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G.A. Woodard
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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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MINI14.13 - Small Molecule Demonstrates Potent Tumor Suppression by Inhibiting the PI3K/AKT Pathway in Non-Small Cell Lung Cancer (ID 721)
10:45 - 12:15 | Author(s): G.A. Woodard
- Abstract
- Presentation
Background:
The phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) pathway is frequently activated in many malignancies including non-small cell lung cancer (NSCLC). Dysregulation of this pathway leads drives oncogenic genes and imparts resistance to conventional chemotherapy. We identified a small molecule AKT pathway inhibitor as a potential lead compound.
Methods:
The AKT pathway inhibitor was tested in vitro on a panel of NSCLC cell lines A427, A549, NCI-H1703, NCI-H2170, NCI-H1650, and NCI-H1975. Cell viability was determined by MTS assay after 72 hours of drug treatment. Activation kinases in the PI3K/AKT/mTOR pathway was determined by western blot analysis.
Results:
Treatment with the PI3K/AKT pathway inhibitor caused potent concentration-dependent inhibition of cell proliferation with a half maximal inhibitory concentration (IC~50~) in the nanomolar range. Kirsten rat sarcoma (KRAS) mutant cell lines were the most sensitivity to the PI3K/AKT pathway inhibitor while epidermal growth factor receptor (EGFR) mutant cell lines were more resistant. Western blot analysis showed inhibition of AKT and mTOR phosphorylation at nanomolar concentrations.
Conclusion:
A novel small molecule AKT inhibitor inhibits growth of NSCLC cells in vitro, is potent against KRAS mutants, and shows promise as a small molecule targeted chemotherapy drug for NSCLC.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-089 - Prospective Use of Prognostic Molecular Assay Identifies Patients at Risk for Recurrence and Changes Clinical Management in Early-Stage NSCLC (ID 1497)
09:30 - 17:00 | Author(s): G.A. Woodard
- Abstract
Background:
Adjuvant chemotherapy recommendations depend on identification of early-stage non-small-cell lung cancer (NSCLC) patients at high-risk of recurrence. Current National Comprehensive Cancer Network (NCCN) guidelines use certain clinicopathologic features to make this recommendation for stage Ib-IIa patients. An internationally validated, 14-gene expression assay has been shown retrospectively to better stratify mortality risk in non-squamous NSCLC than conventional staging.
Methods:
Following up on a previously reported cohort of 52 patients, prospective molecular risk-stratification by the 14-gene test was performed in 66 patients with a mean follow up of 20.7 ±14.1 months. Disease-free survival and lung cancer mortality rates were compared between high- and low-risk patients by both molecular risk-stratification and NCCN “high-risk” characteristics.
Results:
Patients with low-, intermediate-, and high-risk based on molecular testing had recurrence rates of 4%, 8%, and 28% (p=.031, Fisher’s exact test) and lung cancer mortalities of 0%, 0%, and 16% (p=.039), respectively. Molecular high-risk was associated with shorter disease-free survival (p=.043, Kaplan-Meier log-rank). Molecular risk assessment was discordant from NCCN “high-risk” features in 15 of 25 stage Ib-IIa patients (60%). NCCN criteria failed to significantly predict either recurrence or mortality with recurrence rates of 8% and 23% (p=.077, Fisher’s exact test) and lung cancer related mortality of 3% and 12% (p=.165) among patients with NCCN low- and high-risk features respectively. Molecular high-risk scores changed adjuvant chemotherapy recommendations in 3 of 10 (30%) patients who otherwise did not meet NCCN criteria for adjuvant chemotherapy.
Conclusion:
This study demonstrates that prospective application of a 14-gene prognostic assay significantly predicts differences in disease-free survival. This prognostic information differs from NCCN high-risk clinicopathologic features and has clinical utility in better informing adjuvant chemotherapy recommendations.
