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DAB389EGF fusion protein therapy of refractory glioblastoma multiforme
Kimberley A Cohen1, TieFu Liu, Reid Bissonette
1Department of Medicine and Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Abstract:
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.
Insights
Novel fusion protein DAB389EGF shows promise for treating aggressive brain tumors like glioblastoma. Convection-enhanced delivery may overcome treatment barriers, enabling future clinical trials.
Area of Science:
- Oncology
- Biotechnology
- Neuroscience
Background:
- High-grade primary brain tumors, including anaplastic astrocytomas and glioblastoma multiforme, exhibit local invasiveness and resistance to chemotherapy and radiation.
- Current treatment options are limited, necessitating the development of novel therapeutic strategies.
- Fusion proteins combining peptide toxins with brain tumor-targeting ligands represent a promising therapeutic class.
Purpose of the Study:
- To evaluate the therapeutic potential of DAB389EGF, a fusion protein targeting the epidermal growth factor receptor (EGFR), for high-grade primary brain tumors.
- To explore the use of convection-enhanced delivery (CED) for localized administration of DAB389EGF, aiming to overcome systemic delivery challenges.
Main Methods:
- DAB389EGF, a fusion protein comprising diphtheria toxin domains and human epidermal growth factor (EGF), was designed for selective toxicity to EGFR-overexpressing cells.
- The study proposes utilizing convection-enhanced delivery (CED) for direct, localized administration of DAB389EGF to brain tumors.
- Preclinical models, including cell lines and animal models, are available for assessing the efficacy of this therapeutic approach.
Main Results:
- DAB389EGF demonstrates selective toxicity against cells overexpressing the epidermal growth factor receptor (EGFR), a common characteristic of nearly half of high-grade primary brain tumors.
- CED is hypothesized to facilitate high local concentrations of DAB389EGF, potentially mitigating systemic toxicity and rapid clearance issues associated with conventional delivery.
Conclusions:
- DAB389EGF holds significant therapeutic potential for treating EGFR-overexpressing primary brain tumors.
- Convection-enhanced delivery offers a viable strategy to enhance the efficacy and safety of DAB389EGF by enabling localized treatment.
- Further preclinical evaluation is warranted, with potential for clinical trials in the near future given the availability of clinical-grade DAB389EGF.