Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer.
OBJECTIVE
Maintenance of telomeres by telomerase is critical for the continuing proliferation of most advanced cancer cells. Telomerase activity has been detected in the vast majority of cancer cells but not most normal cells, making the enzyme an attractive target for anticancer therapy. The aim of this study was to address the breast cancer translational potential of the novel telomerase inhibitor, GRN163L.


METHODS
In the present study, we investigated the effects of GRN163L treatment on a panel of breast cancer cells representing different tumor subtypes with varying genetic backgrounds, including ER+, ER-, HER2+, BRCA1 mutant breast tumor cells as well as doxorubicin-resistant cancer cells. To investigate the in vivo effects of GRN163L, we employed a breast cancer xenograft and metastasis model that simulates a clinical situation in which a patient arrives with a primary tumor that may be then treated or surgically removed.


RESULTS
GRN163L effectively inhibited telomerase activity in a dose-dependent fashion in all breast cancer cell lines resulting in progressive telomere shortening. A mismatch control oligonucleotide showed no effect on telomerase activity and GRN163L did not significantly affect telomere shortening in normal human mammary epithelial cells or in endothelial cells. Breast cancer cells that exhibited telomerase inhibition also exhibited significant reduction in colony formation and tumorigenicity. Furthermore, GRN163L suppressed tumor growth and lung metastases (P = 0.017) of MDA-MB-231 cells in vivo after 4 weeks of treatment.


CONCLUSIONS
These results show in vivo effectiveness of GRN163L in breast cancer and support its promising clinical potential for breast cancer treatment.
Hochreiter
Amelia E
AE
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-5251, USA.
Xiao
Hongling
H
Goldblatt
Erin M
EM
Gryaznov
Sergei M
SM
Miller
Kathy D
KD
Badve
Sunil
S
Sledge
George W
GW
Herbert
Brittney-Shea
BS
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides; D009842:Oligopeptides / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000648:ultrastructure; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D009841:Oligonucleotides; D009842:Oligopeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D019098:Telomerase; C505952:GRN163L peptide