Reference Detail

Ref Type

Journal Article

PMID

(25193512)

Authors

Hunter FW, Hsu HL, Su J, Pullen SM, Wilson WR, Wang J

Title

Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	13	11	2014 Nov	2501-14	Mol Cancer Ther

URL

Abstract Text

Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor clinical outcome and few validated drug targets. Two prevalent features of TNBC, tumor hypoxia and derangement of homologous recombination (HR) repair, are potentially exploitable for therapy. This study investigated whether hypoxia-activated prodrugs (HAP) of DNA-damaging cytotoxins may inhibit growth of TNBC by simultaneously addressing these two targets. We measured in vitro activity of HAP of DNA breakers (tirapazamine, SN30000) and alkylators (TH-302, PR-104, SN30548) in TNBC cell lines and isogenic models, and related this to measures of HR repair and expression of prodrug-activating enzymes. Antitumor activity of HAP was examined in isogenic BRCA2-knockout xenograft models and compared with platinum chemotherapy. All five HAP selectively inhibited growth of TNBC cell lines under hypoxia. Sensitivity to HAP was not strongly associated with BRCA1 genotype. However, HAP sensitivity was enhanced by suppression of HR (assessed by radiation-induced RAD51 focus formation) when BRCA1 and PALB2 were knocked down in a common (MDA-MB-231) background. Furthermore, knockout of BRCA2 markedly sensitized DLD-1 cells to the clinical nitrogen mustard prodrugs TH-302 and PR-104 and significantly augmented sterilization of clonogens by these agents in xenografts, both as monotherapy and in combination with radiotherapy, but had less effect on activity of the benzotriazine di-N-oxide SN30000. PR-104 monotherapy was more effective than cisplatin at inhibiting growth of BRCA2-knockout tumors at equitoxic doses. This study demonstrates the potential for HAP of nitrogen mustards to simultaneously exploit hypoxia and HR defects in tumors, with translational implications for TNBC and other HR-deficient malignancies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PALB2 dec exp	triple-receptor negative breast cancer	sensitive	PR-104	Preclinical	Actionable	In a preclinical study, knockdown of PALB2 enhanced growth inhibition by PR-104 in triple-negative breast cancer cell lines in culture (PMID: 25193512).	25193512
PALB2 dec exp	triple-receptor negative breast cancer	sensitive	Evofosfamide	Preclinical	Actionable	In a preclinical study, knockdown of PALB2 enhanced growth inhibition by Evofosfamide (TH-302) in triple-negative breast cancer cell lines in culture (PMID: 25193512).	25193512
PALB2 dec exp	triple-receptor negative breast cancer	sensitive	Cisplatin	Preclinical	Actionable	In a preclinical study, knockdown of PALB2 enhanced growth inhibition by Platinol (cisplatin) in triple-negative breast cancer cell lines in culture (PMID: 25193512).	25193512
PALB2 dec exp	triple-receptor negative breast cancer	sensitive	Chlorambucil	Preclinical	Actionable	In a preclinical study, knockdown of PALB2 enhanced growth inhibition by Ambochlorin (chlorambucil) in triple-negative breast cancer cell lines in culture (PMID: 25193512).	25193512
PALB2 dec exp	triple-receptor negative breast cancer	sensitive	SN30000	Preclinical	Actionable	In a preclinical study, knockdown of PALB2 enhanced growth inhibition by SN30000 in triple-negative breast cancer cell lines in culture (PMID: 25193512).	25193512