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Title: Identification and functional study of a VEGFR-1 locus predicting bevacizumab treatment outcome
Other Titles: Identificatie en functionele studie van een VEGFR-1 locus predictief voor de respons op bevacizumab behandeling
Authors: Claes, Bart
Issue Date: 3-Jul-2012
Abstract: Insights into the molecular genetics of cancer have fueled the development of so-called “targeted therapies”, specifically directed at molecules involved in cancer growth. One of these extensively studied molecules is the vascular endothelial growth factor VEGF, which stimulates the growth of new blood vessels – a process also termed angiogenesis. Since tumors stimulate the formation of new blood vessels to sustain their growth, neutralizing the activity of VEGF was expected to inhibit excessive tumor angiogenesis, impairing tumor growth and ultimately extending patient survival. A milestone achievement came in 2004 with the approval of the anti-VEGF antibody bevacizumab (Avastin ) for clinical use, after it prolonged the survival of colorectal cancer patients when combined with chemotherapy. Bevacizumab has meanwhile also been approved for the treatment of certain types of lung, renal, breast and brain cancer, and is being investigated for the treatment of other cancer types as well. While many thousands of patients have benefited from anti-angiogenic treatment with bevacizumab, clinical challenges remain.The survival benefit offered by bevacizumab is transient for most patients in a general (unselected) population, because some are intrinsically non-responsive, while others develop adaptive resistance during treatment. It is thus crucial to understand why some patients respond well to bevacizumab while others do not, and based on these insights, to identify biomarkers that can select patients that will benefit most from bevacizumab treatment. A promising approach for biomarker identification is the study of human genetic variations. Indeed, genetic factors are known to contribute to individual variation in VEGF responsiveness. The response to VEGF neutralization by bevacizumab may thus be similarly determined by genetic variability in the patient DNA. Genetic studies could therefore provide important insights by elucidating how genetic variations in the VEGF signaling pathway affect bevacizumab treatment outcome. However, previous studies evaluating genetic variations were mostly limited to a small number of polymorphisms, a limited number of studied patients, or could not replicate initial findings in subsequent studies.The objective of this thesis therefore was to perform a comprehensive screening of genetic variations in the VEGF pathway that could affect bevacizumab treatment outcome. Single nucleotide polymorphisms or SNPs were selected based on the HapMap, a reference database of human genetic variation, in order to capture genetic variation more completely across 14 important VEGF pathway genes. Evaluation of these SNPs in the DNA of pancreatic cancer patients participating to a phase III clinical study of bevacizumab (AViTA) revealed a genetic locus in the VEGFR-1 TK domain as a predictive marker for bevacizumab treatment outcome. Importantly, this locus associated specifically with survival in patients receiving bevacizumab, as no effects were present in placebo-treated patients. Further genetic study revealed the presence of a synonymous SNP, rs7993418, underlying the association of this VEGFR-1 locus with bevacizumab treatment outcome. This SNP affects codon bias for a tyrosine residue in the VEGFR-1 TK domain, leading to enhanced VEGFR-1 mRNA translation efficiency and increased VEGFR-1 protein expression. Since VEGFR-1 is considered a negative regulator of VEGF signaling, these findings explain how rs7993418 in the VEGFR-1 locus causes resistance to bevacizumab treatment. Finally, association of this locus with bevacizumab treatment outcome was also confirmed in a second phase III clinical study in renal cancer patients (AVOREN). In conclusion, the genetic and molecular studies performed in this thesis indicate that SNPs belonging to a VEGFR-1 locus might have clinical relevance to serve as a genetic biomarker for bevacizumab treatment.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Translational Genetics (Vesalius Research Center) (+)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)

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