Virtual Library
Start Your Search
T. Yamada
Author of
-
+
P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.03-032 - In vivo Imaging Models for Preclinical Screening of Molecular Targeted Drugs against Brain Metastasis (ID 4433)
14:30 - 14:30 | Author(s): T. Yamada
- Abstract
Background:
Background: Molecular targeted drugs are generally effective on tumors with driver oncogene, including EGFR, ALK, and NTRK1. However, patients with these oncogenes frequently experience progression of brain metastasis during the targeted drug treatment. Thus, it is essential to establish more effective treatment for controlling brain metastasis.
Methods:
Methods: We established in vivo imaging brain tumor models by intracranial inoculation of human cancer cell lines, such as lung adenocarcinoma H1975 cells with EGFR-L858R and T790M mutations, HGF-dependent gastric cancer NUGC4 cells, and TPM3-NTRK1-fusion gene positive colorectal cancer KM12SM cells, in SCID mice. We investigated the activity of several molecular targeted drugs on cell proliferation of these cell lines in vitro. In addition, we evaluated the efficacy of these drugs on brain tumor models, comparing with extracranial tumor models.
Results:
Results: In vitro conditions, H1975 cells were sensitive to the 3[rd] generation EGFR inhibitor, osimertinib. HGF stimulated proliferation of gastric cancer NUGC4 cells, and the HGF-induced proliferation was inhibited by crizotinib, which has anti-MET activity, in a dose-dependent manner. KM12SM cells, which are the highly liver metastatic variant derived from TPM3-NTRK1 fusion gene positive colon cancer KM12C cells. KM12SM were sensitive to TRK-A inhibitors, crizotinib and entrectinib. In H1975-cell in vivo models, osimertinib (25mg/kg) inhibited the progression of both brain tumors and subcutaneous tumors. In NUGC4-cell in vivo models, crizotinib (50mg/kg) delayed the progression of brain tumors as well as peritoneal carcinomatosis, and prolonged the survival of the tumor bearing mice. In KM12SM-cell in vivo models, we evaluated the effect of crizotinib (50mg/kg) or entrectinib (15mg/kg) in the brain tumor model and liver metastasis model. Crizotinib treatment slightly delayed the progression of brain tumors but failed to prolong the survival of the recipient mice. Entrectinib treatment more discernibly delayed the progression of brain tumors and did prolong the survival. These results indicate that the effect of targeted drugs against brain tumors can be different from that against extracranial tumors.
Conclusion:
Conclusion: Our in vivo imaging brain tumor models may be useful for preclinical drug screening against brain metastasis.
-
+
P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.03b-069 - LKB1 Loss is a Novel Determinant of MEK Sensitivity Due to Alterations in AKT/FOXO3 Signaling (ID 3941)
14:30 - 14:30 | Author(s): T. Yamada
- Abstract
Background:
The use of MEK inhibitors for non-small cell lung cancer (NSCLC) has shown little efficacy in clinical trials, even in the case of tumors with mutant KRAS where one might predict good outcomes. From these data, it is clear that the success of MEK inhibitors is going to rely on finding a biomarker that predicts sensitivity to this type of therapy. Our area of interest is finding a way to treat LKB1 mutant tumors and, surprisingly, an in silico screen of drug sensitivity data for NSCLC cell lines determined that four MEK inhibitors were among the top drugs that were significantly associated with LKB1 loss.
Methods:
We determined the effects MEK inhibition by evaluating 23 lung cancer cell lines with known LKB1 status. In addition, we investigated MEK sensitivity by restoring wild-type (Wt) LKB1 in lung cancer cell lines with LKB1 loss in vitro, or by silencing LKB1 in lung cancer cell LKB1-Wt lines both in vitro and in vivo experiments.
Results:
MEK inhibition with trametinib led to a significant reduction in cell viability in LKB1 mutant cell lines when compared to cell lines with wild type LKB1. Transduction of LKB1 resulted in significant MEK resistance in six of the seven LKB1 add-back lines, while silencing LKB1 induced MEK sensitivity in all five LKB1-Wt lines tested. The mechanism behind these observed results appears to be through phosphorylation of AKT and its downstream target FOXO3, which are important determinants of the apoptotic response to MEK inhibition. With LKB1 transduction into mutant cell lines we see an increase in the activating phosphorylation of AKT, a protein involved in survival mechanisms, and an increase in the deactivating phosphorylation of FOXO3, a transcription factor implicated in increased levels of apoptosis.
Conclusion:
Our data suggest that the identification of LKB1 activity may be promising biomarker for the sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway in NSCLC.
