PARP inhibitor combination therapy

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Abstract

In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies.

Introduction

The PARP (Poly(ADP-ribose) polymerase) family of enzymes utilise beta nicotinamide adenine dinucleotide (β-NAD+) to covalently add Poly(ADP-ribose) (PAR) chains onto target proteins, a process termed PARylation (De Vos et al., 2012). This form of post-translational modification has the ability to alter the function of target proteins and has been found to be involved in a diverse set of cellular processes including chromatin modification, transcription regulation, the control of cell division, Wnt signalling and the maintenance of telomeres (Gibson and Kraus, 2012). The best-studied PARP enzyme is PARP1, which has a well-established role in the repair of damaged DNA (reviewed in (De Vos et al., 2012)). As part of this role, PARP1 is involved in the repair of single stranded DNA breaks (Woodhouse et al., 2008), but has also been implicated in the repair of other DNA lesions (Krishnakumar and Kraus, 2010). PARP1 binds to damaged DNA via a series of Zinc finger domains, and then PARylates a series of DNA repair effector proteins, releasing nicotinamide as a by product (Krishnakumar and Kraus, 2010). Subsequently, PARP1 autoPARylation causes the release of the protein from DNA (De Vos et al., 2012).

The role of PARP1 and the related enzyme PARP2, in DNA repair, prompted the development of potent small molecule PARP1/2 inhibitors (PARPi) (reviewed in (Zaremba and Curtin, 2007)). Their original proposed use was as chemo- or radiosensitizing agents. Indeed, as early as the 1980s, a toolbox PARP superfamily inhibitor, 3-aminobenzamide (3AB), was shown to enhance the cytotoxic effect of the DNA methylating agent, dimethyl sulphate (Purnell and Whish, 1980). Classical structure activity relationship-based drug discovery efforts led to the discovery of the first set of clinical PARPi to enter clinical trials; rucaparib (AG014699, PF-01367338/Pfizer), veliparib (ABT-888/Abbott Pharmaceuticals), olaparib (AZD2281, KuDOS/AstraZeneca, now marketed as Lynparza), and niraparib (MK-4827, Merck/Tesaro) (recently reviewed in (Lord et al., 2015)). In general, these inhibitors tend to have PARP1 IC50 (the drug concentration needed to kill 50% of a cell population) values in the nanomolar range, but more recently, a second generation of more potent PARPi with picomolar PARP1 IC50 values, such as talazoparib (BMN 673, Biomarin/Medivation) have been developed (Shen et al., 2013). Each of these small molecule inhibitors impairs the catalytic activity of PARP1 by interacting with the β-NAD+ binding catalytic domain. However, there are distinct differences in other aspects of their function. For example, recent work has suggested that the cytotoxicity caused by PARPi is in part caused by PARP1 being “trapped” on DNA by PARPi (Murai et al., 2012), a likely consequence of impairing PARP1 autoPARylation. It seems that whereas drugs such as talazoparib and olaparib are effective PARP1 trapping agents, veliparib has considerably less trapping activity (Murai et al., 2012, Murai et al., 2014b) (Fig. 1, Fig. 2)

Although clinical PARPi were developed with a chemo- or radiosensitisation role in mind, their utility as single agents has overtaken this effort. PARP1/2 inhibitors can selectively target tumour cells with defects in either the BRCA1 or BRCA2 tumour suppressor genes that normally maintain the integrity of the genome by mediating a DNA repair process, known as homologous recombination (HR) (recently reviewed in (Lord et al., 2015)). This “synthetic lethal” effect of PARPi is likely caused by PARPi causing a persistent DNA lesion that is normally repaired by HR; in the absence of BRCA gene function and HR, tumour cells seem unable to effectively repair these DNA lesions and die, whilst normal (non-tumour) cells are unaffected (Bryant et al., 2005, Farmer et al., 2005). The effectiveness of PARPi in being able to selectively target BRCA mutant tumour cells in pre-clinical model systems (tumour cell lines and animal models) was reflected in clinical trials where significant and sustained anti-tumour responses were observed in heavily pre-treated breast or ovarian cancer patients with germ-line BRCA1 or BRCA2 mutations (Lord et al., 2015). Additionally, efficacy was observed when olaparib was used in a Phase 2 clinical trial as a maintenance therapy in high-grade serous ovarian cancer (HGSOC) following carboplatin first-line therapy. For example, when compared to patients receiving placebo after carboplatin, HGSOC patients who received olaparib maintenance therapy exhibited a marked improvement in progression free survival (PFS) (8.4 months compared to 4.8 months in the placebo arm). HGSOC is a disease with a relatively high frequency of BRCA mutations and in this same clinical trial, patients harbouring BRCA1 or BRCA2 gene mutations showed the most profound improvement in PFS (11.2 months) (Ledermann et al., 2012, Ledermann et al., 2014). On the basis of these trial results, olaparib was approved for use by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2014, specifically as a maintenance monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated, advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy (Simon, 2014).

Although PARPi can elicit profound and sustained anti-tumour responses in BRCA-mutant patients, in some cases PARPi resistance emerges (Lord and Ashworth, 2013). In BRCA mutant patients, clinical PARPi resistance has been associated with the presence of additional mutations in the either the BRCA1 or BRCA2 genes. These “secondary” mutations, which have been observed in tumour DNA recovered from patients with profound PARPi resistance (Barber et al., 2013), restore the open reading frame (ORF) of either the BRCA1 or 2 gene and cause the formation of a functional protein product that can restore HR and repair the DNA lesion caused by PARPi (Edwards et al., 2008, Sakai et al., 2009). Additional mechanisms of acquired resistance to PARPi have been proposed and include up-regulation of P-glycoprotein (PGP) pumps (which transport small molecules such as PARPi across the plasma membrane), additional loss of function in either DNA repair proteins, 53BP1 and REV7, or stabilization of the BRCT domain of mutant BRCA1 by the heat-shock protein 90 (HSP90) (Lord and Ashworth, 2013).

Further investigation of PARPi utility outwith a BRCA context has also been explored. Several sporadic tumours have been shown to exhibit a BRCAness phenotype, where they possess molecular and histopathological characteristics similar to BRCA-deficient disease (Turner et al., 2004). For example, cell lines with oncogenic fusions such as EWS-FLI1 (caused by a chromosomal translocation) characteristic of Ewing sarcoma (EWS) exhibit sensitivity to PARPi (Brenner et al., 2012, Garnett et al., 2012). However, a Phase 2 clinical trial evaluating efficacy of a single-agent PARPi therapeutic approach exhibited no partial or complete response in 12 Ewing sarcoma patients (NCT01583543) (Choy et al., 2014). Defects in the ATM DNA repair tumour suppressor gene have also been associated with PARPi sensitivity (McCabe et al., 2006, Williamson et al., 2010); in contrast to EWS, clinical responses to ATM mutant prostate cancers have recently been described (Mateo et al., 2015).

Before we summarise the current understanding of PARPi combinatorial effects, it is perhaps useful to consider why combination therapy might be useful in addition to single agent treatment. Combinations of therapeutic agents that have fundamentally different mechanisms of action and varying normal tissue toxicity have great potential for improving survival outcomes for cancer patients. In some instances, some agents fail to have any anti-tumour effects when used as single agents, but can elicit effects when combined with secondary agents. Although the use of single agent PARPi has received considerable attention as of late, a large body of data evaluating the potential of PARPi in combination has accrued over the last decade. Specifically, strategies to optimize the use of PARPi as chemopotentiators, as well as to circumvent the development of resistance have been, and remain, under investigation.

Section snippets

Combinations of PARPi with cytotoxic chemotherapy

Together with radiotherapy and surgery, cytotoxic chemotherapy remains the backbone of many cancer treatments. However, chemotherapy responses are treatments limited by either de novo or acquired resistance and therefore combination therapies that improve chemotherapy responses are eagerly sought. Many chemotherapies work by causing DNA damage and/or exploiting DNA repair defects that exist in tumour cells and therefore additional drugs, such as PARP inhibitors, which also impair DNA repair

PARPi in combination with radiation

The therapeutic effect of high dose ionizing radiation (IR) arises from DNA damage to which some tumours are particularly sensitive (Mo et al., 2015). IR exposure results in the rapid activation and recruitment of PARP1 to damaged DNA (Satoh et al., 1993). Furthermore, PARP-1-null cell lines and mice exhibit exquisite sensitization to IR (de Murcia et al., 1997, Schreiber et al., 1995) and clinical PARPi induce radiosensitization in pre-clinical model systems (Chalmers et al., 2004, Jacobson et

PARPi in combination with targeted agents

Although PARP inhibitor combinations with chemotherapies and IR have received the most attention, a growing body of investigation has assessed the potential for combination therapy involving agents targeted against molecular alterations in cancer.

PARPi combined with immunotherapeutics

Therapies that harness the host immune system have been revolutionary in the treatment of a subset of cancers (Chen and Mellman, 2013). Currently most success has been achieved with immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1/PDL-1. Response to these agents appears to correlate with the mutagenic burden of the tumour; presumably these mutations produce a larger number of neo-antigens, which can be recognised by the immune system (Rizvi et al., 2015). It is possible, therefore,

PARP inhibitor combinations – challenges and opportunities

It is clear from the data described above that there is already considerable evidence that combination therapies involving PARPi could be of considerable utility in a wide variety of cancers. Along with others, we believe the re-categorization of PARPi based on their dual molecular mechanism of action (PARP inhibitor via catalytic inhibition or PARP poison via PARP trapping) is imperative to correctly assess appropriate combinatorial approaches (Fojo and Bates, 2013, Murai et al., 2012, Murai

Conflict of interest statement

CJL and AA are named inventors on patents describing the use of PARP inhibitors and stand to gain from their development as part of the ICRs “Rewards to Investors” scheme.

Acknowledgments

We thank Breast Cancer Now (formerly Breakthrough Breast Cancer and the Breast Cancer Campaign), Cancer Research UK, The Wellcome Trust, The Breast Cancer Research Foundation, The Komen Foundation and UCSF for funding our work.

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