Therapeutic potential of PARP inhibitors for metastatic breast cancer

Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step towards individualization of breast cancer therapy. The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors, with their novel and selective mechanism of action, are an example of this strategy. PARP plays a key role in DNA repair mechanisms, particularly the base excision repair pathway. Initially developed as inhibitors able to enhance the cytotoxicity of radiation and certain DNA-damaging agents, they have more recently been shown to have single-agent activity in certain tumors. Inhibition of PARP in a DNA repair-defective tumor can lead to gross genomic instability and cell death by exploiting the paradigm of synthetic lethality. Several studies have evaluated the role of PARP inhibitors for treatment of breast cancer, particularly in the context of BRCA-mutated and triple-negative breast cancers. In addition, inhibition of PARPs repair functions for chemotherapy-induced DNA lesions has been shown to potentiate the effect of some chemotherapy regimens. This article discusses the current understanding of PARP inhibition as a treatment for metastatic breast cancer, evidence from clinical trials and addresses its future implications.     

PARP inhibitors in breast cancer: BRCA and beyond

DNA repair is essential for the survival of both normal and cancer cells. An elaborate set of signaling pathways detect single-strand and double-strand DNA breaks and mediate either DNA repair or apoptosis if the damage is too great to repair. Poly(adenosine diphosphate [ADP]-ribose) polymerases (PARPs) play a key role in the repair of base damage via the base excision repair pathway. Pharmacological inhibition of PARP induces cell death in tumors with mutations in certain DNA repair pathways--such as the BRCA pathways of double-strand break repair--and when combined with chemotherapies that cause DNA damage. PARP inhibitors are being investigated as a monotherapy for the treatment of patients with BRCA 1/2 mutations; in the treatment of triple-negative breast cancer, because of its molecular similarities to BRCA1-mutated malignancies; and as a strategy to potentiate the DNA-damaging effects of chemotherapy and radiation. The aim of this article is to review the preclinical data and rationale for PARP inhibitor use in the aforementioned settings, as well as the current status of the clinical development of these agents in the treatment of breast cancer, along with future directions for research in this field. Trials have been identified via searches of PubMed, clinicaltrials.gov, and the Proceedings of the American Society of Clinical Oncology Annual Meeting and the San Antonio Breast Cancer Symposium.     

Development of PARP inhibitors in gynecological malignancies

PARP inhibitors demonstrate synthetic lethality in tumors with BRCA1/2 mutations and other homologous recombination repair deficiencies by interfering with DNA repair and causing direct toxicity to DNA through PARP trapping. PARP inhibitors have been shown to be beneficial in the treatment of BRCA1/2-mutated ovarian cancers, which has led to a shift in the treatment paradigm of this disease. Further studies to establish the role of PARP inhibitors during earlier stages of treatment are ongoing. The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including their use in the neoadjuvant and adjuvant settings. PARP inhibitor combination strategies with chemotherapy, targeted agents, radiotherapy, and immunotherapy are also being explored. The role of predictive biomarkers, including molecular signatures and homologous recombination deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to improved patient stratification to enhance the clinical utility of PARP inhibitors. This may also allow the use of PARP inhibitors to be extended beyond tumors with specific homologous recombination DNA repair gene mutations in the future. An improved understanding of the mechanisms underlying PARP inhibitor resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which patients we should be treating with PARP inhibitors and where these agents should come in over the course of treatment.     

PARP抑制剂治疗晚期乳腺癌的作用机制及相关研究进展

多聚二磷酸腺苷核糖聚合酶（poly ADP-ribose polymerase，PARP）抑制剂可使乳腺癌细胞的单链DNA损伤修复受阻，而BRCA突变可造成乳腺癌细胞的双链DNA损伤修复功能缺失，因此PARP抑制剂治疗乳腺癌易感基因（breast cancer susceptibility gene，BRCA）突变乳腺癌是通过同时阻断单链DNA和双链DNA损伤修复，导致细胞的DNA损伤修复失败，使癌细胞死亡。目前已研发出多种敏感性和特异性较高的PARP抑制剂，该类药物主要抑制PARP1和PARP2两种亚型。本文总结PARP抑制剂用于治疗BRCA突变乳腺癌的作用机制，并对多种PARP抑制剂单用或联合化疗药物治疗晚期乳腺癌的研究进展进行综述。      

Response of subtype-specific human breast cancer-derived cells to poly(ADP-ribose) polymerase and checkpoint kinase 1 inhibition

When DNA damage is detected, checkpoint signal networks are activated to stop the cell cycle, and DNA repair processes begin. Inhibitory compounds targeting components of DNA damage response pathways have been identified and are being used in clinical trials, in combination with chemotherapeutic agents, to enhance cancer therapy. Inhibitors of checkpoint kinases, Chk1 and Chk2, have been shown to sensitize tumor cells to DNA damaging agents, and treatment of BRCA1/2-deficient tumor cells, as well as triple negative breast cancers, with poly(ADP-ribose) polymerase (PARP) inhibitors has shown promise. But systematic studies to determine which tumor subtypes are likely to respond to these specific inhibitors have not been reported. The current study was designed to test sensitivity of specific breast cancer subtype-derived cells to two classes of these new inhibitory drugs, PARP and Chk1 inhibitors. Luminal, HER2 overexpressing, and triple negative breast cancer-derived cells were tested for sensitivity to killing by PARP inhibitors, ABT-888 and BSI-201, and Chk1 inhibitor, PF-00477736, alone or in combination with gemcitabine or carboplatin. Each of the triple negative breast cancer cell lines showed strong sensitivity to the Chk1 inhibitor, but only the BRCA1-deficient breast cancer cell lines showed sensitivity to the PARP inhibitors, suggesting that in vitro testing of cancer cell lines of specific subtypes, with panels of the different PARP and Chk1 inhibitors, will contribute to stratification of patients for clinical trials using these classes of inhibitors.     

Poly(ADP-ribose) polymerase inhibitors in cancer treatment: A clinical perspective

Inbuilt mechanisms of DNA surveillance and repair are integral to the maintenance of genomic stability. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in DNA damage response processes. PARP inhibition has been successfully employed as a novel therapeutic strategy to enhance the cytotoxic effects of DNA-damaging agents. We have shown that PARP inhibition has substantial single agent antitumour activity with a wide therapeutic index in homologous DNA repair-defective tumours such as those arising in BRCA1 and BRCA2 mutation carriers. This is the first successful clinical application of a synthetic lethal approach to targeting cancer. Exploitation of defects in DNA repair pathways through targeted inhibition of salvage repair pathways is an exciting anticancer approach, with potentially broad clinical applicability. Several PARP inhibitors are now in clinical development. This review outlines the biological function and rationale of targeting PARP, details pre-clinical and clinical data and discusses the promises and challenges involved in developing these antitumour agents.     

The Fanconi anemia pathway and Breast Cancer: A comprehensive review of clinical data

The development of breast cancer depends on several risk factors, including environmental, lifestyle and genetic factors. Despite the evolution of DNA sequencing techniques and biomarker detection, the epidemiology and mechanisms of various breast cancer susceptibility genes have not been elucidated yet. Dysregulation of the DNA damage response causes genomic instability and increases the rate of mutagenesis and the risk of carcinogenesis. The Fanconi Anemia (FA) pathway is an important component of the DNA damage response and plays a critical role in the repair of DNA interstrand crosslinks and genomic stability. The FA pathway involves 22 recognized genes and specific mutations have been identified as the underlying defect in the majority of FA patients. A thorough understanding of the function and epidemiology of these genes in breast cancer is critical for the development and implementation of individualized therapies that target unique tumor profiles. Targeted therapies (PARP inhibitors) exploiting the FA pathway gene defects have been developed and have shown promising results. This narrative review summarizes the current literature on the involvement of FA genes in sporadic and familial breast cancer with a focus on clinical data derived from large cohorts.     

PARP Inhibitors for the Treatment and Prevention of Breast Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors, a novel class of drugs that target tumors with DNA repair defects, have received tremendous enthusiasm. Early preclinical studies identified BRCA1 and BRCA2 tumors to be highly sensitive to PARP inhibitors as a result of homologous recombination defect. Based on this premise, PARP inhibitors have been tested in early phase clinical trials as a single agent in BRCA1 or BRCA2 mutation carriers and in combination with chemotherapy in triple-negative breast cancer patients. For high-risk populations, use of PARP inhibition as a prevention agent has been postulated, but no robust preclinical or clinical studies exist yet. We review the preclinical and clinical studies in treatment of breast cancer and rationale for use of PARP inhibitors as a prevention agent for high-risk populations. Of significance, PARP inhibitors vary significantly in mechanism of action, dosing intervals, and toxicities, which are highlighted in this review.     

BRCA1/2突变和同源重组修复缺陷(HRD)检测在乳腺癌中的临床研究进展

乳腺癌已成为发病率最高的癌症。DNA修复缺陷是乳腺癌最重要的特征之一。先前的研究表明,乳腺癌易感基因1/2(breast cancer susceptibility gene 1/2,BRCA1/2)突变是预测乳腺癌同源重组修复缺陷(homologous recombination deficiency, HRD)最主要的生物标志物,能识别铂类药物和多腺苷二磷酸核糖聚合酶(poly ADP ribose polymerase, PARP)抑制剂治疗的获益人群。美国食品药品监督管理局(FDA)已批准Olaparib和Talazoparib两种PARP抑制剂,用于BRCA1/2突变的早期和晚期乳腺癌的辅助治疗。但中国尚未获批。现有研究表明,一部分非BRCA1/2突变的乳腺癌患者也具有HRD特征,可以从铂类药物或PARP抑制剂中获益。本综述总结了涉及到BRCA1/2突变、同源重组修复(homologous recombination repair, HRR)基因突变和HRD状态检测的临床研究。阐明了各种检测方法在识别乳腺癌患者HRD状态和预测疗效方面的价值,并提出应尽快开发用于中国乳腺癌HR...     

Clinical development of PARP inhibitors

DNA repair pathways enable tumor cells to survive chemotherapy- and radiation-induced DNA damage. Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. PARP inhibitors are an area of active clinical investigation in oncology, as they exploit synthetic lethality in tumors with defective homologous recombination(HR)and potentiate the cytotoxic effect of chemotherapy and radiation. Defects in HR pathways are not restricted to BRCA-associated tumors, however, various other cancer types may also be characterized by a lack of HR and are hence susceptible to PARP inhibition. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation both in vitro and in vivo. To date, at least nine different companies have initiated clinical oncology trials with PARP inhibitors, ranging in stages from phase 0 to 3. Recent studies have indicated that tumor cells with defective HR repair pathways, the classic example being BRCA mutations, are exquisitely sensitive to PARP inhibitors. This review summarizes findings and concepts regarding the role of PARP inhibition, as well as the challenges that will be faced in the clinical development of these agents. The identification of predictive markers for sensitivity to PARP inhibition represents a priority area for research.     

聚ADP核糖聚合酶-1及其抑制剂在肿瘤细胞中的研究进展

聚ADP核糖聚合酶-1（PARP-1）在DNA单链断裂的碱基切除修复中具有非常重要的作用,在人类多种肿瘤中过度表达且过度表达者预后较差。利用合成致死原理,对于因BRCA1或BRCA2基因突变而同源重组修复DNA双链断裂缺陷的肿瘤细胞,抑制其PARP-1活性将导致肿瘤细胞死亡。PARP抑制剂对于携带BRCA基因突变肿瘤患者具有一定的治疗作用,其临床应用价值已在多项临床试验中得到了证实。PARP-1可能会成为肿瘤治疗的重要靶点。      

The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer

Advanced cancer is the second leading cause of death in the western world. Chemotherapy and radiation are the two main treatment modalities currently available to improve patient outcomes, but treatment related toxicity and the emergence of resistance limit their effectiveness. Hence there is an urgent need to develop novel treatment strategies. Rapid advances in cancer biology have identified key pathways involved in the repair of DNA damage induced by chemotherapeutic agents and irradiation. Efficient DNA repair in the cancer cell is an important mechanism for therapeutic resistance. Up to 130 genes have been identified that are associated with human DNA repair. Several of these proteins are emerging as important predictive and prognostic factors in solid tumours. Inhibition of DNA repair has the potential to enhance the efficacy of currently available DNA damaging agents. In recent years, several promising drug targets have been identified and novel drugs synthesised that target specific DNA repair proteins. These agents have shown impressive anti-cancer effects in preclinical studies in combination with chemotherapy or irradiation. Their role in human cancer is now being investigated in early phase clinical trials in combination with chemotherapy. MGMT inhibitors, PARP inhibitors and methoxyamine are currently in early stages of clinical development. Innovative clinical trial designs are essential to evaluate the potential of DNA repair inhibitor in cancer therapy.     

A decade of clinical development of PARP inhibitors in perspective

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.     

PARP inhibitors and breast cancer: update and perspectives

Poly(ADP-ribose) polymerase (PARP) family has become a promising therapeutic target in various malignancies including breast cancer. When homologous recombination repair is deficient, as it is observed in BRCA1/2-mutated tumor models, inhibition of PARP was shown to induce massive and selective tumor cell death (the so-called "synthetic lethality"). In breast cancer, PARP inhibitors have been developed as single-agent in BRCA1/2-mutated tumors or in combination with chemotherapy. Recently, a randomized phase III clinical trial failed to demonstrate any survival improvement by combining the iPARP iniparib to chemotherapy in triple-negative metastatic breast cancer patients. This emphasizes the need for future development of this class of compounds to resolve critical issues such as optimal schedule of administration and association to other anticancer treatments, as well as identification of pertinent biomarkers predictive for efficacy.     

Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology.

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.     

PARP Inhibitors and Prostate Cancer: To Infinity and Beyond BRCA

The U.S. Food and Drug Administration recently approved two poly‐adenosine diphosphate‐ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker‐positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non‐BRCA DNA damage repair genes.Implications for PracticeThe treatment potential of PARP inhibition has been well characterized in patients with BRCA1 and BRCA2 mutations, but there is compelling evidence for expanding the use of PARP inhibitors to mutations of other non‐BRCA DNA damage repair (DDR) genes. This could increase the percentage of patients that may benefit from treatment with PARP inhibitors alone or in combination with other therapies. Understanding the significance of PARP inhibitor‐sensitizing alterations in other common non‐BRCA DDR genes will help guide clinical decisions to provide targeted treatment options to a wider population of patients.     

Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer

AimPoly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies.MethodsWe tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells.ResultsIn a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis.ConclusionTaken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development.     

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation–associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbor mutations in the BRCA1 or BRCA2 genes. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic, high-grade serous ovarian cancers and other cancers including endometrial cancer. In this review, we discuss the clinical development of PARP inhibitors in ovarian cancer and explore challenges that need to be addressed if the full potential of these agents is to be realized.     

Crosstalk of DNA double‐strand break repair pathways in poly(ADP‐ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2‐mutated cancer

Germline mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of the DNA double‐strand break (DSB) repair process. Therefore, the DNA‐repair defect characteristic of cancer cells brings about a therapeutic advantage for poly(ADP‐ribose) polymerase (PARP) inhibitor‐induced synthetic lethality. PARP inhibitor‐based therapeutics initially cause cancer lethality but acquired resistance mechanisms have been found and need to be elucidated. In particular, it is essential to understand in detail the mechanism of DNA damage and repair to PARP inhibitor treatment. Further investigations have shown the roles of BRCA1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA1‐deficient cells could be entirely different from that in BRCA2‐deficient cells after PARP inhibitor treatment. The present review describes synthetic lethality and acquired resistance mechanisms to PARP inhibitor through the DSB repair pathway and subsequent repair process. In addition, recent knowledge of resistance mechanisms is discussed. Our model should contribute to the development of novel therapeutic strategies.     

Novel splice‐switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action

Tumors carrying hereditary mutations in BRCA1, which attenuate the BRCA1 DNA damage repair pathway, are more susceptible to dual treatment with PARP inhibitors and DNA damaging therapeutics. Conversely, breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition. We describe a method that triggers susceptibility to PARP inhibition in BRCA1‐functional tumor cells. BRCA1 exon 11 is a key for the function of BRCA1 in DNA damage repair. Analysis of the BRCA1 exon 11 splicing mechanism identified a key region within this exon which, when deleted, induced exon 11 skipping. An RNA splice‐switching oligonucleotide (SSO) developed to target this region was shown to artificially stimulate skipping of exon 11 in endogenous BRCA1 pre‐mRNA. SSO transfection rendered wild‐type BRCA1 expressing cell lines more susceptible to PARP inhibitor treatment, as demonstrated by a reduction in cell survival at all SSO concentrations tested. Combined SSO and PARP inhibitor treatment increased γH2AX expression indicating that SSO‐dependent skipping of BRCA1 exon 11 was able to promote DSBs and therefore synthetic lethality. In conclusion, this SSO provides a new potential therapeutic strategy for targeting BRCA1‐functional breast cancer by enhancing the effect of PARP inhibitors.