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


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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    • "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.
    Frontiers in Oncology 02/2014; 4:42. DOI:10.3389/fonc.2014.00042
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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.
    PLoS ONE 04/2013; 8(4):e60408. DOI:10.1371/journal.pone.0060408 · 3.23 Impact Factor
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    • "HR is a complex process involving many components including ATM, ATR, CHK1, RAD51 and its homologues, the FANC proteins, MRE11/RAD50/NBS1 (MRN) and loss of function in any of these components may confer sensitivity to PARPi [Mccabe et al. 2006]. PARPi may also be synthetically lethal in cases where epigenetic silencing of BRCA occurs [Drew et al. 2010]. This effect in sporadic breast and ovarian cancers was referred to as 'BRCAness' [Ashworth, 2008] but it is now apparent that this BRCA-centric view is misleading as defects in other HR components are associated with a variety of cancers, e.g. "
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    ABSTRACT: The modulation of DNA repair pathways for therapeutic benefit in cancer has now become a reality with the development of poly (ADP-ribose) polymerase inhibitors (PARPi). PARP is involved in single-strand DNA breaks, which in the presence of defective homologous recombination repair lead to double-strand DNA breaks, the most lethal form of DNA damage. These agents therefore may be the drugs of choice for BRCA mutant breast and ovarian cancers. PARPi result in synergistic antitumor effects when combined with cisplatin, temozolomide, topoisomerase inhibitors and ionizing radiation. The indications for PARPi lie beyond BRCA mutations and may include genomic and functional defects in DNA repair and damage response pathways. Several PARPi are in the clinical development phase at this time and, given the recent failure of a phase III clinical trial of iniparib in triple-negative breast cancer, the identification of structural and functional differences between these inhibitors becomes critical. Acquired resistance to PARPi is being noted and represents an important limitation in this field. A concise review of the literature in this field is presented.
    rapeutic Advances in Medical Oncology, The 11/2011; 3(6):257-67. DOI:10.1177/1758834011417039 · 2.83 Impact Factor
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