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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
VEGF-A Expression Correlates with TP53 Mutations in Non-Small Cell Lung Cancer: Implications for Antiangiogenesis
Maria Schwaederlé1, Vladimir Lazar2, Pierre Validire3
1Center for Personalized Cancer Therapy, UCSD Moores Cancer Center, La Jolla, California. mschwaederle@ucsd.edu rkurzrock@ucsd.edu Vladimir.LAZAR@gustaveroussy.fr.
Abstract:
Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P = 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types.
Insights
TP53 mutations in non-small cell lung cancer (NSCLC) correlate with increased VEGF-A expression. This finding suggests mutant TP53 may predict a better response to bevacizumab therapy, an antiangiogenic drug.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Bevacizumab, an antiangiogenic drug targeting VEGF-A, has modest efficacy in oncology due to a lack of predictive biomarkers.
- Molecular aberrations, such as TP53 mutations, are common in cancers and can influence angiogenesis.
Purpose of the Study:
- To investigate the association between TP53 mutations and VEGF-A expression in non-small cell lung cancer (NSCLC).
- To explore the potential of TP53 as a predictive biomarker for bevacizumab treatment response.
Main Methods:
- Multiple regression analysis of transcriptomic data from 123 NSCLC patients.
- Correlation analysis between TP53 mutation status and VEGF-A expression levels.
Main Results:
- A statistically significant association was found between TP53 mutations and higher VEGF-A expression (P = 0.006).
- This finding provides a potential mechanistic link for improved bevacizumab outcomes in patients with mutant TP53 tumors.
Conclusions:
- TP53 mutations are linked to increased VEGF-A expression in NSCLC.
- TP53 may serve as a predictive biomarker for bevacizumab response in NSCLC and potentially other cancer types, warranting further investigation.
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