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S. Miyoshi
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.02 - TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant (ID 1646)
10:50 - 10:55 | Author(s): S. Miyoshi
- Abstract
- Presentation
Background:
TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). These tyrosine kinases are known to be overexpressed in many malignant tumors including some NSCLCs and to play an oncogenic role in cancer cells.
Methods:
We investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. Drug sensitivity of TAE226 to various NSCLC cell lines was determined by MTS assay. Interaction of TAE226 and variant EGFR proteins was evaluated by in vitro binding assay, and kinetic interaction analysis to calculate K~d~ value. Finally, the effect of TAE226 on NSCLC was investigated using a xenograft mouse model.
Results:
TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity.
Conclusion:
We showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation. Our results showed that the EGFR L858R/T790M (or delE746_A750/T790M) mutant retains the binding affinity to TAE226 comparable to that of the L858R (or delE746_A750) mutant, suggesting that TAE226, or its relatives, is promising to overcome acquired TKI resistance mediated by EGFR T790M mutation.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-031 - Feasibility of Median Sternotomy Approach for Locally Advanced Lung Cancer (ID 2126)
09:30 - 09:30 | Author(s): S. Miyoshi
- Abstract
Background:
Trimodality therapy is one of therapeutic options for local advanced lung cancer. While a posterolateral thoracotomy was used as the standard approach, a median sternotomy with or without transverse thoracotomy is applied if necessary. In our institution, we have applied median approach for patients who need dissection of contralateral mediastinal lymph nodes or clamp of great vessels, mainly pulmonary artery, for a safe resection. The purpose of this study was to evaluate the feasibility and clinical outcome of median sternotomy approach for locally advanced lung cancer after chemoradiotherapy.
Methods:
Between March 2002 and December 2014, 35 non-small-cell lung cancer patients underwent radical surgery with median sternotomy approach after induction chemoradiotherapy . The medical records were reviewed to investigate clinical outcomes including perioperative complications.
Results:
The median patient age was 59 years (range: 41–77 years). There were 28 men and 7 women in the series. The histological subtype was adenocarcinoma in 21 patients, squamous cell carcinoma in 14. 16 patients had stage IIIA disease, and 19 had stage IIIB disease. The median postoperative hospital stay was 23 days. As notable perioperative complications, 12 patients revealed tachycardia that needs medication, 6 pneumonia, 3 radiation-induced pneumonitis, one wound ablation, one bronchial stump fistula, and one chylothorax. All of them were manageable. There was no treatment-related death in this cohort. As patients’ survival, the 3-year and 5-year overall survival rates were 77.7 % and 67.1 %, respectively. The 1-year and 3-year recurrence-free survival rates were 75.4 % and 63.4 %, respectively.
Conclusion:
Our experience indicates that median sternotomy approach for locally advanced lung cancer after ChRT is feasible procedure after chemoradiotherapy.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-036 - Primary Pulmonary Melanoma: A Report of Two Cases (ID 2109)
09:30 - 09:30 | Author(s): S. Miyoshi
- Abstract
Background:
Malignant melanoma is a refractory malignancy with a dismal prognosis. It generally arises from the skin in most cases, and cases of primary pulmonary malignant melanoma are rare and often behave aggressively. We have treated two cases of localized primary pulmonary malignant melanoma by surgical resection. Although cutaneous melanomas often carry activating mutations in the BRAF gene (V600E) and express programmed death ligand 1 (PD-L1), little is known about primary pulmonary malignant melanoma.
Methods:
We determined the BRAF mutational status (exons 11 and 15) by direct sequencing in the two tumors. Next, we performed a target sequencing analysis using the Human Lung Cancer Panel (Qiagen, Hilden, Germany), which targets 20 lung cancer-related genes including most of the exons in BRAF, using the same samples. We evaluated the expression of PD-L1 on the surface of the tumor cells by immunohistochemical testing in formalin-fixed, paraffin-embedded tumor specimens with the use of a rabbit monoclonal antihuman PD-L1 antibody.
Results:
No BRAF mutations and PD-L1 expression were detected in both of two cases. We detected a p53 mutation, which was thought to be a potential somatic mutation, in one of the two cases using a sequencing panel targeting 20 lung cancer-related genes.
Conclusion:
We encountered two cases of malignant melanoma of the lung that did not carry activating mutations in the BRAF gene. Further molecular analyses may uncover the characteristics of primary malignant melanoma.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-065 - Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies (ID 3006)
09:30 - 09:30 | Author(s): S. Miyoshi
- Abstract
Background:
We previously identified the tumor suppressor gene REIC/Dkk-3 whose expression is reduced in many human cancers, and overexpression of REIC/Dkk-3 by an adenovirus (Ad-REIC) exhibited a dramatic therapeutic effect on several human cancers through a mechanism triggered by endoplasmic reticulum (ER) stress. In addition to the direct anti-tumor effect, we also have shown that Ad-REIC has a host-mediated bystander effect on human prostate cancer and scirrhous gastric cancer through REIC-mediated cancer vaccination and production of IL-7. In this study, we examined possible direct and indirect distant bystander effects of Ad-REIC via activation of systemic anti-tumor immunity on thoracic malignancies.
Methods:
We examined anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma (MM) cell lines in vitro. In addition, we examined the direct and distant bystander effect of Ad-REIC in bilateral flank allograft tumor model using immunocompetent BALB/c mice. Mice received intratumoral injection of Ad-REIC into the right-flank tumors, and the effect in bilateral-flank tumors were examined. Dissected bilateral flank tumors after sacrifice were also subjected to immunohistochemical analysis.
Results:
Ad-REIC treatment showed anti-tumor effect in many of lung cancer and MM cell lines in vitro due to the activation of c-Jun N-terminal kinase (JNK). REIC/Dkk-3 was highly expressed after Ad-SGE-REIC treatment in Ad-SGE-REIC sensitive cell lines, while it was not or weakly expressed in some cells, which were resist to Ad-SGE-REIC treatment. In an in vivo model, Ad-REIC treatment inhibited the tumorigenic growth of not only direct injected tumor but also distant non-injected tumor. In immunohistochemical examination, infiltration of CD49b positive NK cells and expression of MHC Class-I molecules H60 and Rae-1 were revealed in bilateral tumors, suggesting that Ad-REIC treatment showed bystander anti-tumor effect through immune system-mediated apoptosis, and protein expression of MHC class-I molecules induces NK cell infiltration to the tumor.
Conclusion:
We newly revealed that Ad-REIC treatment induced MHC Class-I expression both in primary and distant tumor sites, which lead NK cell infiltration. Ad-REIC treatment showed not only direct anti-tumor effect but also indirect bystander effect through immune system stimulation in immunocompetent mice model. Our findings suggest that Ad-REIC therapy is a promising treatment for MM and lung cancer
