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The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy:

The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy: Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol The potential for poly (ADP-ribose) (2011) 3(6) 257267 DOI: 10.1177/ polymerase inhibitors in cancer therapy ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ M. Javle and N. J. Curtin journalsPermissions.nav 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, temo- zolomide, 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 criti- cal. 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. Keywords: BRCA2 gene, DNA repair-deficiency disorders, poly (ADP-ribose) polymerases Correspondence to: Genomic instability: an ‘enabling’ advantage. These variant subclones may outgrow Nicola Curtin, PhD characterisation of cancer normal, unaffected tissues and successive clonal Professor of Experimental Cancer Therapeutics, The human genome is continually exposed to expansions of mutated cells may be responsible Northern Institute for potentially deleterious genotoxic events. These for the multistep process of tumorigenesis. While Cancer Research, Medical School, University of events could be endogenous, including oxidative hematologic malignancies have only a limited Newcastle upon Tyne, stress from normal metabolism and DNA repli- number of genetic alterations, in the case of NE2 4HH, UK n.j.curtin@ncl.ac.uk cation and recombination aberrations or exoge- solid tumors, myriad genetic alterations lead to Milind Javle, MD nous, resulting from exposure to genotoxic agents genetic heterogeneity. Genomic instability has Associate Professor, such as chemical mutagens and ultraviolet light. been described as an enabling characteristic of UT-MD Anderson Cancer Center, Houston, TX, USA Several detection and signaling pathways are acti- cancer and is broadly classified into microsatellite vated by DNA damage, resulting in the recruit- instability associated with the mutator pheno- ment and activation of groups of proteins to type, and chromosome instability recognized by repair the incurred damage by the appropriate gross chromosomal abnormalities [Hanahan and DNA repair pathway. This results either in cell Weinberg, 2011]. cycle arrest, thereby allowing sufficient time for repair to take place, or in the case of irreparable Several DNA repair pathways are responsible for damage, programmed cell death. the maintenance of genomic integrity, each of which repairs a specific type of DNA damage. It follows therefore that the genes responsible for These include nonhomologous end joining DNA damage detection and repair essentially (NHEJ), homologous recombination (HR), base behave as tumor suppressors and their defects excision repair (BER, also called single-strand would enable tumorigenesis in the presence of break repair [SSBR]), nucleotide excision repair ongoing genotoxic stress. The consequent genetic (NER), mismatch repair (MMR) and translesion or epigenetic alterations such as mutations, synthesis (TLS). Each of these pathways repairs a methylation or histone modifications result in specific DNA defect. For instance, MMR is genomic instability, which can lead to the evolu- involved in the detection and repair of base mis- tion of a subclone of cells with a selective growth matches, insertions and deletions, BER/SSBR http://tam.sagepub.com 257 Therapeutic Advances in Medical Oncology 3 (6) removes incorrect bases and repairs resultant cytotoxicity of PARP inhibitors (PARPi) in HR- nicks while NHEJ and HR are involved in the defective cells [Patel et al. 2011]. While PARPi repair of DNA double-strand breaks (DSBs) are effective in the case of BRCA1 or BRCA2 and repair of DNA crosslinks is complex involv- mutations, the paradigm of synthetic lethality ing NER, HR and possibly other pathways. can also be extended to other cancers, including Interestingly, although DNA repair defects lead sporadic cases. HR is a complex process involving to increased tumorigenesis, a paradoxical situa- many components including ATM, ATR, tion arises from the fact that in cancer cells, sus- CHK1, RAD51 and its homologues, the FANC tained replication in the presence of genotoxic proteins, MRE11/RAD50/NBS1 (MRN) and stress also requires some intact DNA repair path- loss of function in any of these components ways. Thus, cancers with aberrant DNA repair may confer sensitivity to PARPi [Mccabe et al. pathways become ‘addicted’ to one or more 2006]. PARPi may also be synthetically lethal in retained intact repair pathways to preserve their cases where epigenetic silencing of BRCA occurs growth. This can represent a resistance mecha- [Drew et al. 2010]. This effect in sporadic breast nism to certain types of DNA damaging chemo- and ovarian cancers was referred to as ‘BRCA- therapy and radiotherapy. Targeting the ness’ [Ashworth, 2008] but it is now apparent upregulated DNA repair pathway can enhance that this BRCA-centric view is misleading as the DNA damage and antitumor activity induced defects in other HR components are associated by radiotherapy and chemotherapy. These upre- with a variety of cancers, e.g. ATM defects in gulated DNA damage signaling and repair path- mantle-cell lymphoma, which may also benefit ways that cancer cells are addicted to may also from PARPi therapy [Williamson et al. 2010]. represent the cancer’s ‘Achilles’ heel’. A specific EMSY and PTEN have also been implicated as inhibitor to the pathway could potentially lead to they regulate the activity of other components of a selective antitumor effect by preventing the HR [Cousineau and Belmaaza, 2011; Mcellin repair of intrinsic DNA damage by exploiting et al. 2010]. the principle of synthetic lethality. PARP structurefunction relationship Synthetic lethality At the current time, a total of 16 PARP family Originally described by the geneticist members have been identified of which PARP1, Dobzhansky in the 1940s, synthetic lethality PARP2, PARP4 (Vault-PARP), Tankyrase-1 and refers to an interaction in which the individual 2 have confirmed poly (ADP)-ribosylating activ- deletion of either of two genes has no effect but ity and only PARP-1 and PARP-2 are involved in the combined deletion of both genes is cytotoxic DNA repair [Schreiber et al. 2006]. Recently, (Figure 1). Synthetic lethality can also be PARP-3 was identified as cooperating with exploited in the treatment of cancer as in the PARP-1 in DNA DSB repair, but deletion of case with cancer susceptibility syndromes, such PARP-3 alone does not compromise survival as BRCA1 or BRCA2 mutations. The latter after DNA damage and the mechanisms remain genes play a key role in maintaining genomic to be fully elucidated [Boehler et al. 2011]. integrity due to their involvement in HR, an PARP-1 was the first member of this family to important repair pathway for DNA DSBs. be discovered and its function in the maintenance Cancer cells with aberrant HR secondary to of genomic integrity has been well documented. BRCA mutations are critically dependent on In response to DNA single-strand breaks result- BER/SSBR for viability. The enzyme, poly ing from genotoxic stimuli, the PARP reaction (ADP-ribose) polymerase 1 (PARP-1) is critical uses nicotinamide adenine dinucleotide (NAD) for BER/SSBR (described below). Inhibition of as a substrate to generate poly (ADP-ribose) PARP-1 leads to an accumulation of unrepaired (PAR) [De Murcia, G. and Menissier De SSBs and therefore is synthetically lethal in the Murcia, J. 1994; De Murcia, G et al. 1994]. case of BRCA1 or BRCA2 mutations due to the accumulation of fatal replication fork collapse PARP-1 and PARP-2 form homodimers and het- and DSBs as was demonstrated by two indepen- erodimers at DNA breaks catalyzing the forma- dent groups [Bryant et al. 2005; Farmer et al. tion of long PAR chains covalently attached to 2005]. Recent evidence suggests that activation PARP-1 itself (automodification) or other of NHEJ is necessary for synthetic lethality, sug- nuclear proteins, e.g. histone H1 heteromodifica- gesting that the error-prone repair of replication- tion adjacent to the DNA breaks. These nega- associated DSBs is associated with the tively charged polymers form a scaffold and 258 http://tam.sagepub.com M Javle and NJ Curtin Figure 1. Poly (ADP-ribose) polymerase (PARP) is upregulated in conditions causing genotoxic stress, leading to increased single- strand break repair. In cases of homologous recombination (HR) deficiency, this becomes the main pathway for DNA repair and therefore its inhibition leads to synthetic lethality. PARPi, PARP inhibitor. recruit other proteins that are critical in BER [De localization signal, an automodification domain Murcia et al. 1994] and chromatin remodeling and a carboxy-terminal catalytic ‘PARP-signa- [Ahel et al. 2009; Timinszky et al. 2009]. ture’ domain that is responsible for PAR forma- tion [De Murcia et al. 1994]. The DNA-binding PARP activity also promotes the activation of domain also contains two zinc fingers that are mitotic recombination 11 (MRE11) and required for the detection of DNA strand Nijmegen breakage syndrome (NBS), members breaks resulting eventually in PARP-1 activation of the DNA damage-sensing MRN complex while a third zinc finger motif coordinates DNA- which activates ATM to sites of double-stand dependent enzyme activation. DNA damage [Haince et al. 2007]. Thus, the role of PARP-1 in DNA repair extends beyond The baseline activity of PARP-1 is low, but is the repair of DNA single-strand breaks. PARP-1 stimulated by DNA strand breaks. PARP is upre- not only plays a critical role in genomic mainte- gulated in several cancers, implying its possible nance but is also involved in transcriptional reg- role in cancer growth and survival [Virag and ulation, energy metabolism and cell death and Szabo, 2002]. In colorectal cancer, for instance, these roles are discussed below. PARP-1 mRNA overexpression was detected in over 70% of colorectal cancers and correlated PARP-1 has three distinct domains: an amino with the expression of beta-catenin, c-myc, terminal DNA-binding domain, a nuclear cyclin D1 and MMP-7 [Nosho et al. 2006]. http://tam.sagepub.com 259 Therapeutic Advances in Medical Oncology 3 (6) Inhibition of PARP is detrimental to cancer cells. colleagues, noted that while chemical inhibition However, PARP inhibition may not result in crit- of PARP-1 markedly enhanced the efficacy of ical injury to normal cells. PARP-1 knockout low-dose radiation, such an effect was lacking mice have been reported to grow normally in PARP-1 knockout models. The latter may be [Shall and De Murcia, 2000], however, the inac- explainable on the basis of PARP-2 upregulation, tivation of both PARP-1 and PARP-2, confers which may compensate for the absence of PARP- embryonic lethality [Schreiber et al. 2002]. 1 [Chalmers et al. 2004]. Thus PARPi, by Owing to the very close structural homology of inhibiting both PARP-1 and PARP-2, are likely the catalytic domains of PARP-1 and PARP-2, it to have more profound effects than indicated by is thought that most PARPi inhibit both enzymes. genetic knockout of only one of the two enzymes. Therefore, PARP inhibition in the clinical setting Select PARP-1 inhibitors in clinical trials are dis- could potentially cause serious adverse effects but cussed below. the experience to date suggests that profound AG014699 (PF-01367338) PARP inhibition is associated with very mild tox- AG014699 is a phosphate salt of AG14447 with icity. The clinical application of PARPi is there- aqueous solubility and was selected as suitable for fore an active area of research and development. clinical trial from a panel of 42 potential PARPi based on its chemo- and radio-potentiating effect Development of PARP Inhibitors [Thomas et al. 2007]. This PARPi, and its fore- The first-generation PARPi included nicotin- runner AG14361, showed spectacular activity in amide, benzamides and substituted benzamides xenograft models in combination with temozolo- such as 3-aminobenzamide (3-AB). These mide, resulting in complete and durable tumor agents had relatively low potency and specificity regression [Thomas et al. 2007; Calabrese et al. and, therefore, second-generation benzamides 2004]. AG14361 also caused a twofold to three- and more recently, third-generation inhibitors, fold enhancement of irinotecan-induced and most of which are competitive NADþ inhibitors radiation-induced tumor growth delay. and based on 3-AB structure, such as the nico- tinamide pharmacophore have been developed AG014699 was the first PARPi to enter clinical (Figure 2). The preclinical/clinical development trial for cancer therapy and has been studied in of PARPi has been as: (a) single agents in cases of phase I and phase II clinical trials in combination deficient DNA repair mechanisms such as with temozolomide for the treatment of meta- BRCA1 or BRCA2 mutations; (b) combined static melanoma. In the phase I study, dose esca- with cytotoxics (PARPi sensitize tumor cells to lation was driven by pharmacodynamic chemotherapeutic anticancer agents that induce measurement of PARP inhibition and the PARP DNA damage through BER; these agents include inhibitory dose (PID) was estimated at 12 mg/m temozolomide, platinum analogues and topoi- based on 7497% inhibition of PARP activity in peripheral lymphocytes and a >50% PARP inhi- somerase-1 inhibitors); or (c) as radiation sensi- bition in tumor biopsies posttreatment. tizers [Calabrese et al. 2004]. Radiosensitization AG014699 showed linear pharmacokinetics by PARP inhibition is enhanced in the presence with no interaction with temozolomide of defective DNA repair and is more pronounced [Plummer et al. 2008]. The recommended in rapidly dividing cancer tissues in the S phase as phase II dose was 200 mg/m of temozolomide compared with normal, noncycling cells and may with 12 mg/m of AG014699. In the phase II thus result in an enhanced safety ratio [Dungey study, a doubling of response rate and time to et al. 2008]. PARP knockout models have been tumor progression were noted as compared with utilized to confirm the chemo- and radio-poten- temozolomide alone, but at the cost of signifi- tiation of the PARPi. Both PARP-1 knockout and cantly higher myelosuppression in the combina- PARP-2 knockout mice are hypersensitive to ion- tion arm. At the present time, single-agent izing radiation (IR) and DNA alkylating agents studies in ovarian or breast cancers in BRCA (as reviewed by Rouleau et al. [2010]). In preclin- ical cancer models, Tentori and colleagues noted mutation carriers and combination studies with that melanoma models with stably silenced cisplatin, pemetrexed and epirubicin are being PARP-1 expression were highly sensitive to temo- conducted. The combination of AG014699 zolomide. In the same study, decreased tumori- with these latter drugs not classically associated genicity and angiogenesis were noted in the with PARP may be based on the observation that PARP-1/ melanoma models [Tentori et al. AG014699 is vasoactive, potentially increasing 2008]. On the other hand, Chalmers and drug delivery to the tumor [Ali et al. 2009]. 260 http://tam.sagepub.com M Javle and NJ Curtin Figure 2. Structure of 3-aminobenzamide (3-AB) and the recent poly (ADP-ribose) polymerase inhibitors (PARPi) developed from the nicotinamide pharmacophore. The Ki of AG014699/PF-01367388 and the IC values for most other inhibitors are presented to show potency, but it should be noted that these values are not directly comparable due to different experimental conditions, e.g. substrate concentrations. Veliparib (ABT-888) associated with this agent with 32 ongoing clini- Veliparib has been developed as a PARP-1 and cal trials of velaparib in combination with cyto- PARP-2 inhibitor with K(i)s of 5.2 and 2.9 nmol/ toxics in ovarian, breast, colorectal, prostate, liver l, respectively [Penning et al. 2009]. It is orally cancers, neurologic malignancies and leukemias. bioavailable and crosses the bloodbrain barrier. ABT-888 potentiated the cytotoxic effect of Olaparib (AZD2281) temozolomide in several human tumor models Olaparib (AZD2281) also inhibits PARP-1 and and IR in HCT116 human colon cancers PARP-2 at nanomolar concentrations [Menear [Clarke et al. 2009; Palma et al. 2009; et al. 2008]. Preclinical studies have largely con- Donawho et al. 2007]. The activity of platinum centrated on investigations of synthetic lethality analogues and cyclophosphamide were also in BRCA1 or BRCA2 defective models or com- enhanced by ABT-888 in the BRCA1 and 2 binations with platinum in these models defective MX-1 xenografts but ABT-888 had no [Rottenberg et al. 2008]. Radiosensitization in a single-agent activity in this model in the schedule glioma model has also been demonstrated used [Donawho et al. 2007]. Velaparib was inves- [Dungey et al. 2008]. Studies with human ovar- tigated in an innovative phase 0 trial, the first ian cancer xenografts demonstrated that olaparib such study in oncology [Kummar et al. 2009]. had single-agent activity and increased the effi- The primary study endpoint was target modula- cacy of carboplatin in xenografts defective in tion by the PARPi. PARP activity, when mea- BRCA2 but not those with normal BRCA func- sured after a single dose of veliparib was tion [Kortmann et al. 2011]. Olaparib was significantly inhibited at the 25 and 50 mg observed to increase the toxicity of topotecan in doses. There is an extensive clinical trial program animal models [Zander et al. 2010]. The first http://tam.sagepub.com 261 Therapeutic Advances in Medical Oncology 3 (6) clinical study of PARP inhibition in BRCA cancers [Vona-Davis et al. 2008]. Both, mutant cancers was with this agent. In this BRCA1-associated cancers and sporadic TN phase I study which enrolled 60 patients, olaparib tumors share a high degree of genomic instability, doses were escalated from 10 mg daily for 2 of implying an impaired ability to repair DNA every 3 weeks to 600 mg twice daily [Fong et al. damage. HR defects seen in TN breast cancer 2009a]. The dose of 200 mg twice daily was include BRCA1 methylation, overexpression of selected for further study in a select cohort of deregulators including ID4 and HMG as well as 23 patients with BRCA mutations. In this aberrations of MRE11, ATM and PALB2 [Alli group, nine had partial responses according to et al. 2009; Alexander et al. 2010]. Iniparib the NCI response evaluation criteria (RECIST). (BSI-201), when combined with gemcitabine A total of 19 of the 23 patients had BRCA-asso- and carboplatin for the treatment of TN breast cancer, has been studied in a randomized phase ciated tumors, including breast, ovarian, and prostate cancers. II trial compared with the same chemotherapy alone. The addition of iniparib increased disease Given these interesting preliminary data, two control rate (56% to 34%), response rate (52% multicenter, international phase II studies of ola- to 32%), progression-free survival (5.9 to parib in patients with breast or ovarian cancers 3.6 months) and overall survival (12.3 to 7.7 having BRCA1 or BRCA2 mutations were con- months) without increasing toxicity ducted [Fong et al. 2009b; Tutt et al. 2010]. [O’shaughnessy et al. 2011]. A follow-up phase Patients enrolled were refractory to standard che- III study, however, was negative as it did not motherapeutic regimens. A total of 27 patients in meet the prespecified criteria for significance for the first cohort received 400 mg of olaparib twice coprimary endpoints of overall survival and pro- daily for 28 days, and 27 patients in the second gression-free survival. Given the structural and cohort received 100 mg of olaparib twice daily. mechanistic differences between iniparib and The overall response rate was 41% with other PARPi, these negative results do not neces- 400 mg, and 22% with 100 mg olaparib. The sarily imply a ‘class effect’ and further study of median time to progression was 5.7 and 3.8 TN breast cancer with other PARPi should be months, respectively. The common adverse encouraged. effects were mild, including fatigue, nausea and INO-1001 vomiting. A parallel study using the two dosage This agent is an isoindolinone derivative and is regimens in 55 BRCA-mutated carriers with being developed for both oncological and cardio- ovarian cancer confirmed an overall response vascular indications. Preclinical studies demon- rate of 33% in the 400 mg group, and 12.5% in strate its protective effect in models of cardiac the 100 mg group. These proof-of-concept stud- dysfunction [Pacher et al. 2006] and reversal of ies confirmed that BRCA1 or BRCA2 mutational temozolomide resistance in MMR-defective status serves as a predictive marker for PARPi. xenografts [Cheng et al. 2005]. This was the first PARP-1 inhibitor to be investigated for car- Iniparib (BSI-201) Unlike other PARPi that compete with NADþ diovascular disease and has been granted orphan for the PARP catalytic site, iniparib (4-iodo, 3- drug status by the US Food and Drug nitrobenzamide) is unique in that it targets the Administration for the prevention of postopera- zinc finger domain and prevents PARP-1 activa- tive aortic aneurysm repair complications. In this tion by DNA breaks [Mendeleyev et al. 1995]. phase II study, INO-1001 may have reduced the Therefore, it may have differential effects as com- plasma levels of C-reactive protein and the pared with other synthetic catalytic PARPi. inflammatory marker interleukin-6, without Moreover, as this inhibitor has also been shown reducing plasma markers of myocardial injury. to inhibit other enzymes such as GAPDH [Bauer No serious toxic events ensued in this trial et al. 2002], it would be dangerous to conclude [Morrow et al. 2009]. This agent is being devel- that its anticancer effects are solely attributable to oped in oncology in melanoma and glioma and as PARP inhibition. This agent has been extensively a single agent in cancer for BRCA1- and investigated in triple-negative (TN) breast BRCA2-deficient tumors. Phase I studies of cancers. INO-001 at 100, 200 and 400 mg/m in combi- nation with temozolomide indicated a short ter- TN breast cancers are believed to share the minal half life and the dose-limiting toxicities molecular characteristics of BRCA1-associated observed at the highest dose were 262 http://tam.sagepub.com M Javle and NJ Curtin myelosuppression and elevated liver enzymes are very sensitive to 6-thioguanine as HR is [Bedikian et al. 2009]. involved in the repair of 6-thioguanine-induced DSBs [Issaeva et al. 2010]. 6-thioguanine is not Other PARPi in preclinical and phase I trial a substrate for p glycoprotein and is a potent cyto- stages include GPI21016 (MGI/Eisai), MK- toxic in PARP-resistant tumors. Furthermore, 4827 (Merck), BMN-673 (Biomarin) and CEP- these investigators noted that genetically reverted 9722 (Cephalon). Additional information on BRCA2 defective tumors also retain sensitivity to these inhibitors can be found in a review by 6-thioguanine. Altogether, these findings suggest Ferraris [Ferraris, 2010]. that 6-thioguanine may be efficient in also killing advanced and drug-resistant BRCA1 or BRCA2 Resistance mechanisms for PARPi defective tumors. Acquired resistance to targeted agents is common and PARPi are no exception in this regard. As the Patient selection for PARPi trials clinical development of PARPi is still at an early A major challenge is to identify predictive mar- stage, the underlying resistance mechanisms have kers for PARPi therapy for those sporadic cancers not yet been elucidated. However, preclinical that may benefit due to functional defects in the studies offer interesting possibilities. CAPAN-1 HR pathways. Several surrogate markers have pancreatic cancer cells lines are BRCA2 deficient been described, none of which are widely avail- secondary to a 6174delT frameshift mutation, able in the clinical setting at the current time. which makes them exquisitely sensitive to Gene-expression arrays have been investigated PARPi. CAPAN-1 cells cannot form damage- for their predictive value [Jazaeri et al. 2002]. induced RAD51 foci, as they are HR-defective. Turner and colleagues hypothesized that a PARPi-resistant clones were highly resistant to gene and protein expression signature may the drug (over 1000-fold), and were also cross- have the ability to identify the BRCA-ness pro- resistant to the DNA crosslinking agent, cis- file in patients [Turner et al. 2004]. platin. Interestingly, these resistant clones Konstantinopoulos and colleagues defined a acquired the ability to form RAD51 foci after BRCA-like gene expression profile that PARPi treatment or exposure to irradiation sug- correlated with PARPi and platinum gesting that re-acquisition of HR capability may sensitivity [Konstantinopoulos et al. 2010]. be the mechanism of acquired resistance. In sup- Phosphorylation of the Ser-139 residue of the port of this, DNA sequencing of PARP inhibitor- histone variant H2AX, forming gH2AX, is an resistant clones revealed new BRCA2 isoforms as early cellular response to the induction of DNA a result of intragenic deletion of the c.6174delT DSBs. Detection of this phosphorylation event mutation and restoration of the open reading has emerged as a highly specific and sensitive frame [Edwards et al. 2008; Sakai et al. 2008; molecular marker for monitoring DNA damage Swisher et al. 2008]. Recently, 53BP1 has been initiation and resolution. This accumulation is shown to promote error-prone NHEJ in BRCA1 detectable by immunofluorescence using an anti- mutant cells and that loss of 53BP1 partially body to gH2AX. Rad51 is a crucial downstream restores HR function and can rescue from DNA protein involved in HR repair, which is reloca- damaging agent and PARPi sensitivity lized within the nucleus in response to DNA [Bouwman et al. 2010; Bunting et al. 2010]. damage. Rad51 foci can also be visualized by Loss of 53BP1 appears to be relatively common immunofluorescent microscopy and are thought in TN and BRCA1-mutant breast cancer sam- to represent assemblies of proteins at these sites ples [Bouwman et al. 2010]. of HR repair. Combination gH2AX/RAD51 immunofluorescence has been investigated in An alternative mechanism was described with ola- primary ovarian cancer cell cultures parib [Rottenberg et al. 2008]. In this case, resis- [Mukhopadhyay et al. 2010] and primary acute tance may be related to the upregulation of the myeloid leukemia (AML) cultures [Gaymes et al. ABCB1a/b genes, which encode P-glycoprotein 2009]. Both studies demonstrated that raised multidrug resistance drug efflux pumps; this gH2AX and decreased RAD51 foci expression effect could be reversed with the P-glycoprotein predicts PARPi sensitivity. Graeser and col- inhibitor, tariquidar. A recent study investigated leagues investigated RAD51 immunofluores- the role of 6-thioguanine in reversing this resis- cence in replicating (geminin positive) cells in tance mechanism. Issaeva and colleagues first breast cancer biopsy specimens from women noted that BRCA1, BRCA2 or XRCC3 tumors receiving neoadjuvant anthracycline therapy. http://tam.sagepub.com 263 Therapeutic Advances in Medical Oncology 3 (6) The RAD51 score was predictive of complete previously received research support and consul- response in women receiving neoadjuvant ther- tancy fees from BiPAR sciences. apy for breast cancer [Graeser et al. 2010]. Although cumbersome, these assays currently represent the most reliable way to identify HR References Ahel, D., Horejsi, Z., Wiechens, N., Polo, S.E., defects, particularly in light of the recent studies Garcia-Wilson, E., Ahel, I. et al. (2009) Poly(ADP- showing that even in BRCA1-mutant tumors, ribose)-dependent regulation of DNA repair by the coincident loss of 53BP1 can restore HR function chromatin remodeling enzyme ALC1. Science and PARPi resistance [Bouwman et al. 2010; 325: 12401243. Bunting et al. 2010]. Alexander, B.M., Sprott, K., Farrow, D.A., Wang, X., D’andrea, A.D., Schnitt, S.J. et al. (2010) DNA repair Conclusions protein biomarkers associated with time to recurrence in triple-negative breast cancer. Clin Cancer Res Genomic instability in cancer may result from an 16: 57965804. imbalance of DNA damage signaling and repair pathways; upregulated pathways may confer Ali, M., Telfer, B.A., Mccrudden, C., O’rourke, M., Thomas, H.D., Kamjoo, M. et al. (2009) Vasoactivity resistance to certain types of genotoxic agent of AG014699, a clinically active small molecule but may also be necessary for the survival of the inhibitor of poly(ADP-ribose) polymerase: a contrib- cancer cell. Targeting these pathways may result utory factor to chemopotentiation in vivo? Clin Cancer in single-agent activity specifically in the cancer Res 15: 61066112. cell where repair of endogenously generated Alli, E., Sharma, V.B., Sunderesakumar, P. and Ford, DNA damage is inhibited as well as tumor-selec- J.M. (2009) Defective repair of oxidative DNA damage tive chemo and radio-sensitization. PARPi in triple-negative breast cancer confers sensitivity to increase the anticancer activity of temozolomide, inhibition of poly(ADP-ribose) polymerase. Cancer Res topoisomerase I poisons and IR in a wide range of 69: 35893596. tumor models, an approach that has been vali- Ashworth, A. (2008) A synthetic lethal therapeutic dated by genetic knockdown of PARP-1 and approach: poly(ADP) ribose polymerase inhibitors for PARP-2. However, the most exciting aspect is the treatment of cancers deficient in DNA double- strand break repair. J Clin Oncol 26: 37853790. the discovery that PARPi alone selectively kill cancer cells that lack HR without affecting Bauer, P.I., Mendeleyeva, J., Kirsten, E., Comstock, repair competent cells. This observation has rap- J.A., Hakam, A., Buki, K.G. et al. (2002) Anti-cancer action of 4-iodo-3-nitrobenzamide in combination idly translated into clinical trials where PARPi with buthionine sulfoximine: inactivation of have shown good anticancer activity in BRCA1 poly(ADP-ribose) polymerase and tumor glycolysis and BRCA2 patients with breast, ovarian and and the appearance of a poly(ADP-ribose) polymerase prostate cancer with only mild toxicities. HR is protease. Biochem Pharmacol 63: 455462. a complex and multicomponent pathway and Bedikian, A.Y., Papadopoulos, N.E., Kim, K.B., Hwu, preclinical data indicates that PARPi will be W.J., Homsi, J., Glass, M.R. et al. (2009) A phase Ib useful in tumors lacking any one of a number of trial of intravenous INO-1001 plus oral temozolomide these key proteins. Identification of these poten- in subjects with unresectable stage-III or IV mela- tially PARPi-responsive tumors is the next chal- noma. Cancer Invest 27: 756763. lenge. Gene expression signatures and assays of Boehler, C., Gauthier, L.R., Mortusewicz, O., Biard, HR function can fulfill this function but they are D.S., Saliou, J.M., Bresson, A. et al. (2011) Poly(ADP- currently too expensive and cumbersome to ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. become routine clinical practice. Proc Natl Acad Sci U S A, in press. Bouwman, P., Aly, A., Escandell, J.M., Pieterse, M., Funding Bartkova, J., Van Der Gulden, H. et al. (2010) 53BP1 This research received no specific grant from any loss rescues BRCA1 deficiency and is associated with funding agency in the public, commercial, or not- triple-negative and BRCA-mutated breast cancers. Nat for-profit sectors. Struct Mol Biol 17: 688695. Bryant, H.E., Schultz, N., Thomas, H.D., Parker, Conflict of interest statement K.M., Flower, D., Lopez, E. et al. (2005) Specific Milind Javle has no conflicts of interest to killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434: 913917. declare. Nicola Curtin receives current research support from Pfizer and BioMarin and consul- Bunting, S.F., Callen, E., Wong, N., Chen, H.T., tancy fees from BioMarin and Eisai and has Polato, F., Gunn, A. et al. (2010) 53BP1 inhibits 264 http://tam.sagepub.com M Javle and NJ Curtin homologous recombination in BRCA1-deficient cells Farmer, H., Mccabe, N., Lord, C.J., Tutt, A.N., by blocking resection of DNA breaks. Cell Johnson, D.A., Richardson, T.B. et al. (2005) 141: 243254. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917921. Calabrese, C.R., Almassy, R., Barton, S., Batey, M.A., Calvert, A.H., Canan-Koch, S. et al. (2004) Ferraris, D.V. (2010) Evolution of poly(ADP-ribose) Anticancer chemosensitization and radiosensitization polymerase-1 (PARP-1) inhibitors. From concept to by the novel poly(ADP-ribose) polymerase-1 Inhibitor clinic. J Med Chem 53: 45614584. AG14361. J Natl Cancer Inst 96: 5667. Fong, P.C., Boss, D.S., Yap, T.A., Tutt, A., Wu, P., Chalmers, A., Johnston, P., Woodcock, M., Joiner, M. Mergui-Roelvink, M. et al. (2009a) Inhibition and Marples, B. (2004) PARP-1, PARP-2, and the of poly(ADP-ribose) polymerase in tumors cellular response to low doses of ionizing radiation. Int from BRCA mutation carriers. N Engl J Med J Radiat Oncol Biol Phys 58: 410419. 361: 123134. Cheng, C.L., Johnson, S.P., Keir, S.T., Quinn, J.A., Fong, P.C., Yap, T.A., Boss, D.S., Carden, C.P., Ali-Osman, F., Szabo, C. et al. (2005) Poly(ADP- Mergui-Roelvink, M., Gourley, C. et al. (2009b) Ribose) polymerase-1 inhibition reverses temozolo- Poly(ADP)-ribose polymerase inhibition: frequent mide resistance in a DNA mismatch repair-deficient durable responses in BRCA carrier ovarian cancer malignant glioma xenograft. Mol Cancer Ther correlating with platinum-free interval. J Clin Oncol 4: 13641368. 28: 25122519. Clarke, M.J., Mulligan, E.A., Grogan, P.T., Mladek, Gaymes, T.J., Shall, S., Macpherson, L.J., Twine, A.C., Carlson, B.L., Schroeder, M.A. et al. (2009) N.A., Lea, N.C., Farzaneh, F. et al. (2009) Inhibitors Effective sensitization of temozolomide by ABT-888 is of poly ADP-ribose polymerase (PARP) induce apo- lost with development of temozolomide resistance in ptosis of myeloid leukemic cells: potential for therapy glioblastoma xenograft lines. Mol Cancer Ther of myeloid leukemia and myelodysplastic syndromes. 8: 407414. Haematologica 94: 638646. Cousineau, I. and Belmaaza, A. (2011) EMSY Graeser, M., Mccarthy, A., Lord, C.J., Savage, K., overexpression disrupts the BRCA2/RAD51 Hills, M., Salter, J. et al. (2010) A marker of homol- Pathway in the DNA-damage response: implications ogous recombination predicts pathologic complete for chromosomal instability/recombination syn- response to neoadjuvant chemotherapy in primary dromes as checkpoint diseases. Mol Genet Genomics, breast cancer. Clin Cancer Res 16: 61596168. in press. Haince, J.F., Kozlov, S., Dawson, V.L., Dawson, T.M., De Murcia, G. and Menissier De Murcia, J. (1994) Hendzel, M.J., Lavin, M.F. et al. (2007) Ataxia telan- Poly(ADP-ribose) polymerase: a molecular nick- giectasia mutated (ATM) signaling network is modu- sensor. Trends Biochem Sci 19: 172176. lated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol De Murcia, G., Schreiber, V., Molinete, M., Saulier, Chem 282: 1644116453. B., Poch, O., Masson, M. et al. (1994) Structure and function of poly(ADP-ribose) polymerase. Mol Cell Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Biochem 138: 1524. cancer: the next generation. Cell 144: 646674. Donawho, C.K., Luo, Y., Penning, T.D., Bauch, J.L., Issaeva, N., Thomas, H.D., Djureinovic, T., Jaspers, Bouska, J.J., Bontcheva-Diaz, V.D. et al. (2007) ABT- J.E., Stoimenov, I., Kyle, S. et al. (2010) 6- 888, an orally active poly(ADP-ribose) polymerase Thioguanine selectively kills BRCA2-defective tumors inhibitor that potentiates DNA-damaging agents in and overcomes PARP inhibitor resistance. Cancer Res preclinical tumor models. Clin Cancer Res 70: 62686276. 13: 27282737. Jazaeri, A.A., Yee, C.J., Sotiriou, C., Brantley, K.R., Drew, Y., Mulligan, E.A., Vong, W.T., Thomas, H.D., Boyd, J. and Liu, E.T. (2002) Gene expres- Kahn, S., Kyle, S. et al. (2010) Therapeutic poten- sion profiles of BRCA1-linked, BRCA2-linked, and tial of poly(ADP-ribose) polymerase inhibitor sporadic ovarian cancers. J Natl Cancer Inst AG014699 in human cancers with mutated or 94: 9901000. methylated BRCA1 or BRCA2. J Natl Cancer Inst Konstantinopoulos, P.A., Spentzos, D., Karlan, B.Y., 103: 334346. Taniguchi, T., Fountzilas, E., Francoeur, N. et al. Dungey, F.A., Loser, D.A. and Chalmers, A.J. (2008) (2010) gene expression profile of BRCAness that cor- Replication-dependent radiosensitization of human relates with responsiveness to chemotherapy and with glioma cells by inhibition of poly(ADP-ribose) poly- outcome in patients with epithelial ovarian cancer. merase: mechanisms and therapeutic potential. Int J J Clin Oncol 28: 35553561. Radiat Oncol Biol Phys 72: 11881197. Kortmann, U., Mcalpine, J.N., Xue, H., Guan, J., Ha, Edwards, S.L., Brough, R., Lord, C.J., Natrajan, R., G., Tully, S. et al. (2011) Tumor growth inhibition by Vatcheva, R., Levine, D.A. et al. (2008) Resistance to olaparib in BRCA2 germline-mutated patient-derived therapy caused by intragenic deletion in BRCA2. ovarian cancer tissue xenografts. Clin Cancer Res Nature 451: 11111115. 17: 783791. http://tam.sagepub.com 265 Therapeutic Advances in Medical Oncology 3 (6) Kummar, S., Kinders, R., Gutierrez, M.E., Palma, J.P., Wang, Y.C., Rodriguez, L.E., Rubinstein, L., Parchment, R.E., Phillips, L.R. et al. Montgomery, D., Ellis, P.A., Bukofzer, G. et al. (2009) (2009) Phase 0 clinical trial of the poly (ADP- ABT-888 confers broad in vivo activity in combination ribose) polymerase inhibitor ABT-888 in patients with temozolomide in diverse tumors. Clin Cancer Res with advanced malignancies. J Clin Oncol 15: 72777290. 27: 27052711. Patel, A.G., Sarkaria, J.N. and Kaufmann, S.H. (2011) Mccabe, N., Turner, N.C., Lord, C.J., Kluzek, K., Nonhomologous end joining drives poly(ADP-ribose) Bialkowska, A., Swift, S. et al. (2006) Deficiency in the polymerase (PARP) inhibitor lethality in homologous repair of DNA damage by homologous recombination recombination-deficient cells. Proc Natl Acad Sci U S A 108: 34063411. and sensitivity to poly(ADP-ribose) polymerase inhi- bition. Cancer Res 66: 81098115. Penning, T.D., Zhu, G.D., Gandhi, V.B., Gong, J., Mcellin, B., Camacho, C.V., Mukherjee, B., Hahm, Liu, X., Shi, Y. et al. (2009) Discovery of the poly(ADP-ribose) polymerase (PARP) inhibitor 2- B., Tomimatsu, N., Bachoo, R.M. et al. (2010) PTEN [(R)-2-methylpyrrolidin-2-Yl]-1h-benzimidazole-4- loss compromises homologous recombination repair in carboxamide (ABT-888) for the treatment of cancer. J astrocytes: implications for glioblastoma therapy with Med Chem 52: 514523. temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res 70: 54575464. Plummer, R., Jones, C., Middleton, M., Wilson, R., Evans, J., Olsen, A. et al. (2008) Phase I study of the Mendeleyev, J., Kirsten, E., Hakam, A., Buki, K.G. poly(ADP-ribose) polymerase inhibitor, AG014699, in and Kun, E. (1995) Potential chemotherapeutic combination with temozolomide in patients with activity of 4-iodo-3-nitrobenzamide. Metabolic reduc- advanced solid tumors. Clin Cancer Res tion to the 3-nitroso derivative and induction of cell 14: 79177923. death in tumor cells in culture. Biochem Pharmacol 50: 705714. Rottenberg, S., Jaspers, J.E., Kersbergen, A., Van Der Burg, E., Nygren, A.O., Zander, S.A. et al. (2008) Menear, K.A., Adcock, C., Boulter, R., Cockcroft, High sensitivity of BRCA1-deficient mammary tumors X.L., Copsey, L., Cranston, A. et al. (2008) 4-[3-(4- to the PARP inhibitor AZD2281 alone and in combi- Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluor- nation with platinum drugs. Proc Natl Acad Sci U S A obenzyl]-2H-PHTH alazin-1-one: a novel bioavailable 105: 1707917084. inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51: 65816591. Rouleau, M., Patel, A., Hendzel, M.J., Kaufmann, S.H. and Poirier, G.G. (2010) PARP inhibition: Morrow, D.A., Brickman, C.M., Murphy, S.A., Baran, PARP1 and beyond. Nat Rev Cancer 10: 293301. K., Krakover, R., Dauerman, H. et al. (2009) A ran- domized, placebo-controlled trial to evaluate the tol- Sakai, W., Swisher, E.M., Karlan, B.Y., Agarwal, erability, safety, pharmacokinetics, and M.K., Higgins, J., Friedman, C. et al. (2008) pharmacodynamics of a potent inhibitor of poly(ADP- Secondary mutations as a mechanism of cisplatin ribose) polymerase (INO-1001) in patients with ST- resistance in BRCA2-mutated cancers. Nature elevation myocardial infarction undergoing primary 451: 11161120. percutaneous coronary intervention: results of the TIMI 37 Trial. J Thromb Thrombolysis 27: 359364. Schreiber, V., Ame, J.C., Dolle, P., Schultz, I., Rinaldi, B., Fraulob, V. et al. (2002) Poly(ADP- Mukhopadhyay, A., Elattar, A., Cerbinskaite, A., ribose) polymerase-2 (PARP-2) is required for Wilkinson, S.J., Drew, Y., Kyle, S. et al. (2010) efficient base excision DNA repair in association Development of a functional assay for homologous with PARP-1 and XRCC1. J Biol Chem recombination status in primary cultures of epithelial 277: 2302823036. ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Schreiber, V., Dantzer, F., Ame, J.C. and De Murcia, Res 16: 23442351. G. (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517528. Nosho, K., Yamamoto, H., Mikami, M., Taniguchi, H., Takahashi, T., Adachi, Y. et al. (2006) Shall, S. and De Murcia, G. (2000) Poly(ADP-ribose) Overexpression of poly(ADP-ribose) polymerase-1 polymerase-1: what have we learned from the deficient (PARP-1) in the early stage of colorectal carcinogene- mouse model? Mutat Res 460: 115. sis. Eur J Cancer 42: 23742381. Swisher, E.M., Sakai, W., Karlan, B.Y., Wurz, K., O’shaughnessy, J., Osborne, C., Pippen, J.E., Yoffe, Urban, N. and Taniguchi, T. (2008) Secondary M., Patt, D., Rocha, C. et al. (2011) Iniparib plus BRCA1 mutations in BRCA1-mutated ovarian carci- chemotherapy in metastatic triple-negative breast nomas with platinum resistance. Cancer Res cancer. N Engl J Med 364: 205214. 68: 25812586. Pacher, P., Liaudet, L., Mabley, J.G., Cziraki, A., Tentori, L., Muzi, A., Dorio, A.S., Bultrini, S., Hasko, G. and Szabo, C. (2006) Beneficial effects of a Mazzon, E., Lacal, P.M. et al. (2008) Stable depletion novel ultrapotent poly(ADP-ribose) polymerase of poly (ADP-ribose) polymerase-1 reduces in vivo inhibitor in murine models of heart failure. Int J Mol melanoma growth and increases chemosensitivity. Eur Med 17: 369375. J Cancer 44: 13021314. 266 http://tam.sagepub.com M Javle and NJ Curtin Thomas, H.D., Calabrese, C.R., Batey, M.A., Virag, L. and Szabo, C. (2002) The therapeutic Canan, S., Hostomsky, Z., Kyle, S. et al. (2007) potential of poly(ADP-ribose) polymerase inhibitors. Preclinical selection of a novel poly(ADP-ribose) Pharmacol Rev 54: 375429. polymerase inhibitor for clinical trial. Mol Cancer Ther Vona-Davis, L., Rose, D.P., Hazard, H., Howard- 6: 945956. Mcnatt, M., Adkins, F., Partin, J. et al. (2008) Triple- Timinszky, G., Till, S., Hassa, P.O., Hothorn, M., negative breast cancer and obesity in a rural Kustatscher, G., Nijmeijer, B. et al. (2009) A macro- Appalachian population. Cancer Epidemiol Biomarkers domain-containing histone rearranges chromatin upon Prev 17: 33193324. sensing PARP1 activation. Nat Struct Mol Biol Williamson, C.T., Muzik, H., Turhan, A.G., Zamo, 16: 923929. A., O’connor, M.J., Bebb, D.G. et al. (2010) Atm Turner, N., Tutt, A. and Ashworth, A. (2004) Deficiency Sensitizes Mantle Cell Lymphoma Cells to Hallmarks of ’BRCAness’ in sporadic cancers. Nat Rev Poly(Adp-Ribose) Polymerase-1 Inhibitors. Mol Cancer 4: 814819. Cancer Ther 9: 347–357. Tutt, A., Robson, M., Garber, J.E., Domchek, S.M., Zander, S.A., Kersbergen, A., Van Der Burg, E., De Audeh, M.W., Weitzel, J.N. et al. (2010) Oral Water, N., Van Tellingen, O., Gunnarsdottir, S. et al. poly(ADP-ribose) polymerase inhibitor olaparib in (2010) Sensitivity and acquired resistance of Visit SAGE journals online patients with BRCA1 or BRCA2 mutations and BRCA1;P53-deficient mouse mammary tumors to the http://tam.sagepub.com advanced breast cancer: a proof-of-concept trial. topoisomerase I inhibitor topotecan. Cancer Res Lancet 376: 235244. 70: 17001710. http://tam.sagepub.com 267 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy:

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Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol The potential for poly (ADP-ribose) (2011) 3(6) 257267 DOI: 10.1177/ polymerase inhibitors in cancer therapy ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ M. Javle and N. J. Curtin journalsPermissions.nav 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, temo- zolomide, 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 criti- cal. 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. Keywords: BRCA2 gene, DNA repair-deficiency disorders, poly (ADP-ribose) polymerases Correspondence to: Genomic instability: an ‘enabling’ advantage. These variant subclones may outgrow Nicola Curtin, PhD characterisation of cancer normal, unaffected tissues and successive clonal Professor of Experimental Cancer Therapeutics, The human genome is continually exposed to expansions of mutated cells may be responsible Northern Institute for potentially deleterious genotoxic events. These for the multistep process of tumorigenesis. While Cancer Research, Medical School, University of events could be endogenous, including oxidative hematologic malignancies have only a limited Newcastle upon Tyne, stress from normal metabolism and DNA repli- number of genetic alterations, in the case of NE2 4HH, UK n.j.curtin@ncl.ac.uk cation and recombination aberrations or exoge- solid tumors, myriad genetic alterations lead to Milind Javle, MD nous, resulting from exposure to genotoxic agents genetic heterogeneity. Genomic instability has Associate Professor, such as chemical mutagens and ultraviolet light. been described as an enabling characteristic of UT-MD Anderson Cancer Center, Houston, TX, USA Several detection and signaling pathways are acti- cancer and is broadly classified into microsatellite vated by DNA damage, resulting in the recruit- instability associated with the mutator pheno- ment and activation of groups of proteins to type, and chromosome instability recognized by repair the incurred damage by the appropriate gross chromosomal abnormalities [Hanahan and DNA repair pathway. This results either in cell Weinberg, 2011]. cycle arrest, thereby allowing sufficient time for repair to take place, or in the case of irreparable Several DNA repair pathways are responsible for damage, programmed cell death. the maintenance of genomic integrity, each of which repairs a specific type of DNA damage. It follows therefore that the genes responsible for These include nonhomologous end joining DNA damage detection and repair essentially (NHEJ), homologous recombination (HR), base behave as tumor suppressors and their defects excision repair (BER, also called single-strand would enable tumorigenesis in the presence of break repair [SSBR]), nucleotide excision repair ongoing genotoxic stress. The consequent genetic (NER), mismatch repair (MMR) and translesion or epigenetic alterations such as mutations, synthesis (TLS). Each of these pathways repairs a methylation or histone modifications result in specific DNA defect. For instance, MMR is genomic instability, which can lead to the evolu- involved in the detection and repair of base mis- tion of a subclone of cells with a selective growth matches, insertions and deletions, BER/SSBR http://tam.sagepub.com 257 Therapeutic Advances in Medical Oncology 3 (6) removes incorrect bases and repairs resultant cytotoxicity of PARP inhibitors (PARPi) in HR- nicks while NHEJ and HR are involved in the defective cells [Patel et al. 2011]. While PARPi repair of DNA double-strand breaks (DSBs) are effective in the case of BRCA1 or BRCA2 and repair of DNA crosslinks is complex involv- mutations, the paradigm of synthetic lethality ing NER, HR and possibly other pathways. can also be extended to other cancers, including Interestingly, although DNA repair defects lead sporadic cases. HR is a complex process involving to increased tumorigenesis, a paradoxical situa- many components including ATM, ATR, tion arises from the fact that in cancer cells, sus- CHK1, RAD51 and its homologues, the FANC tained replication in the presence of genotoxic proteins, MRE11/RAD50/NBS1 (MRN) and stress also requires some intact DNA repair path- loss of function in any of these components ways. Thus, cancers with aberrant DNA repair may confer sensitivity to PARPi [Mccabe et al. pathways become ‘addicted’ to one or more 2006]. PARPi may also be synthetically lethal in retained intact repair pathways to preserve their cases where epigenetic silencing of BRCA occurs growth. This can represent a resistance mecha- [Drew et al. 2010]. This effect in sporadic breast nism to certain types of DNA damaging chemo- and ovarian cancers was referred to as ‘BRCA- therapy and radiotherapy. Targeting the ness’ [Ashworth, 2008] but it is now apparent upregulated DNA repair pathway can enhance that this BRCA-centric view is misleading as the DNA damage and antitumor activity induced defects in other HR components are associated by radiotherapy and chemotherapy. These upre- with a variety of cancers, e.g. ATM defects in gulated DNA damage signaling and repair path- mantle-cell lymphoma, which may also benefit ways that cancer cells are addicted to may also from PARPi therapy [Williamson et al. 2010]. represent the cancer’s ‘Achilles’ heel’. A specific EMSY and PTEN have also been implicated as inhibitor to the pathway could potentially lead to they regulate the activity of other components of a selective antitumor effect by preventing the HR [Cousineau and Belmaaza, 2011; Mcellin repair of intrinsic DNA damage by exploiting et al. 2010]. the principle of synthetic lethality. PARP structurefunction relationship Synthetic lethality At the current time, a total of 16 PARP family Originally described by the geneticist members have been identified of which PARP1, Dobzhansky in the 1940s, synthetic lethality PARP2, PARP4 (Vault-PARP), Tankyrase-1 and refers to an interaction in which the individual 2 have confirmed poly (ADP)-ribosylating activ- deletion of either of two genes has no effect but ity and only PARP-1 and PARP-2 are involved in the combined deletion of both genes is cytotoxic DNA repair [Schreiber et al. 2006]. Recently, (Figure 1). Synthetic lethality can also be PARP-3 was identified as cooperating with exploited in the treatment of cancer as in the PARP-1 in DNA DSB repair, but deletion of case with cancer susceptibility syndromes, such PARP-3 alone does not compromise survival as BRCA1 or BRCA2 mutations. The latter after DNA damage and the mechanisms remain genes play a key role in maintaining genomic to be fully elucidated [Boehler et al. 2011]. integrity due to their involvement in HR, an PARP-1 was the first member of this family to important repair pathway for DNA DSBs. be discovered and its function in the maintenance Cancer cells with aberrant HR secondary to of genomic integrity has been well documented. BRCA mutations are critically dependent on In response to DNA single-strand breaks result- BER/SSBR for viability. The enzyme, poly ing from genotoxic stimuli, the PARP reaction (ADP-ribose) polymerase 1 (PARP-1) is critical uses nicotinamide adenine dinucleotide (NAD) for BER/SSBR (described below). Inhibition of as a substrate to generate poly (ADP-ribose) PARP-1 leads to an accumulation of unrepaired (PAR) [De Murcia, G. and Menissier De SSBs and therefore is synthetically lethal in the Murcia, J. 1994; De Murcia, G et al. 1994]. case of BRCA1 or BRCA2 mutations due to the accumulation of fatal replication fork collapse PARP-1 and PARP-2 form homodimers and het- and DSBs as was demonstrated by two indepen- erodimers at DNA breaks catalyzing the forma- dent groups [Bryant et al. 2005; Farmer et al. tion of long PAR chains covalently attached to 2005]. Recent evidence suggests that activation PARP-1 itself (automodification) or other of NHEJ is necessary for synthetic lethality, sug- nuclear proteins, e.g. histone H1 heteromodifica- gesting that the error-prone repair of replication- tion adjacent to the DNA breaks. These nega- associated DSBs is associated with the tively charged polymers form a scaffold and 258 http://tam.sagepub.com M Javle and NJ Curtin Figure 1. Poly (ADP-ribose) polymerase (PARP) is upregulated in conditions causing genotoxic stress, leading to increased single- strand break repair. In cases of homologous recombination (HR) deficiency, this becomes the main pathway for DNA repair and therefore its inhibition leads to synthetic lethality. PARPi, PARP inhibitor. recruit other proteins that are critical in BER [De localization signal, an automodification domain Murcia et al. 1994] and chromatin remodeling and a carboxy-terminal catalytic ‘PARP-signa- [Ahel et al. 2009; Timinszky et al. 2009]. ture’ domain that is responsible for PAR forma- tion [De Murcia et al. 1994]. The DNA-binding PARP activity also promotes the activation of domain also contains two zinc fingers that are mitotic recombination 11 (MRE11) and required for the detection of DNA strand Nijmegen breakage syndrome (NBS), members breaks resulting eventually in PARP-1 activation of the DNA damage-sensing MRN complex while a third zinc finger motif coordinates DNA- which activates ATM to sites of double-stand dependent enzyme activation. DNA damage [Haince et al. 2007]. Thus, the role of PARP-1 in DNA repair extends beyond The baseline activity of PARP-1 is low, but is the repair of DNA single-strand breaks. PARP-1 stimulated by DNA strand breaks. PARP is upre- not only plays a critical role in genomic mainte- gulated in several cancers, implying its possible nance but is also involved in transcriptional reg- role in cancer growth and survival [Virag and ulation, energy metabolism and cell death and Szabo, 2002]. In colorectal cancer, for instance, these roles are discussed below. PARP-1 mRNA overexpression was detected in over 70% of colorectal cancers and correlated PARP-1 has three distinct domains: an amino with the expression of beta-catenin, c-myc, terminal DNA-binding domain, a nuclear cyclin D1 and MMP-7 [Nosho et al. 2006]. http://tam.sagepub.com 259 Therapeutic Advances in Medical Oncology 3 (6) Inhibition of PARP is detrimental to cancer cells. colleagues, noted that while chemical inhibition However, PARP inhibition may not result in crit- of PARP-1 markedly enhanced the efficacy of ical injury to normal cells. PARP-1 knockout low-dose radiation, such an effect was lacking mice have been reported to grow normally in PARP-1 knockout models. The latter may be [Shall and De Murcia, 2000], however, the inac- explainable on the basis of PARP-2 upregulation, tivation of both PARP-1 and PARP-2, confers which may compensate for the absence of PARP- embryonic lethality [Schreiber et al. 2002]. 1 [Chalmers et al. 2004]. Thus PARPi, by Owing to the very close structural homology of inhibiting both PARP-1 and PARP-2, are likely the catalytic domains of PARP-1 and PARP-2, it to have more profound effects than indicated by is thought that most PARPi inhibit both enzymes. genetic knockout of only one of the two enzymes. Therefore, PARP inhibition in the clinical setting Select PARP-1 inhibitors in clinical trials are dis- could potentially cause serious adverse effects but cussed below. the experience to date suggests that profound AG014699 (PF-01367338) PARP inhibition is associated with very mild tox- AG014699 is a phosphate salt of AG14447 with icity. The clinical application of PARPi is there- aqueous solubility and was selected as suitable for fore an active area of research and development. clinical trial from a panel of 42 potential PARPi based on its chemo- and radio-potentiating effect Development of PARP Inhibitors [Thomas et al. 2007]. This PARPi, and its fore- The first-generation PARPi included nicotin- runner AG14361, showed spectacular activity in amide, benzamides and substituted benzamides xenograft models in combination with temozolo- such as 3-aminobenzamide (3-AB). These mide, resulting in complete and durable tumor agents had relatively low potency and specificity regression [Thomas et al. 2007; Calabrese et al. and, therefore, second-generation benzamides 2004]. AG14361 also caused a twofold to three- and more recently, third-generation inhibitors, fold enhancement of irinotecan-induced and most of which are competitive NADþ inhibitors radiation-induced tumor growth delay. and based on 3-AB structure, such as the nico- tinamide pharmacophore have been developed AG014699 was the first PARPi to enter clinical (Figure 2). The preclinical/clinical development trial for cancer therapy and has been studied in of PARPi has been as: (a) single agents in cases of phase I and phase II clinical trials in combination deficient DNA repair mechanisms such as with temozolomide for the treatment of meta- BRCA1 or BRCA2 mutations; (b) combined static melanoma. In the phase I study, dose esca- with cytotoxics (PARPi sensitize tumor cells to lation was driven by pharmacodynamic chemotherapeutic anticancer agents that induce measurement of PARP inhibition and the PARP DNA damage through BER; these agents include inhibitory dose (PID) was estimated at 12 mg/m temozolomide, platinum analogues and topoi- based on 7497% inhibition of PARP activity in peripheral lymphocytes and a >50% PARP inhi- somerase-1 inhibitors); or (c) as radiation sensi- bition in tumor biopsies posttreatment. tizers [Calabrese et al. 2004]. Radiosensitization AG014699 showed linear pharmacokinetics by PARP inhibition is enhanced in the presence with no interaction with temozolomide of defective DNA repair and is more pronounced [Plummer et al. 2008]. The recommended in rapidly dividing cancer tissues in the S phase as phase II dose was 200 mg/m of temozolomide compared with normal, noncycling cells and may with 12 mg/m of AG014699. In the phase II thus result in an enhanced safety ratio [Dungey study, a doubling of response rate and time to et al. 2008]. PARP knockout models have been tumor progression were noted as compared with utilized to confirm the chemo- and radio-poten- temozolomide alone, but at the cost of signifi- tiation of the PARPi. Both PARP-1 knockout and cantly higher myelosuppression in the combina- PARP-2 knockout mice are hypersensitive to ion- tion arm. At the present time, single-agent izing radiation (IR) and DNA alkylating agents studies in ovarian or breast cancers in BRCA (as reviewed by Rouleau et al. [2010]). In preclin- ical cancer models, Tentori and colleagues noted mutation carriers and combination studies with that melanoma models with stably silenced cisplatin, pemetrexed and epirubicin are being PARP-1 expression were highly sensitive to temo- conducted. The combination of AG014699 zolomide. In the same study, decreased tumori- with these latter drugs not classically associated genicity and angiogenesis were noted in the with PARP may be based on the observation that PARP-1/ melanoma models [Tentori et al. AG014699 is vasoactive, potentially increasing 2008]. On the other hand, Chalmers and drug delivery to the tumor [Ali et al. 2009]. 260 http://tam.sagepub.com M Javle and NJ Curtin Figure 2. Structure of 3-aminobenzamide (3-AB) and the recent poly (ADP-ribose) polymerase inhibitors (PARPi) developed from the nicotinamide pharmacophore. The Ki of AG014699/PF-01367388 and the IC values for most other inhibitors are presented to show potency, but it should be noted that these values are not directly comparable due to different experimental conditions, e.g. substrate concentrations. Veliparib (ABT-888) associated with this agent with 32 ongoing clini- Veliparib has been developed as a PARP-1 and cal trials of velaparib in combination with cyto- PARP-2 inhibitor with K(i)s of 5.2 and 2.9 nmol/ toxics in ovarian, breast, colorectal, prostate, liver l, respectively [Penning et al. 2009]. It is orally cancers, neurologic malignancies and leukemias. bioavailable and crosses the bloodbrain barrier. ABT-888 potentiated the cytotoxic effect of Olaparib (AZD2281) temozolomide in several human tumor models Olaparib (AZD2281) also inhibits PARP-1 and and IR in HCT116 human colon cancers PARP-2 at nanomolar concentrations [Menear [Clarke et al. 2009; Palma et al. 2009; et al. 2008]. Preclinical studies have largely con- Donawho et al. 2007]. The activity of platinum centrated on investigations of synthetic lethality analogues and cyclophosphamide were also in BRCA1 or BRCA2 defective models or com- enhanced by ABT-888 in the BRCA1 and 2 binations with platinum in these models defective MX-1 xenografts but ABT-888 had no [Rottenberg et al. 2008]. Radiosensitization in a single-agent activity in this model in the schedule glioma model has also been demonstrated used [Donawho et al. 2007]. Velaparib was inves- [Dungey et al. 2008]. Studies with human ovar- tigated in an innovative phase 0 trial, the first ian cancer xenografts demonstrated that olaparib such study in oncology [Kummar et al. 2009]. had single-agent activity and increased the effi- The primary study endpoint was target modula- cacy of carboplatin in xenografts defective in tion by the PARPi. PARP activity, when mea- BRCA2 but not those with normal BRCA func- sured after a single dose of veliparib was tion [Kortmann et al. 2011]. Olaparib was significantly inhibited at the 25 and 50 mg observed to increase the toxicity of topotecan in doses. There is an extensive clinical trial program animal models [Zander et al. 2010]. The first http://tam.sagepub.com 261 Therapeutic Advances in Medical Oncology 3 (6) clinical study of PARP inhibition in BRCA cancers [Vona-Davis et al. 2008]. Both, mutant cancers was with this agent. In this BRCA1-associated cancers and sporadic TN phase I study which enrolled 60 patients, olaparib tumors share a high degree of genomic instability, doses were escalated from 10 mg daily for 2 of implying an impaired ability to repair DNA every 3 weeks to 600 mg twice daily [Fong et al. damage. HR defects seen in TN breast cancer 2009a]. The dose of 200 mg twice daily was include BRCA1 methylation, overexpression of selected for further study in a select cohort of deregulators including ID4 and HMG as well as 23 patients with BRCA mutations. In this aberrations of MRE11, ATM and PALB2 [Alli group, nine had partial responses according to et al. 2009; Alexander et al. 2010]. Iniparib the NCI response evaluation criteria (RECIST). (BSI-201), when combined with gemcitabine A total of 19 of the 23 patients had BRCA-asso- and carboplatin for the treatment of TN breast cancer, has been studied in a randomized phase ciated tumors, including breast, ovarian, and prostate cancers. II trial compared with the same chemotherapy alone. The addition of iniparib increased disease Given these interesting preliminary data, two control rate (56% to 34%), response rate (52% multicenter, international phase II studies of ola- to 32%), progression-free survival (5.9 to parib in patients with breast or ovarian cancers 3.6 months) and overall survival (12.3 to 7.7 having BRCA1 or BRCA2 mutations were con- months) without increasing toxicity ducted [Fong et al. 2009b; Tutt et al. 2010]. [O’shaughnessy et al. 2011]. A follow-up phase Patients enrolled were refractory to standard che- III study, however, was negative as it did not motherapeutic regimens. A total of 27 patients in meet the prespecified criteria for significance for the first cohort received 400 mg of olaparib twice coprimary endpoints of overall survival and pro- daily for 28 days, and 27 patients in the second gression-free survival. Given the structural and cohort received 100 mg of olaparib twice daily. mechanistic differences between iniparib and The overall response rate was 41% with other PARPi, these negative results do not neces- 400 mg, and 22% with 100 mg olaparib. The sarily imply a ‘class effect’ and further study of median time to progression was 5.7 and 3.8 TN breast cancer with other PARPi should be months, respectively. The common adverse encouraged. effects were mild, including fatigue, nausea and INO-1001 vomiting. A parallel study using the two dosage This agent is an isoindolinone derivative and is regimens in 55 BRCA-mutated carriers with being developed for both oncological and cardio- ovarian cancer confirmed an overall response vascular indications. Preclinical studies demon- rate of 33% in the 400 mg group, and 12.5% in strate its protective effect in models of cardiac the 100 mg group. These proof-of-concept stud- dysfunction [Pacher et al. 2006] and reversal of ies confirmed that BRCA1 or BRCA2 mutational temozolomide resistance in MMR-defective status serves as a predictive marker for PARPi. xenografts [Cheng et al. 2005]. This was the first PARP-1 inhibitor to be investigated for car- Iniparib (BSI-201) Unlike other PARPi that compete with NADþ diovascular disease and has been granted orphan for the PARP catalytic site, iniparib (4-iodo, 3- drug status by the US Food and Drug nitrobenzamide) is unique in that it targets the Administration for the prevention of postopera- zinc finger domain and prevents PARP-1 activa- tive aortic aneurysm repair complications. In this tion by DNA breaks [Mendeleyev et al. 1995]. phase II study, INO-1001 may have reduced the Therefore, it may have differential effects as com- plasma levels of C-reactive protein and the pared with other synthetic catalytic PARPi. inflammatory marker interleukin-6, without Moreover, as this inhibitor has also been shown reducing plasma markers of myocardial injury. to inhibit other enzymes such as GAPDH [Bauer No serious toxic events ensued in this trial et al. 2002], it would be dangerous to conclude [Morrow et al. 2009]. This agent is being devel- that its anticancer effects are solely attributable to oped in oncology in melanoma and glioma and as PARP inhibition. This agent has been extensively a single agent in cancer for BRCA1- and investigated in triple-negative (TN) breast BRCA2-deficient tumors. Phase I studies of cancers. INO-001 at 100, 200 and 400 mg/m in combi- nation with temozolomide indicated a short ter- TN breast cancers are believed to share the minal half life and the dose-limiting toxicities molecular characteristics of BRCA1-associated observed at the highest dose were 262 http://tam.sagepub.com M Javle and NJ Curtin myelosuppression and elevated liver enzymes are very sensitive to 6-thioguanine as HR is [Bedikian et al. 2009]. involved in the repair of 6-thioguanine-induced DSBs [Issaeva et al. 2010]. 6-thioguanine is not Other PARPi in preclinical and phase I trial a substrate for p glycoprotein and is a potent cyto- stages include GPI21016 (MGI/Eisai), MK- toxic in PARP-resistant tumors. Furthermore, 4827 (Merck), BMN-673 (Biomarin) and CEP- these investigators noted that genetically reverted 9722 (Cephalon). Additional information on BRCA2 defective tumors also retain sensitivity to these inhibitors can be found in a review by 6-thioguanine. Altogether, these findings suggest Ferraris [Ferraris, 2010]. that 6-thioguanine may be efficient in also killing advanced and drug-resistant BRCA1 or BRCA2 Resistance mechanisms for PARPi defective tumors. Acquired resistance to targeted agents is common and PARPi are no exception in this regard. As the Patient selection for PARPi trials clinical development of PARPi is still at an early A major challenge is to identify predictive mar- stage, the underlying resistance mechanisms have kers for PARPi therapy for those sporadic cancers not yet been elucidated. However, preclinical that may benefit due to functional defects in the studies offer interesting possibilities. CAPAN-1 HR pathways. Several surrogate markers have pancreatic cancer cells lines are BRCA2 deficient been described, none of which are widely avail- secondary to a 6174delT frameshift mutation, able in the clinical setting at the current time. which makes them exquisitely sensitive to Gene-expression arrays have been investigated PARPi. CAPAN-1 cells cannot form damage- for their predictive value [Jazaeri et al. 2002]. induced RAD51 foci, as they are HR-defective. Turner and colleagues hypothesized that a PARPi-resistant clones were highly resistant to gene and protein expression signature may the drug (over 1000-fold), and were also cross- have the ability to identify the BRCA-ness pro- resistant to the DNA crosslinking agent, cis- file in patients [Turner et al. 2004]. platin. Interestingly, these resistant clones Konstantinopoulos and colleagues defined a acquired the ability to form RAD51 foci after BRCA-like gene expression profile that PARPi treatment or exposure to irradiation sug- correlated with PARPi and platinum gesting that re-acquisition of HR capability may sensitivity [Konstantinopoulos et al. 2010]. be the mechanism of acquired resistance. In sup- Phosphorylation of the Ser-139 residue of the port of this, DNA sequencing of PARP inhibitor- histone variant H2AX, forming gH2AX, is an resistant clones revealed new BRCA2 isoforms as early cellular response to the induction of DNA a result of intragenic deletion of the c.6174delT DSBs. Detection of this phosphorylation event mutation and restoration of the open reading has emerged as a highly specific and sensitive frame [Edwards et al. 2008; Sakai et al. 2008; molecular marker for monitoring DNA damage Swisher et al. 2008]. Recently, 53BP1 has been initiation and resolution. This accumulation is shown to promote error-prone NHEJ in BRCA1 detectable by immunofluorescence using an anti- mutant cells and that loss of 53BP1 partially body to gH2AX. Rad51 is a crucial downstream restores HR function and can rescue from DNA protein involved in HR repair, which is reloca- damaging agent and PARPi sensitivity lized within the nucleus in response to DNA [Bouwman et al. 2010; Bunting et al. 2010]. damage. Rad51 foci can also be visualized by Loss of 53BP1 appears to be relatively common immunofluorescent microscopy and are thought in TN and BRCA1-mutant breast cancer sam- to represent assemblies of proteins at these sites ples [Bouwman et al. 2010]. of HR repair. Combination gH2AX/RAD51 immunofluorescence has been investigated in An alternative mechanism was described with ola- primary ovarian cancer cell cultures parib [Rottenberg et al. 2008]. In this case, resis- [Mukhopadhyay et al. 2010] and primary acute tance may be related to the upregulation of the myeloid leukemia (AML) cultures [Gaymes et al. ABCB1a/b genes, which encode P-glycoprotein 2009]. Both studies demonstrated that raised multidrug resistance drug efflux pumps; this gH2AX and decreased RAD51 foci expression effect could be reversed with the P-glycoprotein predicts PARPi sensitivity. Graeser and col- inhibitor, tariquidar. A recent study investigated leagues investigated RAD51 immunofluores- the role of 6-thioguanine in reversing this resis- cence in replicating (geminin positive) cells in tance mechanism. Issaeva and colleagues first breast cancer biopsy specimens from women noted that BRCA1, BRCA2 or XRCC3 tumors receiving neoadjuvant anthracycline therapy. http://tam.sagepub.com 263 Therapeutic Advances in Medical Oncology 3 (6) The RAD51 score was predictive of complete previously received research support and consul- response in women receiving neoadjuvant ther- tancy fees from BiPAR sciences. apy for breast cancer [Graeser et al. 2010]. Although cumbersome, these assays currently represent the most reliable way to identify HR References Ahel, D., Horejsi, Z., Wiechens, N., Polo, S.E., defects, particularly in light of the recent studies Garcia-Wilson, E., Ahel, I. et al. (2009) Poly(ADP- showing that even in BRCA1-mutant tumors, ribose)-dependent regulation of DNA repair by the coincident loss of 53BP1 can restore HR function chromatin remodeling enzyme ALC1. Science and PARPi resistance [Bouwman et al. 2010; 325: 12401243. Bunting et al. 2010]. Alexander, B.M., Sprott, K., Farrow, D.A., Wang, X., D’andrea, A.D., Schnitt, S.J. et al. (2010) DNA repair Conclusions protein biomarkers associated with time to recurrence in triple-negative breast cancer. Clin Cancer Res Genomic instability in cancer may result from an 16: 57965804. imbalance of DNA damage signaling and repair pathways; upregulated pathways may confer Ali, M., Telfer, B.A., Mccrudden, C., O’rourke, M., Thomas, H.D., Kamjoo, M. et al. (2009) Vasoactivity resistance to certain types of genotoxic agent of AG014699, a clinically active small molecule but may also be necessary for the survival of the inhibitor of poly(ADP-ribose) polymerase: a contrib- cancer cell. Targeting these pathways may result utory factor to chemopotentiation in vivo? Clin Cancer in single-agent activity specifically in the cancer Res 15: 61066112. cell where repair of endogenously generated Alli, E., Sharma, V.B., Sunderesakumar, P. and Ford, DNA damage is inhibited as well as tumor-selec- J.M. (2009) Defective repair of oxidative DNA damage tive chemo and radio-sensitization. PARPi in triple-negative breast cancer confers sensitivity to increase the anticancer activity of temozolomide, inhibition of poly(ADP-ribose) polymerase. Cancer Res topoisomerase I poisons and IR in a wide range of 69: 35893596. tumor models, an approach that has been vali- Ashworth, A. (2008) A synthetic lethal therapeutic dated by genetic knockdown of PARP-1 and approach: poly(ADP) ribose polymerase inhibitors for PARP-2. However, the most exciting aspect is the treatment of cancers deficient in DNA double- strand break repair. J Clin Oncol 26: 37853790. the discovery that PARPi alone selectively kill cancer cells that lack HR without affecting Bauer, P.I., Mendeleyeva, J., Kirsten, E., Comstock, repair competent cells. This observation has rap- J.A., Hakam, A., Buki, K.G. et al. (2002) Anti-cancer action of 4-iodo-3-nitrobenzamide in combination idly translated into clinical trials where PARPi with buthionine sulfoximine: inactivation of have shown good anticancer activity in BRCA1 poly(ADP-ribose) polymerase and tumor glycolysis and BRCA2 patients with breast, ovarian and and the appearance of a poly(ADP-ribose) polymerase prostate cancer with only mild toxicities. HR is protease. Biochem Pharmacol 63: 455462. a complex and multicomponent pathway and Bedikian, A.Y., Papadopoulos, N.E., Kim, K.B., Hwu, preclinical data indicates that PARPi will be W.J., Homsi, J., Glass, M.R. et al. (2009) A phase Ib useful in tumors lacking any one of a number of trial of intravenous INO-1001 plus oral temozolomide these key proteins. Identification of these poten- in subjects with unresectable stage-III or IV mela- tially PARPi-responsive tumors is the next chal- noma. Cancer Invest 27: 756763. lenge. Gene expression signatures and assays of Boehler, C., Gauthier, L.R., Mortusewicz, O., Biard, HR function can fulfill this function but they are D.S., Saliou, J.M., Bresson, A. et al. (2011) Poly(ADP- currently too expensive and cumbersome to ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. become routine clinical practice. Proc Natl Acad Sci U S A, in press. Bouwman, P., Aly, A., Escandell, J.M., Pieterse, M., Funding Bartkova, J., Van Der Gulden, H. et al. (2010) 53BP1 This research received no specific grant from any loss rescues BRCA1 deficiency and is associated with funding agency in the public, commercial, or not- triple-negative and BRCA-mutated breast cancers. Nat for-profit sectors. Struct Mol Biol 17: 688695. Bryant, H.E., Schultz, N., Thomas, H.D., Parker, Conflict of interest statement K.M., Flower, D., Lopez, E. et al. (2005) Specific Milind Javle has no conflicts of interest to killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434: 913917. declare. Nicola Curtin receives current research support from Pfizer and BioMarin and consul- Bunting, S.F., Callen, E., Wong, N., Chen, H.T., tancy fees from BioMarin and Eisai and has Polato, F., Gunn, A. et al. (2010) 53BP1 inhibits 264 http://tam.sagepub.com M Javle and NJ Curtin homologous recombination in BRCA1-deficient cells Farmer, H., Mccabe, N., Lord, C.J., Tutt, A.N., by blocking resection of DNA breaks. Cell Johnson, D.A., Richardson, T.B. et al. (2005) 141: 243254. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917921. Calabrese, C.R., Almassy, R., Barton, S., Batey, M.A., Calvert, A.H., Canan-Koch, S. et al. (2004) Ferraris, D.V. (2010) Evolution of poly(ADP-ribose) Anticancer chemosensitization and radiosensitization polymerase-1 (PARP-1) inhibitors. From concept to by the novel poly(ADP-ribose) polymerase-1 Inhibitor clinic. J Med Chem 53: 45614584. AG14361. J Natl Cancer Inst 96: 5667. Fong, P.C., Boss, D.S., Yap, T.A., Tutt, A., Wu, P., Chalmers, A., Johnston, P., Woodcock, M., Joiner, M. Mergui-Roelvink, M. et al. (2009a) Inhibition and Marples, B. (2004) PARP-1, PARP-2, and the of poly(ADP-ribose) polymerase in tumors cellular response to low doses of ionizing radiation. Int from BRCA mutation carriers. N Engl J Med J Radiat Oncol Biol Phys 58: 410419. 361: 123134. Cheng, C.L., Johnson, S.P., Keir, S.T., Quinn, J.A., Fong, P.C., Yap, T.A., Boss, D.S., Carden, C.P., Ali-Osman, F., Szabo, C. et al. (2005) Poly(ADP- Mergui-Roelvink, M., Gourley, C. et al. (2009b) Ribose) polymerase-1 inhibition reverses temozolo- Poly(ADP)-ribose polymerase inhibition: frequent mide resistance in a DNA mismatch repair-deficient durable responses in BRCA carrier ovarian cancer malignant glioma xenograft. Mol Cancer Ther correlating with platinum-free interval. J Clin Oncol 4: 13641368. 28: 25122519. Clarke, M.J., Mulligan, E.A., Grogan, P.T., Mladek, Gaymes, T.J., Shall, S., Macpherson, L.J., Twine, A.C., Carlson, B.L., Schroeder, M.A. et al. (2009) N.A., Lea, N.C., Farzaneh, F. et al. (2009) Inhibitors Effective sensitization of temozolomide by ABT-888 is of poly ADP-ribose polymerase (PARP) induce apo- lost with development of temozolomide resistance in ptosis of myeloid leukemic cells: potential for therapy glioblastoma xenograft lines. Mol Cancer Ther of myeloid leukemia and myelodysplastic syndromes. 8: 407414. Haematologica 94: 638646. Cousineau, I. and Belmaaza, A. (2011) EMSY Graeser, M., Mccarthy, A., Lord, C.J., Savage, K., overexpression disrupts the BRCA2/RAD51 Hills, M., Salter, J. et al. (2010) A marker of homol- Pathway in the DNA-damage response: implications ogous recombination predicts pathologic complete for chromosomal instability/recombination syn- response to neoadjuvant chemotherapy in primary dromes as checkpoint diseases. Mol Genet Genomics, breast cancer. Clin Cancer Res 16: 61596168. in press. Haince, J.F., Kozlov, S., Dawson, V.L., Dawson, T.M., De Murcia, G. and Menissier De Murcia, J. (1994) Hendzel, M.J., Lavin, M.F. et al. (2007) Ataxia telan- Poly(ADP-ribose) polymerase: a molecular nick- giectasia mutated (ATM) signaling network is modu- sensor. Trends Biochem Sci 19: 172176. lated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol De Murcia, G., Schreiber, V., Molinete, M., Saulier, Chem 282: 1644116453. B., Poch, O., Masson, M. et al. (1994) Structure and function of poly(ADP-ribose) polymerase. Mol Cell Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Biochem 138: 1524. cancer: the next generation. Cell 144: 646674. Donawho, C.K., Luo, Y., Penning, T.D., Bauch, J.L., Issaeva, N., Thomas, H.D., Djureinovic, T., Jaspers, Bouska, J.J., Bontcheva-Diaz, V.D. et al. (2007) ABT- J.E., Stoimenov, I., Kyle, S. et al. (2010) 6- 888, an orally active poly(ADP-ribose) polymerase Thioguanine selectively kills BRCA2-defective tumors inhibitor that potentiates DNA-damaging agents in and overcomes PARP inhibitor resistance. Cancer Res preclinical tumor models. Clin Cancer Res 70: 62686276. 13: 27282737. Jazaeri, A.A., Yee, C.J., Sotiriou, C., Brantley, K.R., Drew, Y., Mulligan, E.A., Vong, W.T., Thomas, H.D., Boyd, J. and Liu, E.T. (2002) Gene expres- Kahn, S., Kyle, S. et al. (2010) Therapeutic poten- sion profiles of BRCA1-linked, BRCA2-linked, and tial of poly(ADP-ribose) polymerase inhibitor sporadic ovarian cancers. J Natl Cancer Inst AG014699 in human cancers with mutated or 94: 9901000. methylated BRCA1 or BRCA2. J Natl Cancer Inst Konstantinopoulos, P.A., Spentzos, D., Karlan, B.Y., 103: 334346. Taniguchi, T., Fountzilas, E., Francoeur, N. et al. Dungey, F.A., Loser, D.A. and Chalmers, A.J. (2008) (2010) gene expression profile of BRCAness that cor- Replication-dependent radiosensitization of human relates with responsiveness to chemotherapy and with glioma cells by inhibition of poly(ADP-ribose) poly- outcome in patients with epithelial ovarian cancer. merase: mechanisms and therapeutic potential. Int J J Clin Oncol 28: 35553561. Radiat Oncol Biol Phys 72: 11881197. Kortmann, U., Mcalpine, J.N., Xue, H., Guan, J., Ha, Edwards, S.L., Brough, R., Lord, C.J., Natrajan, R., G., Tully, S. et al. (2011) Tumor growth inhibition by Vatcheva, R., Levine, D.A. et al. (2008) Resistance to olaparib in BRCA2 germline-mutated patient-derived therapy caused by intragenic deletion in BRCA2. ovarian cancer tissue xenografts. Clin Cancer Res Nature 451: 11111115. 17: 783791. http://tam.sagepub.com 265 Therapeutic Advances in Medical Oncology 3 (6) Kummar, S., Kinders, R., Gutierrez, M.E., Palma, J.P., Wang, Y.C., Rodriguez, L.E., Rubinstein, L., Parchment, R.E., Phillips, L.R. et al. Montgomery, D., Ellis, P.A., Bukofzer, G. et al. (2009) (2009) Phase 0 clinical trial of the poly (ADP- ABT-888 confers broad in vivo activity in combination ribose) polymerase inhibitor ABT-888 in patients with temozolomide in diverse tumors. Clin Cancer Res with advanced malignancies. J Clin Oncol 15: 72777290. 27: 27052711. Patel, A.G., Sarkaria, J.N. and Kaufmann, S.H. (2011) Mccabe, N., Turner, N.C., Lord, C.J., Kluzek, K., Nonhomologous end joining drives poly(ADP-ribose) Bialkowska, A., Swift, S. et al. (2006) Deficiency in the polymerase (PARP) inhibitor lethality in homologous repair of DNA damage by homologous recombination recombination-deficient cells. Proc Natl Acad Sci U S A 108: 34063411. and sensitivity to poly(ADP-ribose) polymerase inhi- bition. Cancer Res 66: 81098115. Penning, T.D., Zhu, G.D., Gandhi, V.B., Gong, J., Mcellin, B., Camacho, C.V., Mukherjee, B., Hahm, Liu, X., Shi, Y. et al. (2009) Discovery of the poly(ADP-ribose) polymerase (PARP) inhibitor 2- B., Tomimatsu, N., Bachoo, R.M. et al. (2010) PTEN [(R)-2-methylpyrrolidin-2-Yl]-1h-benzimidazole-4- loss compromises homologous recombination repair in carboxamide (ABT-888) for the treatment of cancer. J astrocytes: implications for glioblastoma therapy with Med Chem 52: 514523. temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res 70: 54575464. Plummer, R., Jones, C., Middleton, M., Wilson, R., Evans, J., Olsen, A. et al. (2008) Phase I study of the Mendeleyev, J., Kirsten, E., Hakam, A., Buki, K.G. poly(ADP-ribose) polymerase inhibitor, AG014699, in and Kun, E. (1995) Potential chemotherapeutic combination with temozolomide in patients with activity of 4-iodo-3-nitrobenzamide. Metabolic reduc- advanced solid tumors. Clin Cancer Res tion to the 3-nitroso derivative and induction of cell 14: 79177923. death in tumor cells in culture. Biochem Pharmacol 50: 705714. Rottenberg, S., Jaspers, J.E., Kersbergen, A., Van Der Burg, E., Nygren, A.O., Zander, S.A. et al. (2008) Menear, K.A., Adcock, C., Boulter, R., Cockcroft, High sensitivity of BRCA1-deficient mammary tumors X.L., Copsey, L., Cranston, A. et al. (2008) 4-[3-(4- to the PARP inhibitor AZD2281 alone and in combi- Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluor- nation with platinum drugs. Proc Natl Acad Sci U S A obenzyl]-2H-PHTH alazin-1-one: a novel bioavailable 105: 1707917084. inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51: 65816591. Rouleau, M., Patel, A., Hendzel, M.J., Kaufmann, S.H. and Poirier, G.G. (2010) PARP inhibition: Morrow, D.A., Brickman, C.M., Murphy, S.A., Baran, PARP1 and beyond. Nat Rev Cancer 10: 293301. K., Krakover, R., Dauerman, H. et al. (2009) A ran- domized, placebo-controlled trial to evaluate the tol- Sakai, W., Swisher, E.M., Karlan, B.Y., Agarwal, erability, safety, pharmacokinetics, and M.K., Higgins, J., Friedman, C. et al. (2008) pharmacodynamics of a potent inhibitor of poly(ADP- Secondary mutations as a mechanism of cisplatin ribose) polymerase (INO-1001) in patients with ST- resistance in BRCA2-mutated cancers. Nature elevation myocardial infarction undergoing primary 451: 11161120. percutaneous coronary intervention: results of the TIMI 37 Trial. J Thromb Thrombolysis 27: 359364. Schreiber, V., Ame, J.C., Dolle, P., Schultz, I., Rinaldi, B., Fraulob, V. et al. (2002) Poly(ADP- Mukhopadhyay, A., Elattar, A., Cerbinskaite, A., ribose) polymerase-2 (PARP-2) is required for Wilkinson, S.J., Drew, Y., Kyle, S. et al. (2010) efficient base excision DNA repair in association Development of a functional assay for homologous with PARP-1 and XRCC1. J Biol Chem recombination status in primary cultures of epithelial 277: 2302823036. ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Schreiber, V., Dantzer, F., Ame, J.C. and De Murcia, Res 16: 23442351. G. (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517528. Nosho, K., Yamamoto, H., Mikami, M., Taniguchi, H., Takahashi, T., Adachi, Y. et al. (2006) Shall, S. and De Murcia, G. (2000) Poly(ADP-ribose) Overexpression of poly(ADP-ribose) polymerase-1 polymerase-1: what have we learned from the deficient (PARP-1) in the early stage of colorectal carcinogene- mouse model? Mutat Res 460: 115. sis. Eur J Cancer 42: 23742381. Swisher, E.M., Sakai, W., Karlan, B.Y., Wurz, K., O’shaughnessy, J., Osborne, C., Pippen, J.E., Yoffe, Urban, N. and Taniguchi, T. (2008) Secondary M., Patt, D., Rocha, C. et al. (2011) Iniparib plus BRCA1 mutations in BRCA1-mutated ovarian carci- chemotherapy in metastatic triple-negative breast nomas with platinum resistance. Cancer Res cancer. N Engl J Med 364: 205214. 68: 25812586. Pacher, P., Liaudet, L., Mabley, J.G., Cziraki, A., Tentori, L., Muzi, A., Dorio, A.S., Bultrini, S., Hasko, G. and Szabo, C. (2006) Beneficial effects of a Mazzon, E., Lacal, P.M. et al. (2008) Stable depletion novel ultrapotent poly(ADP-ribose) polymerase of poly (ADP-ribose) polymerase-1 reduces in vivo inhibitor in murine models of heart failure. Int J Mol melanoma growth and increases chemosensitivity. Eur Med 17: 369375. J Cancer 44: 13021314. 266 http://tam.sagepub.com M Javle and NJ Curtin Thomas, H.D., Calabrese, C.R., Batey, M.A., Virag, L. and Szabo, C. (2002) The therapeutic Canan, S., Hostomsky, Z., Kyle, S. et al. (2007) potential of poly(ADP-ribose) polymerase inhibitors. Preclinical selection of a novel poly(ADP-ribose) Pharmacol Rev 54: 375429. polymerase inhibitor for clinical trial. Mol Cancer Ther Vona-Davis, L., Rose, D.P., Hazard, H., Howard- 6: 945956. Mcnatt, M., Adkins, F., Partin, J. et al. (2008) Triple- Timinszky, G., Till, S., Hassa, P.O., Hothorn, M., negative breast cancer and obesity in a rural Kustatscher, G., Nijmeijer, B. et al. (2009) A macro- Appalachian population. Cancer Epidemiol Biomarkers domain-containing histone rearranges chromatin upon Prev 17: 33193324. sensing PARP1 activation. Nat Struct Mol Biol Williamson, C.T., Muzik, H., Turhan, A.G., Zamo, 16: 923929. A., O’connor, M.J., Bebb, D.G. et al. (2010) Atm Turner, N., Tutt, A. and Ashworth, A. (2004) Deficiency Sensitizes Mantle Cell Lymphoma Cells to Hallmarks of ’BRCAness’ in sporadic cancers. Nat Rev Poly(Adp-Ribose) Polymerase-1 Inhibitors. Mol Cancer 4: 814819. Cancer Ther 9: 347–357. Tutt, A., Robson, M., Garber, J.E., Domchek, S.M., Zander, S.A., Kersbergen, A., Van Der Burg, E., De Audeh, M.W., Weitzel, J.N. et al. (2010) Oral Water, N., Van Tellingen, O., Gunnarsdottir, S. et al. poly(ADP-ribose) polymerase inhibitor olaparib in (2010) Sensitivity and acquired resistance of Visit SAGE journals online patients with BRCA1 or BRCA2 mutations and BRCA1;P53-deficient mouse mammary tumors to the http://tam.sagepub.com advanced breast cancer: a proof-of-concept trial. topoisomerase I inhibitor topotecan. Cancer Res Lancet 376: 235244. 70: 17001710. http://tam.sagepub.com 267

Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Aug 15, 2011

Keywords: BRCA2 gene; DNA repair-deficiency disorders; poly (ADP-ribose) polymerases

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