Thursday, October 4, 2012
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Phosphoinositide-3 kinase (PI3K); poly(AD-ribose) polymerase
(PARP); breast cancer 1 early onset (BRCA1); BRCA2
In vitro and mouse studies suggest combining PARP and PI3K
inhibitors could help treat metastatic breast cancer.
In a mouse model of BRCA1-related breast cancer, inhibition of PI3K with BKM120 decreased
angiogenesis compared with vehicle but increased activity in other
cancer-associated pathways. In the same model and in mice with BRCA1-driven
breast cancer xenografts, BKM120 plus the PARP inhibitor olaparib prevented the
compensatory pathway upregulation and delayed tumor growth better than either
In a second study, small interfering RNA targeting a PI3K isoform in triple
receptor-negative breast cancer cells decreased BRCA1 and BRCA2 levels
compared with no treatment and sensitized the cells to PARP inhibitor-induced
cell death. In mice with triple receptor-negative breast cancer xenografts,
BKM120 plus olaparib inhibited tumor growth more than either treatment alone.
Next steps could include testing the combination in the clinic.
Novartis AG's BKM120 is in
Phase II testing for various cancers. At least 18 other companies have PI3K
inhibitors in clinical and preclinical testing to treat multiple types of
AstraZeneca plc's olaparib
is in Phase II testing to treat solid tumors. At least seven other companies
have PARP inhibitors in clinical and preclinical testing to treat multiple
types of cancer.
Published online Oct. 4, 2012
Patent and licensing status
Juvekar, A. et al.
Cancer Discov.; published online Aug. 22, 2012;
Contact: Gerburg M. Wulf, Beth Israel Deaconess Medical Center,
Ibrahim, Y.H. et al. Cancer Discov.; published online Aug. 22, 2012;
Contact: José Baselga, Massachusetts General Hospital, Boston,
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