Targeting Epidermal Growth Factor Receptors in Recurrent Glioblastoma Via a Novel Epithelial Growth Factor Receptor-Conjugated Nanocell Doxorubicin Delivery System

Targeting Epidermal Growth Factor Receptors in Recurrent Glioblastoma Via a Novel Epithelial... The present standard of care fails to treat the vast majority of patients with glioblastoma multiforme (GBM),1 leaving them with a median survival period of 12.2 to 18.2 mo.2 Disease recurrence or progression is almost inevitable for patients with GBM, despite a multimodality approach using surgery, radiotherapy, and temozolomide chemotherapy. For patients whose tumors recur, the median time to progression is less than 6 mo,3 highlighting the need to develop new therapeutic strategies. Epithelial growth factor receptor (EGFR) is overexpressed in 40% to 50% cases of GBM and is a promising mark for novel therapeutics.4 Investigators have recently established the EnGeneIC delivery vehicle (EDV), a compound that exploits antibody-targeted, bacterially derived, inorganic nanocells that can transport chemotherapeutic agents into EGFR-expressing tumor cells (EnGeneIC, Lane Cove West, Australia). In the first human phase I study, of EGFR-targeting EDVs harboring doxorubicin in adults with recurrent GBM, doses of up to 5 × 109 were safe and well tolerated.5 As a result, a phase I/II USA-based open-label dose exploration clinical trial evaluating the safety of cerebral EDV in recurrent GBM in adults who had received first-line chemotherapy was approved in 2016 (NCT02766699).6 This trial is ongoing, and we are currently enrolling patients into this study at our institution. Recently, an Australian-based team of scientists recently published in Lancet Oncology, the first-in-man, open-label, dose-escalation phase 1 trial utilizing an EDV targeted to malignant pleural mesothelioma, a disease process, which also overexpresses EGFR.7 These EDVs are loaded with miR-16-based mimic microRNA (miRNA) and are intended to neutralize the loss of the miR-15 and miR-16 family miRNAs, which is linked with unsuppressed tumor progression in preclinical representations of malignant pleural mesothelioma. Their outcomes revealed that EDVs, at a dose of 5 × 109 per week with full dexamethasone prophylaxis, was well tolerated by patients and was accompanied by early signs of antitumor activity.7 These studies demonstrate that the delivery of cancer therapeutics via antibody-targeted cytotoxic packaged EDVs shows early efficacy and is well tolerated. The precise distribution of the therapeutic drug to the appropriate tissue remains paramount to the value of treatment and minimization of harmfulness. Although these results are promising, safety and ethical apprehensions must be cautiously dissected in these preliminary clinical trials. REFERENCES 1. Sturm D, Bender S, Jones DT et al.   Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer . 2014; 14( 2): 92- 107. Review. PubMed PMID: 24457416; PubMed Central PMCID: PMC4003223. Google Scholar CrossRef Search ADS PubMed  2. Krex D, Klink B, Hartmann C et al.   Long-term survival with glioblastoma multiforme. Brain . 2007; 130( Pt 10): 2596- 2606. Epub 2007 Sep 4. Review. PubMed PMID: 17785346. Google Scholar CrossRef Search ADS PubMed  3. Wong ET, Hess KR, Gleason MJ et al.   Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol . 1999; 17 (8): 2572- 2578. Google Scholar CrossRef Search ADS PubMed  4. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature . 2008; 455( 7216): 1061- 1068. Epub 2008 Sep 4. CrossRef Search ADS PubMed  5. Whittle JR, Lickliter JD, Gan HK et al.   ( 2015) First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma. J Clin Neurosci  22( 12): 1889- 1894. Google Scholar CrossRef Search ADS PubMed  6. A Study to Evaluate the Safety, Tolerability and immunogenicity of EGFR(V)-EDV-Dox in subjects with recurrent glioblastoma multiforme (GBM) (CerebralEDV). ( 2016). Available at: http://clinicaltrials.gov/ct2 (Identification No. NCT02766699). 7. Van Zandwijk N, Pavlakis N, Kao SC et al.   Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol . 2017; 18( 10): 1386- 1396. Google Scholar CrossRef Search ADS PubMed  Copyright © 2017 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Targeting Epidermal Growth Factor Receptors in Recurrent Glioblastoma Via a Novel Epithelial Growth Factor Receptor-Conjugated Nanocell Doxorubicin Delivery System

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Publisher
Congress of Neurological Surgeons
Copyright
Copyright © 2017 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyx594
Publisher site
See Article on Publisher Site

Abstract

The present standard of care fails to treat the vast majority of patients with glioblastoma multiforme (GBM),1 leaving them with a median survival period of 12.2 to 18.2 mo.2 Disease recurrence or progression is almost inevitable for patients with GBM, despite a multimodality approach using surgery, radiotherapy, and temozolomide chemotherapy. For patients whose tumors recur, the median time to progression is less than 6 mo,3 highlighting the need to develop new therapeutic strategies. Epithelial growth factor receptor (EGFR) is overexpressed in 40% to 50% cases of GBM and is a promising mark for novel therapeutics.4 Investigators have recently established the EnGeneIC delivery vehicle (EDV), a compound that exploits antibody-targeted, bacterially derived, inorganic nanocells that can transport chemotherapeutic agents into EGFR-expressing tumor cells (EnGeneIC, Lane Cove West, Australia). In the first human phase I study, of EGFR-targeting EDVs harboring doxorubicin in adults with recurrent GBM, doses of up to 5 × 109 were safe and well tolerated.5 As a result, a phase I/II USA-based open-label dose exploration clinical trial evaluating the safety of cerebral EDV in recurrent GBM in adults who had received first-line chemotherapy was approved in 2016 (NCT02766699).6 This trial is ongoing, and we are currently enrolling patients into this study at our institution. Recently, an Australian-based team of scientists recently published in Lancet Oncology, the first-in-man, open-label, dose-escalation phase 1 trial utilizing an EDV targeted to malignant pleural mesothelioma, a disease process, which also overexpresses EGFR.7 These EDVs are loaded with miR-16-based mimic microRNA (miRNA) and are intended to neutralize the loss of the miR-15 and miR-16 family miRNAs, which is linked with unsuppressed tumor progression in preclinical representations of malignant pleural mesothelioma. Their outcomes revealed that EDVs, at a dose of 5 × 109 per week with full dexamethasone prophylaxis, was well tolerated by patients and was accompanied by early signs of antitumor activity.7 These studies demonstrate that the delivery of cancer therapeutics via antibody-targeted cytotoxic packaged EDVs shows early efficacy and is well tolerated. The precise distribution of the therapeutic drug to the appropriate tissue remains paramount to the value of treatment and minimization of harmfulness. Although these results are promising, safety and ethical apprehensions must be cautiously dissected in these preliminary clinical trials. REFERENCES 1. Sturm D, Bender S, Jones DT et al.   Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer . 2014; 14( 2): 92- 107. Review. PubMed PMID: 24457416; PubMed Central PMCID: PMC4003223. Google Scholar CrossRef Search ADS PubMed  2. Krex D, Klink B, Hartmann C et al.   Long-term survival with glioblastoma multiforme. Brain . 2007; 130( Pt 10): 2596- 2606. Epub 2007 Sep 4. Review. PubMed PMID: 17785346. Google Scholar CrossRef Search ADS PubMed  3. Wong ET, Hess KR, Gleason MJ et al.   Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol . 1999; 17 (8): 2572- 2578. Google Scholar CrossRef Search ADS PubMed  4. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature . 2008; 455( 7216): 1061- 1068. Epub 2008 Sep 4. CrossRef Search ADS PubMed  5. Whittle JR, Lickliter JD, Gan HK et al.   ( 2015) First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma. J Clin Neurosci  22( 12): 1889- 1894. Google Scholar CrossRef Search ADS PubMed  6. A Study to Evaluate the Safety, Tolerability and immunogenicity of EGFR(V)-EDV-Dox in subjects with recurrent glioblastoma multiforme (GBM) (CerebralEDV). ( 2016). Available at: http://clinicaltrials.gov/ct2 (Identification No. NCT02766699). 7. Van Zandwijk N, Pavlakis N, Kao SC et al.   Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol . 2017; 18( 10): 1386- 1396. Google Scholar CrossRef Search ADS PubMed  Copyright © 2017 by the Congress of Neurological Surgeons

Journal

NeurosurgeryOxford University Press

Published: Mar 1, 2018

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