Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification

Sepúlveda‐Sánchez, Juan Manuel; Vaz, María Ángeles; Balañá, Carmen; Gil-Gil, Miguel; Reynés, Gaspar; Gallego, Óscar; Martinez-García, Maria; Vicente, E.; Quindós, María; Luque, Raquel; Ramos, Adilson Luiz; Ruano, Yolanda; Pérez‐Segura, Pedro; Benavides, Manuel; Sánchez-Gómez, Pilar; Hernández-Laín, Aurelio

doi:10.1093/neuonc/nox105

Cited by 97 publications

(83 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Considering this aspect, immunotherapies may possibly outperform small molecule-based approaches. Despite the wide availability of TKIs clinically approved in oncological treatment, none of these inhibitors is used as a standard approach in GB treatment [64,72,77,179]. As EGFR vIII is a key oncogene with kinase activity-dependent function, it seems reasonable to consider whether the efficacy of TKI-based therapies should not be greater, especially since it has been postulated that the bloodbrain barrier in advanced GB is disrupted and thus should not enable for crossing of small molecules [180].…”

Section: Journal Of Oncologymentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

View full text Add to dashboard Cite

Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

show abstract

Section: Journal Of Oncologymentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…Recent pre-clinical data suggest that dacomitinib effectively blocked the growth of EGFR amplified and/or EGFR mutant glioblastoma cells in vitro and in intracranial xenografts [21] , [22] . Moreover, dacomitinib has shown promise for the treatment of non-small cell lung cancer, squamous cell carcinoma of the head and neck, and in a subset of glioblastomas [23] , [24] , [25] , [26] . The effects of dacomitinib on medulloblastoma or pineoblastoma cell growth have not been assessed.…”

Section: Introductionmentioning

confidence: 99%

A Pre-Clinical Assessment of the Pan-ERBB Inhibitor Dacomitinib in Pediatric and Adult Brain Tumors

et al. 2018

View full text Add to dashboard Cite

Glioblastoma in adults, and medulloblastoma and pineoblastoma that mainly affect children, are aggressive brain tumors. The survival for patients with glioblastoma remains dismal. While the cure rate for medulloblastoma exceeds 70%, this figure has stagnated over the past few decades and survivors still contend with significant long-term debilitating side effects. The prognosis for pineoblastoma is age-dependent, with little chance of a cure for children younger than three years. More effective molecularly targeted strategies are urgently required to treat these cancers. Hyper-activation of epidermal growth factor receptor (EGFR) signaling is characteristic of several different classes of human cancers, including a subset of glioblastoma and medulloblastoma. This has provided the impetus for the development of a suite of EGFR pathway blockers, including second generation irreversible inhibitors, such as dacomitinib. We have developed a comprehensive drug evaluation pipeline, including in vitro interaction analyses and orthotopic xenograft mouse models, to address the efficacy of drugs for brain tumor treatment, enabling the exclusion of potentially ineffective treatments and prioritization of truly beneficial novel treatments for clinical trial. We used this system to examine the effects of dacomitinib as a single agent, or in combination with conventional chemotherapeutics, on the growth of human adult and pediatric brain tumor cell lines. Dacomitinib inhibited EGFR or EGFRvIII activity in vitro in all three tumor types tested, and as a single agent induced a modest increase in survival time for mice bearing glioblastoma, which accurately predicted human clinical trial data. For pediatric medulloblastoma, dacomitinib blocked EGFR/HER signalling in orthotopic xenografts and extended median survival as a single agent, however was antagonistic when used in combination with standard frontline medulloblastoma chemotherapies. The findings caution against the use of dacomitinib for pediatric brain tumor clinical trials.

show abstract

“…TrkB-containing exosomes promote the transfer of aggressiveness between GBM cells (Pinet et al 2016). EGFR inhibition has been proposed as a therapeutic strategy in GBM and has been tested in preclinical (Buendia Duque et al 2019;Parker et al 2013;Zahonero et al 2015) and clinical (Makhlin et al 2019;Sepúlveda-Sánchez et al 2017), with mixed results. One previous study examined the interaction between TrkB and EGFR in experimental GBM and showed that stimulation of neurotrophin signaling can overcome the inhibitory effects of EGFR inhibition on GBM cell growth (Lawn et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma

Pinheiro

Thomaz

Souza

et al. 2020

Preprint

View full text Add to dashboard Cite

A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM.Keywords Brain tumor • Epidermal growth factor receptor • Glioblastoma • Growth factor receptor • Neurotrophin • Tropomyosin receptor kinase B

show abstract

Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification

Abstract: Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Cited by 97 publications

References 32 publications

EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role

A Pre-Clinical Assessment of the Pan-ERBB Inhibitor Dacomitinib in Pediatric and Adult Brain Tumors

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma

Contact Info

Product

Resources

About

Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification

Abstract: Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Cited by 97 publications

References 32 publications

EGFRvIII: An Oncogene with Ambiguous Role

EGFRvIII: An Oncogene with Ambiguous Role

A Pre-Clinical Assessment of the Pan-ERBB Inhibitor Dacomitinib in Pediatric and Adult Brain Tumors

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma

Contact Info

Product

Resources

About

EGFR^vIII: An Oncogene with Ambiguous Role

EGFR^vIII: An Oncogene with Ambiguous Role