Inhibition of Poly(ADP)-Ribose Polymerase as a Therapeutic Strategy for Breast Cancer

January 15, 2010
Elizabeth A. Comen, MD

,
Mark Robson, MD

Oncology, ONCOLOGY Vol 24 No 1, Volume 24, Issue 1

As knowledge increases about the processes underlying cancer, it is becoming feasible to design “targeted therapies” directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through “synthetic lethality” if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in “triple-negative” breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

As knowledge increases about the processes underlying cancer, it is becoming feasible to design “targeted therapies” directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through “synthetic lethality” if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in “triple-negative” breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

Poly-(ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to acceptor proteins.[1,2] This transfer results in the creation of long, negatively charged, branched polymers on the acceptor proteins. The first PARP (PARP1) was described in 1963.[3] The family has since been expanded to include at least 17 members.[2] PARP1 and PARP2 are the most abundant members of the family, and appear to be the only ones localized to the nucleus. PARP1, the major nuclear PARP, is a 116-kDA protein with two N-terminal zinc-finger DNA-binding domains, a nuclear localization signal domain, and a BRCT-repeat automodification domain.[4] At the C-terminus, a catalytic domain containing the “PARP signature” identifies it as a member of the PARP superfamily.

Role of PARPs

PARPs play an important role in a number of cellular damage response pathways.[5] PARPs are involved in inflammation and, through NAD+-depletion, in triggering cell death in response to stresses such as ischemia. However, the function of PARPs that is most relevant to oncology is their role in DNA damage repair. PARP1 and PARP2 are the family members that participate in this process. Most is known about the action of PARP1. PARP2 appears to participate in the same processes, but it likely also has its own unique functions.[6]

Maintenance of genomic integrity is a critical cellular function. A number of exogenous and endogenous insults can result in DNA damage. To address these various forms of potentially lethal injury, cells have evolved a number of different repair pathways.[7] PARP1 is a major component of the base excision repair (BER) pathway, which is directed toward the repair of certain types of damage to the component bases of DNA and single-strand breaks in the DNA structure.[8,9] PARP1 senses and binds to “nicked” DNA through its N-terminal zinc-finger DNA-binding domains, after which it forms a homodimer. After binding, the catalytic activity is engaged and PARP1 automodifies by adding ADP-ribose moieties to the BRCT repeat domain. The extended negatively charged chain appears both to protect the break from further degradation (“anti-recombinogenic”) and to serve as a “beacon” for recruitment of BER effector proteins, such as XRCC1.

PARP1 also appears to modify local histone proteins (especially H1 and H2B) by poly(ADP)-ribosylation. The consequent negative charge may contribute to modification of local chromatin structure, resulting in improved access for repair proteins.[10] Chromatin modification may also be mediated through the action of other proteins, such as ALC1.[11]

PARP1 is not essential for survival. PARP1 knockout mice are viable and fertile.[12] However, these animals are sensitive to DNA-damaging agents such as N-methyl-N-nitrosourea (MNU) and ionizing radiation. Residual PARP2 activity may be compensating for the loss of PARP1, as PARP1/PARP2 double knockout mice are not viable.[13] Other DNA damage repair pathways are also likely to be involved in the rescue of cells with impaired base excision repair.

Single-strand breaks may result in unattached double-strand ends if they are unrepaired when encountered by a replication fork. To avoid this result, the cell engages repair mechanisms that are involved in the repair of double-strand DNA breaks, such as homologous recombination repair and nonhomologous end-joining.[14] Homologous recombination repair is a high-fidelity mechanism that is activated during later S phase, when a sister chromatid is available to serve as a template for resolving the double-strand break. Nonhomologous end-joining is less accurate, and therefore more likely to result in genomic instability, but it is available throughout the cell cycle. Bone marrow cells from PARP1 knockout mice demonstrate an increased prevalence of sister chromatid exchanges under both baseline and stress conditions, indicating that homologous recombination repair mechanisms are engaged in response to endogenous and exogenous DNA damage when PARP1 is absent.[12] The availability of this repair mechanism is thought to be responsible for the continued viability of cells in which PARP1 function is lost.

Synthetic Lethality

FIGURE 1


Schematic Illustration of Synthetic Lethality

As above, double-strand break repair pathways, especially homologous recombination repair, appear to be critical to rescuing cells that are lacking PARP. Therefore, one would predict that cells with defects in homologous recombination repair would be sensitive to loss of single-strand repair capability through inhibition of PARP activity.[15] Conversely, cells that are competent in repairing double-strand breaks would, like PARP1 knockout mice, experience little effect from loss of PARP function, at least under normal conditions.

Synthetic lethality is the phenomenon whereby loss of products from two different genes results in cell death, which does not occur if either gene product is present and functional (Figure 1). The products of BRCA1 and BRCA2 are known to be critical to double-strand DNA break repair mediated by homologous recombination.[16] If PARP activity is lost in BRCA-deficient cells, such as BRCA-associated breast and ovarian cancers, one would therefore expect that exogenous or endogenous DNA damage that is normally addressed by the base excision repair pathway would result in genomic instability and cell death, since the rescue pathway is not available in such cells. Nonmalignant cells from BRCA mutation carriers should be relatively unaffected, however, because these cells still have functional BRCA gene product and are competent in double-strand break repair.

In 2005, two groups clearly demonstrated that inhibition of PARP causes synthetic lethality in BRCA-deficient cells.[17,18] Farmer et al demonstrated that the PARP inhibitors NU1025 and AG14361 were highly cytotoxic in BRCA2-deficient VC-8 cells. In addition, small interfering RNA (siRNA) “knockdown” of BRCA2 in MCF-7 and MDA-MB-231 cells resulted in sensitivity to PARP inhibition.[18] Similarly, Bryant et al showed that BRCA-deficient embryonic stem (ES) cells are sensitive to PARP inhibition, whereas heterozygous or wild-type cells are not affected.[17] Subsequent studies in mice demonstrated that PARP inhibition had a significant impact on orthotopic BRCA null breast cancers transplanted from conditional mutant mice.[19-21]

Taken together, these studies provided the preclinical rationale for studying PARP inhibitors as single agents in patients with BRCA-associated breast and ovarian cancer (see below). The concept of treating cancer by causing synthetic lethality is profoundly novel, and is distinct from the more traditional approaches of chemo- or radiosensitization (ie, accentuation or inhibition of repair of a specific type of damage) or combination therapy (ie, which employs agents that have different mechanisms to cause cellular damage through more than one pathway).

In theory, synthetic lethality through PARP inhibition may be applicable beyond the special circumstance of BRCA-associated cancer. Cells with deficiencies in double-strand DNA break repair resulting from other genetic alterations should also be sensitive to this approach. For example, Lord and colleagues performed a siRNA screen to identify other genes that, when inhibited, conferred sensitivity to PARP inhibition.[22] The same group has described sensitivity to PARP inhibition in cells with null PTEN mutations.[23] These early studies suggest that the synthetic lethality mechanism may be applicable to a wide range of malignancies beyond those arising in BRCA mutation carriers.

‘BRCA-ness’ and Triple-Negative Breast Cancer

The preclinical studies described above suggested that PARP inhibitors would be effective as single agents in the treatment of BRCA-deficient cancers. Classically, such cancers are associated with germline BRCA mutations. Somatic mutations in BRCA1 or BRCA2 appear to be rare in nonhereditary breast or ovarian cancer, although loss of heterozygosity of the genomic regions encompassing these genes is not uncommon. A number of studies have demonstrated reduced expression of BRCA1 protein, however, in certain nonhereditary breast cancers, especially poorly differentiated disease.[24,25] Reduced expression appears to result from either somatic BRCA1 promoter hypermethylation or downregulation consequent to overexpression of regulatory proteins such as Id4.[26-29]

Sporadic breast cancers with reduced BRCA1 expression are usually poorly differentiated tumors that do not express estrogen or progesterone receptors and do not overexpress HER2 (“triple-negative” breast cancer, or TNBC). In addition, many cases of TNBC (but not all) demonstrate a “basal-like” gene-expression pattern, as do most breast cancers arising in BRCA1-mutation carriers. These commonalities have led some to suggest that a subset of TNBC may have a BRCA1 pathway defect that is severe enough to compromise homologous recombination repair.[30] If this is the case, then a subset of TNBC may be sensitive to synthetic lethality induced by PARP inhibition.

A number of caveats should be mentioned with regard to this hypothesis. There is incomplete phenotypic overlap between TNBC, “basal-like” breast cancer defined by gene-expression pattern, and the cancers that arise in BRCA1 mutation carriers.[31] Not all TNBC or “basal-like” cancers are necessarily associated with reduced BRCA1 expression. Even in those that are, it is unclear to what degree homologous recombination repair is compromised. It is therefore premature to assume that PARP inhibition alone will be broadly effective in TNBC by the same synthetic lethality mechanism as in BRCA-associated disease. However, this does not preclude the possibility that the agents may enhance the toxicity of existing chemotherapy agents by increasing the number of double-strand breaks that must be repaired.

PARP Inhibition in Combination Therapy

As a therapeutic strategy, PARP inhibition may have merit even if it does not lead to synthetic lethality by leveraging a defect in homologous recombination repair. Numerous chemotherapy agents (as well as ionizing radiation) induce DNA damage that is usually repaired by the base excision repair pathway, and inhibition of that pathway would be expected to result in increased cytotoxicity. As described above, PARP1 knockout mice were sensitive to treatment with MNU or ionizing radiation, even though they were phenotypically normal and had a normal lifespan in the absence of that stress.[12] This suggests that the ability of the double-strand break repair system to compensate for loss of PARP function is not infinite, and that combinations that increase the stress on that system may be more effective. PARP1 and PARP2 may also have as yet undefined roles in DNA damage repair that, if inhibited, could increase the cytotoxicity of various agents. All of these considerations justify studying the newer generation of potent PARP inhibitors in combinations with conventional cytotoxic agents.

Reference Guide

Therapeutic Agents
Mentioned in This Article

ABT-888
AGO14699
BSI-201
Carboplatin
Gemcitabine (Gemzar)
INO-1001
MK4827
Nicotinamide
Olaparib (AZD2281, KU0059436)
Paclitaxel
Temozolomide (Temodar)
Topotecan
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

At the present time, the most actively investigated partners in combination with PARP inhibitors are platinum-based agents. The major form of DNA damage induced by these drugs is bulky adducts that are repaired by the nucleotide excision repair pathway.[32] However, they also cause double-strand cross-links that are repaired by double-strand break repair pathways. Cells that are defective in double-strand break repair, such as those lacking BRCA1 or BRCA2, are extremely sensitive to platinum-based agents.[33] Preclinical studies of combination therapy with PARP inhibitors and platinum agents in orthotopic transplants of breast cancers from conditional BRCA mutant mice have shown enhanced efficacy (and toxicity).[19,34] In this situation, the lack of homologous recombination repair capability leads to cell death after exposure to the aggregate insult of double-strand breaks resulting from the inability to repair platinum-induced cross-links and similar breaks resulting from replication fork collapse at the site of single-strand breaks that are not repaired due to PARP inhibition.

If there is a homologous repair defect in TNBC, one would expect specific platinum sensitivity in that setting as well. Clinical studies examining this hypothesis are not conclusive. As noted above, the effectiveness of combination platinum/PARP inhibitor therapy may not require a homologous recombination repair defect. Combining a platinum agent with a PARP inhibitor might increase effectiveness by increasing double-strand breaks to the point where even a competent repair system is overwhelmed. By extension, PARP inhibitors may enhance the effectiveness of nonplatinum agents, and combinations may be effective in settings other than those in which a homologous recombination repair defect is predicted to exist.

Clinical Studies

TABLE 1


PARP Inhibitors in Active DevelopmentTABLE 2


Active Clinical Trials of PARP Inhibitors in Breast Cancer

The basis for the design of the first PARP inhibitors was the observation that nicotinamide was a weak inhibitor of PARP activity.[35] Like nicotinamide, agents currently available are designed to inhibit PARP catalytic activity, rather than DNA binding or homodimerization. Several PARP inhibitors are presently being evaluated in both solid and hematologic malignancies (see Tables 1 and 2). Studies have been performed in populations of women with BRCA-associated malignancy, as well as in less highly selected groups of patients.

Studies in BRCA-Associated Cancer

• Olaparib (AZD2281, KU0059436)-The only published studies directly examining the potential for PARP inhibition to impact BRCA-associated cancer through synthetic lethality have been conducted with olaparib. Olaparib is a substituted 4-benzyl-2H-phthalazin-1-one that possesses high inhibitory enzyme and cellular potency for both PARP1 and PARP2. Fong et al recently published the results of an expanded single-agent phase I study in which an effort was made to oversample patients with BRCA-associated malignancy.[36] After reaching a maximum tolerated dose (MTD) in the traditional phase I portion, the investigators expanded the study to include a number of additional patients with documented BRCA-associated cancer.

A total of 60 patients enrolled, 22 of whom had mutations in BRCA1 or BRCA2. Another woman with ovarian cancer had a strongly suggestive family history but declined testing. The patients had breast cancer (15%), ovarian cancer (35%), colorectal cancer (13%), melanoma (7%), sarcoma (7%), or prostate cancer (5%). The MTD was noted to be 400 mg bid, with reversible dose-limiting toxicity noted at a dose of 400 mg po bid (grade 3 mood alteration and fatigue in 1 of 8 patients) and, more prominently, at 600 mg po bid (grade 4 thrombocytopenia and grade 3 somnolence in 2 of 5 patients). The investigational agent was well tolerated overall, with mild gastrointestinal side effects being noted in a minority of patients below the MTD. Objective tumor response was noted in 9 of 60 patients, although some clinical benefit was noted in 17 of 60 (including 12 of 19 individuals with BRCA-associated breast, ovarian, or prostate cancer). Only mutation carriers appeared to experience durable antitumor activity.

In response to the significant findings of the phase I study, a follow-up multicenter proof-of-principle phase II trial of olaparib in BRCA-deficient advanced breast cancers was performed.[37] A total of 54 BRCA-deficient women who had received at least one prior regimen for the treatment of metastatic breast cancer were enrolled. In a single-arm, two-sequential-patient-cohort design, the first 27 patients received continuous oral olaparib in 28-day cycles at 400 mg bid. In the second cohort, 27 patients received 100 mg of olaparib po bid. The primary endpoint was overall response rate. Subjects had received a median of three prior regimens and 44 of 54 had been treated with an anthracycline and taxane. Fatigue was the most common adverse event, usually grade 1 or 2. Grade 1/2 nausea was also common. In the intent-to-treat cohort, objective response rates were 41% (n = 11) and 22% (n = 6) in patients receiving 400 mg bid and 100 mg bid, respectively. The median progression-free survival in the 400 mg bid cohort was 5.7 months, compared with 3.8 months in the 100 mg bid cohort. Similar results were observed in a concurrent study of nearly identical design evaluating the effectiveness of single-agent olaparib in the treatment of BRCA-associated ovarian cancer.[38]

The findings of the olaparib studies have provided important empiric support for the hypothesis that PARP inhibition would be an effective treatment for cancers that harbor defects in homologous recombination repair mechanisms. These observations are now being extended in phase II studies evaluating olaparib in combination with a number of other chemotherapy agents, including platinum agents, in both BRCA-associated and sporadic malignancies.

Studies in Cancers Not Associated With BRCA Mutations

• BSI-201-Olaparib and BSI-201 are the most advanced PARP inhibitors in terms of clinical development. While the reported phase II studies of olaparib have involved subjects with BRCA-associated cancers, the reported phase II study of BSI-201 has been in the somewhat broader population of women with triple-negative breast cancer.

The structure of BSI-201 has not been published. Unlike olaparib, BSI-201 must be administered intravenously. Phase I single-agent as well chemotherapy-combination studies of BSI-201 in patients with advanced solid tumors have demonstrated that BSI-201 is safe and well tolerated.[39,40] In the first-in-human phase I study of BSI-201 in subjects with advanced solid tumors, 23 subjects were treated at seven dose levels ranging from 0.5 mg/kg to 8.0 mg/kg. All doses were well tolerated without identifying an MTD. Gastrointestinal side effects were most common (39%).

A phase Ib study evaluating BSI-201 in combination with topotecan, gemcitabine (Gemzar), temozolomide (Temodar), or carboplatin/paclitaxel was also performed. Primary objectives were to evaluate safety and MTD of BSI-201 in combination with chemotherapy; a secondary objective was clinical benefit. Subjects with advanced solid tumors were treated with BSI-201 doses of 1.1 thru 8.0 mg/ kg, in combination with a physician-choice–dependent chemotherapy. BSI-201 was given intravenously (on days 1 and 4 of each week) with chemotherapy given on study day 1. All combinations were well tolerated, with none of the 21 adverse events attributed to BSI-201. A complete response was seen one patient with ovarian cancer; five patients had a partial response (1 renal carcinoma, 2 breast cancers, 1 uterine cancer, and 1 sarcoma), and 19 patients had stable disease for 2 months or more.

At the 2009 American Society of Clinical Oncology meeting, promising data was presented from a randomized phase II efficacy study investigating whether inhibiting PARP1 activity by combining BSI-201 with gemcitabine/carboplatin in metastatic triple-negative breast cancer patients improves the clinical benefit rate compared with gemcitabine/carboplatin alone.[41] A total of 120 subjects were enrolled in this study. Primary endpoints were clinical benefit rate and toxicity. Secondary endpoints included response rate, progression-free survival, and overall survival. The addition of BSI-201 to gemcitabine/carboplatin did not appear to potentiate toxicities of gemcitabine/carboplatin alone. Adverse event profiles were comparable in the two arms, as were toxicity-related dose reductions. The interim analysis of 116 subjects (of 120 planned) showed a statistically significant improvement in median progression-free survival (6.9 vs 3.3 months; HR = 0.342; P < .0001) and median overall survival (9.2 vs 5.7 months; HR = 0.348; P = .0005) in subjects receiving BSI-201 plus gemcitabine/carboplatin (n = 57), compared with gemcitabine/carboplatin alone (n = 59). BSI-201 plus gemcitabine/carboplatin (n = 42) vs gemcitabine/carboplatin alone (n = 44) improved the clinical benefit rate (62% vs 21%, P = .0002) and objective response rate (48% vs 16%, P = .002). Updated phase II analysis of 123 randomized patients was presented at the 2009 San Antonio Breast Cancer Symposium. The combination of BSI-201 with carboplatin/gemcitabine improved median overall survival (12.2 months) compared to carboplatin/gemcitabine alone (7.7 months; P = .005; HR = 0.5; 95% CI = 0.3–0.82). As with the initial analysis, adverse events did not differ between the two arms.[42]

A multicenter phase III randomized trial is now underway to confirm these findings. Other studies are evaluating the incremental benefit of BSI-201 in a variety of additional disease settings and drug combinations.

Drugs in Early Development

• ABT-888-ABT-888 is one of a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors. Preclinical studies in melanoma, glioma, and breast cancer models demonstrated that ABT-888 potentiated the inhibitory activity of a number of chemotherapeutic agents including temozolomide, platinums, and irinotecan, as well as radiation. The pharmacokinetic and pharmacodynamic properties of ABT-888 in humans were established through a novel phase 0 study that may serve as a model for accelerating development of other novel agents.[43] This approach facilitated the rapid deployment of ABT-888 into combination studies, which are ongoing. At this time, no efficacy results are available.

• AGO14699-AG014699, the phosphate salt of AG14447, was identified through a screening process evaluating 42 candidate agents with a number of different core structures. Subsequently, AG014699 was evaluated as a chemosensitizer in combination with temozolomide in advanced solid tumors.[44] In the first part of the study, 27 pts with solid tumors were enrolled. They received AG014699 (IV infusion with dosing escalated) and temozolomide daily (100 mg/m2 po) × 5 every 28 days. In the second part of the study, 9 patients with metastatic melanoma received a fixed dose of AG014699, and temozolomide was increased to MTD or 200 mg/m2. Doses up to 12 mg/m2 of AG014699 and 200 mg/m2 of temozolomide were given and demonstrated to be safe, well tolerated, and inhibitory of peripheral blood lymphocyte and tumor PARP activity. No dose-limiting toxicities were observed.

A follow up phase II study in 2006 evaluated AG014699 (12 mg/m2) and temozolomide (200 mg/m2) five times daily every 4 weeks in patients with advanced metastatic melanoma. Chemotherapy-naive patients (n = 40) with advanced metastatic melanoma were enrolled. More myelosuppresion was noted in the phase II study than in the phase I study, with grade 4 thrombocytopenia (12%), grade 4 neutropenia (15%), and one toxic death attributed to febrile neutropenia. At the time of presentation, there were four partial responses and four prolonged disease stabilizations, with the remaining patients too early to evaluate. A phase II study is underway to evaluate AG014699 in known carriers of a BRCA1 or BRCA2 mutation with locally advanced or metastatic breast or advanced ovarian cancer.

• MK4827-MK4827 is currently in a phase Ia study in patients with metastatic or locally advanced solid tumors and a phase Ib study in patients with BRCAmutant–associated ovarian cancer. In the phase Ia portion, MK4287 will be administered orally once daily in 21-day cycles with a standard dose escalation schema to evaluate MTD. In phase Ib, MK4827 will be administered orally at a dose/regimen based on the phase Ia data.

• INO-1001-PARP activity appears to be important in triggering cell death in response to ischemic injury. PARP inhibitors are therefore of interest in this setting. INO-1001 has mainly been evaluated in the cardiovascular setting, including in ST-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) as well in cardiovascular surgeries requiring heart lung bypass. Studies in patients with malignancy have not been reported.

Conclusions

Although poly(ADP)-ribosylation has long been known to be an important cellular process, PARP inhibition as a therapeutic approach to cancer has only recently entered clinical trials. There have been notable successes in patients with BRCA-associated malignancy due to the fact that the specific DNA damage repair defect resulting from loss of BRCA function results in sensitivity to synthetic lethality through PARP inhibition. It remains to be seen whether that same mechanism will obtain in other types of cancer, such as triple-negative breast cancer. However, there may be other defects, such as loss of PTEN function, that sensitize cells to synthetic lethality by PARP inhibitors. In addition, these agents may enhance the effectiveness of traditional cytotoxic agents and radiotherapy by a more conventional chemo- or radiosensitization mechanism. The results of studies currently underway will provide a better sense of the best ways to deploy this exciting new approach in the treatment of breast and other cancers.

Financial Disclosure:Dr. Robson has received research funding from KuDOS Pharmaceuticals.

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