Puri
Raj K
RK
Frankel
Arthur E
AE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor