Abstract P6-10-08: Preliminary results of a first in human Phase 1 clinical trial to demonstrate safety and feasibility of chimeric antigen receptor T (CART) cells directed against c-Met in the treatment of breast cancer

Tchou, Julia; Zhang, PJ; Levine, BL; Zhao, Yangbing; Matro, Jennifer M.; DeMichele, Angela; Amy, Christopher M.; Schuchter, Lynn M.; Plesa, Gabriela; Vonderheide, R.H.; June, Carl H.

doi:10.1158/1538-7445.sabcs16-p6-10-08

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“…Antibodies and chemical TKIs are the two major types of therapeutics for the MET-targeting therapy . Although both strategies show promising efficacies, the application of antibodies is limited by their high cost, poor tumor penetration, immunogenicity, and a long time for clearance. , Chemical TKIs also suffer from limitations, including the poor selectivity for RTKs and compromised therapeutic efficacy due to the short circulation time.…”

Section: Results and Discussion Overactivation Of Met In Tumor Margin...mentioning

confidence: 99%

Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling

Fan

Zeng

et al. 2018

Nano Lett.

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Malignant gliomas are the most common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( K = 3.96 × 10 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.

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Section: Results and Discussion Overactivation Of Met In Tumor Margin...mentioning

confidence: 99%

Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling

Fan

Zeng

et al. 2018

Nano Lett.

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Abstract P6-10-08: Preliminary results of a first in human Phase 1 clinical trial to demonstrate safety and feasibility of chimeric antigen receptor T (CART) cells directed against c-Met in the treatment of breast cancer

Abstract: This abstract was withdrawn by the authors.

Cited by 1 publication

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Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling

Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling

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