In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e19097-e19097
Abstract:
e19097 Background: Heat shock protein 90 (Hsp90) maintains the stability and activity of numerous signaling proteins involved in metastasis including FAK (tumor cell adhesion), MET and MMP9 (cell motility), VEGFR and PDGFR (angiogenesis), and HIF-1α (metabolism, proliferation, motility, angiogenesis). In the GALAXY–1 trial in advanced non-small cell lung cancer (NSCLC) patients, docetaxel (D) plus ganetespib (G), an Hsp90 inhibitor, showed encouraging improvement in overall survival compared to D alone. We evaluated the antimetastatic activity of ganetespib in preclinical models, and compared radiological disease progression due to new lesion formation in the two arms of the GALAXY–1 trial. Methods: Effects of ganetespib were investigated on the: (1) migration of cancer cells under normoxic and hypoxic conditions via scratch assay, (2) expression of metastatic signaling factors using immunoblotting and reverse phase array, (3) architecture of NSCLC tumor xenografts including micro-vasculature, hypoxia, and apoptosis by immunostaining, and (4) metastasis to the lung in both tail vein and orthotopic breast cancer in vivo mouse models. In the GALAXY–1 trial, development of new metastatic lesions was evaluated using serial computed tomography scans. Results: In vitro, ganetespib blocked the migration of cancer cells and reduced the expression of key drivers of metastasis including P-AKT, FAK, HER2, IGF-1R, MET, HIF-1α, and VEGF. In vivo, ganetespib significantly reduced tumor angiogenesis and proliferation. In patients, in the population in the GALAXY–1 trial that exhibited the strongest survival improvement (diagnosis of advanced disease 〉 6 months, N=175), radiologic progressions due to new lesion formation were 19 (50%) vs. 5 (17%), for D vs. D+G, respectively, at time of abstract submission. Updated results will be presented. Conclusions: Ganetespib inhibits multiple processes involved in tumor metastasis. Preliminary data from the GALAXY–1 study support reduced frequency of progression due to new metastatic lesion formation in advanced NSCLC patients treated with ganetespib.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.e19097
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
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