Src inhibitors in early breast cancer: a methodology, feasibility and variability study.
Early clinical trials of anticancer agents may be enriched by robust biomarkers of activity. Surrogate measures used in trials of cytotoxic agents, such as tumor size regression, may not be informative when investigating targeted agents that act principally to inhibit invasion or proliferation. This study aimed to determine the validity of invasion-related biomarkers of activity for AZD0530, a potent Src inhibitor currently in clinical development. Focal adhesion kinase (FAK) and paxillin are downstream phosphorylation substrates of Src and mediate tumor cell adhesion and invasiveness. These were therefore selected as biologically relevant markers of Src inhibition. Early breast cancer was chosen as a model as multiple samples can be collected during standard treatment and there is an intervening period in which experimental intervention can be applied. Tumor tissue was collected from diagnostic core biopsies and subsequent surgical tumor excision samples in 29 women with early breast cancer attending a single center. Protein levels were assessed quantitatively by Luminex and qualitatively by immunohistochemistry. AZD0530 inhibited tumor growth in a manner independent of dose and inhibited phosphorylation of FAK and paxillin in a dose-dependent manner in a Calu-6 xenograft model. In the clinical study, agreement of within-visit and also of between-visit measurements was high and the estimated number of patients required to detect a drug effect would be low enough to allow use of these markers as endpoints in future dose selection studies.
Jones
R J
RJ
Centre for Oncology and Applied Pharmacology, CRUK Beatson Laboratories, Garscube Estate, Glasgow, Scotland, UK. r.jones@beatson.gla.ac.uk
Young
O
O
Renshaw
L
L
Jacobs
V
V
Fennell
M
M
Marshall
A
A
Green
T P
TP
Elvin
P
P
Womack
C
C
Clack
G
G
Dixon
J M
JM
D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D005240:Feasibility Studies; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases
D052117:Benzodioxoles; D051419:Paxillin; D011799:Quinazolines; C515233:saracatinib; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases; C000631346:CSK protein, human