Article

Drew Y, Mulligan EA, Vong WT, Thomas HD, Kahn S, Kyle S et al.. Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J Natl Cancer Inst 103: 334-346

Northern Institute for Cancer Research, University of Newcastle Upon Tyne, Medical School, Newcastle Upon Tyne, NE2 4HH, UK.
Journal of the National Cancer Institute (Impact Factor: 12.58). 02/2011; 103(4):334-46. DOI: 10.1093/jnci/djq509
Source: PubMed

ABSTRACT

Background Mutations in BRCA1 and BRCA2 (BRCA1/2), components of the homologous recombination DNA repair (HRR) pathway, are associated with hereditary breast and
ovarian cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic to animal cells with defective HRR,
but results in human cancer cells have been contradictory. We undertook, to our knowledge, the first comprehensive in vitro
and in vivo investigations of the antitumor activity of the PARP inhibitor AG014699 in human cancer cells carrying mutated
or epigenetically silenced BRCA1/2.

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Available from: Gerrit Los, Sep 22, 2015
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    • "All mice recovered weight once treatment was completed. Potentiation of platinum agents has also been reported for PARP1/2 inhibitors [14, 39]. In orthotopic MX-1 human breast cancer xenografts, treatment with E7449 enhanced the antitumor activity of carboplatin (Figure 2C). "
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    ABSTRACT: Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.
    Preview · Article · Oct 2015 · Oncotarget
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    • "However, one case series report patients with gBRCAm did not reveal a benefit to first line platinum chemotherapy in the treatment of advanced pancreatic cancer (97), although this needs to be further evaluated in a selected study for pancreatic cancer with gBRCAm. Preclinical studies have shown single-agent activity of PARPi (98), as well as radiosensitization in combination with chemoradiation in BRCA2-deficient pancreatic cells (25). Studies are ongoing to examine single-agent and combination PARPi therapy in BRCA2 mutant pancreatic cancers. "
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    ABSTRACT: Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.
    Full-text · Article · Feb 2014 · Frontiers in Oncology
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    • "Rucaparib, the first PARPi that was developed and tested in the clinic (in 2003 under the name AG014699) [22], [23], has been also shown to be effective in tumor xenografts of breast, lung, colon, colorectal, and pancreatic cancer [27], [30]. At the same time, it has been shown to be nontoxic in mice that carried at least one functional copy of the BRCA2 gene. "
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    ABSTRACT: Exposure to genotoxic agents, such as irradiation produces DNA damage, the toxicity of which is augmented when the DNA repair is impaired. Poly (ADP-ribose) polymerase (PARP) inhibitors were found to be "synthetic lethal" in cells deficient in BRCA1 and BRCA2 that impair homologous recombination. However, since many tumors, including prostate cancer (PCa) rarely have on such mutations, there is considerable interest in finding alternative determinants of PARP inhibitor sensitivity. We evaluated the effectiveness of radiation in combination with the PARP inhibitor, rucaparib in PCa cells. The combination index for clonogenic survival following radiation and rucaparib treatments revealed synergistic interactions in a panel of PCa cell lines, being strongest for LNCaP and VCaP cells that express ETS gene fusion proteins. These findings correlated with synergistic interactions for senescence activation, as indicated by β--galactosidase staining. Absence of PTEN and presence of ETS gene fusion thus facilitated activation of senescence, which contributed to decreased clonogenic survival. Increased radiosensitivity in the presence of rucaparib was associated with persistent DNA breaks, as determined by χ-H2AX, p53BP1, and Rad51 foci. VCaP cells, which harbor the TMPRSS2-ERG gene fusion and PC3 cells that stably express a similar construct (fusion III) showed enhanced sensitivity towards rucaparib, which, in turn, increased the radiation response to a similar extent as the DNA-PKcs inhibitor NU7441. Rucaparib radiosensitized PCa cells, with a clear benefit of low dose-rate radiation (LDR) administered over a longer period of time that caused enhanced DNA damage. LDR mimicking brachytherapy, which is used successfully in the clinic, was most effective when combined with rucaparib by inducing persistent DNA damage and senescence, leading to decreased clonogenic survival. This combination was most effective in the presence of the TMPRSS2-ERG and in the absence of PTEN, indicating clinical potential for brachytherapy in patients with intermediate and high risk PCa.
    Full-text · Article · Apr 2013 · PLoS ONE
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