Targeted therapy for cancer using PARP inhibitors

Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. This would represent one of the first clinically implemented examples of a synthetic lethal approach for cancer treatment. However, there are still unanswered questions surrounding PARP inhibitors, namely the levels of specificity and potency that are required to elicit BRCA selectivity. The recent identification of mechanisms of cellular resistance to PARP inhibitors may provide indications as to how these drugs may be best used in the clinic.     

The role of PARP inhibitors in the treatment of ovarian carcinomas

Homologous recombination (HR), a key mechanism of DNA double strand break (DSB) repair, is commonly defective in high grade serous carcinomas (HGSC) of the ovary. BRCA1/2 mutations, as well as many other molecular and genetic defects, can lead to impaired HR. Treatment of HR-defective tumours with poly-ADP ribose polymerase (PARP) inhibitors, which block the key mechanism of single strand DNA breaks (SSB), exploits a therapeutic concept called "synthetic lethality". Early experiences with PARP inhibitors in germline BRCA mutation carriers and sporadic HGSCs of the ovary have been promising. The development of PARP inhibitors for ovarian cancer is an area of active research. This article provides an overview of the molecular rationale for the use of PARP inhibitors and summarizes some of the key early clinical data of their use in ovarian cancer.     

Targeted toxins in brain tumor therapy

Targeted toxins, also known as immunotoxins or cytotoxins, are recombinant molecules that specifically bind to cell surface receptors that are overexpressed in cancer and the toxin component kills the cell. These recombinant proteins consist of a specific antibody or ligand coupled to a protein toxin. The targeted toxins bind to a surface antigen or receptor overexpressed in tumors, such as the epidermal growth factor receptor or interleukin-13 receptor. The toxin part of the molecule in all clinically used toxins is modified from bacterial or plant toxins, fused to an antibody or carrier ligand. Targeted toxins are very effective against cancer cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated evidence of a tumor response. Currently, clinical trials with some targeted toxins are complete and the final results are pending. This review summarizes the characteristics of targeted toxins and the key findings of the important clinical studies with targeted toxins in malignant brain tumor patients. Obstacles to successful treatment of malignant brain tumors include poor penetration into tumor masses, the immune response to the toxin component and cancer heterogeneity. Strategies to overcome these limitations are being pursued in the current generation of targeted toxins.     

Current status of viral gene therapy for brain tumours

Malignant glial tumours represent the majority of primary brain tumours. Despite the use of many adjunctive treatment strategies in addition to surgery, the prospect of cure or even long-term survival is poor. In the last decade, there has been an explosion of interest in the development of delivery systems that will allow the expression of exogenous genes in the CNS. For the most part, these systems are based upon modified viruses. To date, the greatest experience has been with retroviruses, herpes simplex virus 1 (HSV), adenovirus and adeno-associated virus (AAV). This review will outline the biology of these viral vectors, modifications permitting in vivo administration and their respective advantages and disadvantages for the treatment of malignant brain tumours. The present obstacles to gene therapy strategies will also be described. To date, no convincing clinical trial has emerged that provides objective proof of the superiority of gene therapy strategies as compared to conventional treatment.     

Current status of viral gene therapy for brain tumours

There is genetic evidence that reducing the activity of peroxisome proliferation receptor-γ (PPAR-γ) may increase insulin sensitivity. SR-202 is a selective antagonist at PPAR-γ, which inhibits the adipocyte differentiation normally seen with the PPAR-γ agonist rosiglitazone. SR-202 also reduces the ability of young mice to put on weight and accumulate fat. The levels of circulating TNF-α correlates with body fat stores and/or hyperinsulinaemia. SR-202- treated wild-type mice have reduced TNF-α levels. When wild-type mice are fed a high-fat diet, the plasma levels of TNF-α are raised, and SR-202 treatment protects against this rise. Feeding mice with a high-fat diet induced insulin resistance measured as increased plasma levels of glucose, insulin and free fatty acids, and SR-202 protected against these changes. The ob/ob mouse is diabetic at 8 weeks and plasma glucose and insulin levels continue to rise over the next 3 weeks, and treatment with SR-202 prevents these increases. The development of PPAR-γ antagonists should continue as the results to date suggest that they have clinical potential for the treatment of diabetes Type 2 and obesity.     

靶向DNA损伤反应途径:PARP抑制剂抗肿瘤治疗研究进展

细胞在长期进化过程中形成的复杂的DNA损伤反应防御机制是维护基因组稳定性的重要途径,DNA损伤反应通路缺陷可导致包括肿瘤在内的多种疾病的发生。DNA损伤反应通路是一个复杂的信号通路,包括DNA损伤修复、凋亡、细胞周期调控等,DNA损伤反应通路已经成为新的抗肿瘤药物靶点。目前,已经开发多种DNA损伤反应通路相关的抑制剂,特别是对BRCA1和BRCA2基因突变的肿瘤,利用协同致死现象而开发的聚腺苷二磷酸核糖聚合酶抑制剂广泛应用于肿瘤个体化治疗。该文重点对DNA损伤反应通路抑制剂中的聚腺苷二磷酸核糖聚合酶抑制剂的作用分子机制、临床治疗、耐药性以及面临的挑战进行综述。     

Emerging PARP inhibitors for treating breast cancer

ABSTRACT

Introduction: Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting.

Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance.

Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance.     

PARP inhibitors for homologous recombination-deficient prostate cancer

Introduction: Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities.

Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non–HR-deficient prostate cancer subgroups.

Expert opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.     

Targeted therapy with kinase inhibitors in aggressive endocrine tumors

Introduction: Kinase inhibitors (KIs) are a class of anticancer drugs that inhibit activity of the enzymes protein kinases, which regulate crucial cellular processes and have a demonstrated role in human oncogenesis. Treatment of advanced forms of endocrine cancer which are not responsive to cytotoxic chemotherapies is challenging and use of KIs is gaining a growing role in this field.

Areas covered: The authors summarize the main genetic alterations known to be linked to endocrine tumors, indicating the rationale for utilizing KIs. Furthermore, they present an updated analysis of clinical trials available on PubMed Central, which were pertinent to the activities of KIs in aggressive endocrine cancer. The authors also discuss the adverse effects of KIs and summarize likely involved underlying mechanisms.

Expert opinion: KIs are effective in obtaining a radiological disease control and an improvement of progression-free survival in several forms of endocrine cancer but will never deliver a knockout blow of the disease, due to mechanisms of adaptation to circumvent the specific molecular blockade. The new frontier of KIs treatment is to identify agents that could synergize activity of KIs. The true goal will be to perform an overall genotyping of each tumor, thus predicting the impact of combined targeted therapies in the context of a particular constellation of mutant genes.     

Clinical perspectives of PARP inhibitors.

Poly(ADP-ribose) polymerase (PARP) activation plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. At the same time, PARP activation is also relevant for the ability of cells to repair injured DNA. Thus, depending on the circumstances, pharmacological inhibitors of PARP may be able to attenuate ischemic and inflammatory cell and organ injury or may be able to enhance the cytotoxicity of antitumor agents. Both aspects of the "double-edged sword" role of PARP can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development, or have already entered the stage of clinical trials, we expect that in the upcoming few years, clinical proof of PARP inhibitors' therapeutic effect will be obtained in human disease. In the current short overview, we summarize the pros and cons and challenges with respect to the clinical use of PARP inhibitors, the expected clinical outcomes and potential risks. It appears that on the cytoprotective aspect of PARP, acute, life-threatening diseases (myocardial infarction, cardiopulmonary bypass in high-risk patients, and other, severe forms of ischemia-reperfusion to other organs including stroke and thoracoabdominal aneurysm repair) may represent some of the prime development indications. In the context of inhibition of DNA repair, combination of PARP inhibitors with certain antitumor agents (for example temozolomide) in patients with tumors with extremely poor prognosis are expected to provide the initial clinical results. Development of PARP inhibitors for additional indications (e.g. chronic use for the therapy of neurodegeneration and neuroinflammation, or diabetic complications) may be more challenging because of the unknown potential long-term side effects of PARP inhibitors.     

Development of PARP inhibitors in oncology

Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA repair mechanisms by detecting and initiating repair after DNA strand breaks. Inhibition of PARP in DNA repair-defective tumors (like those with BRCA1 or BRCA2 mutations) can lead to gross genomic instability and cell death. Likewise, combining PARP inhibition with cytotoxic agents such as chemotherapy or radiation therapy is synergistic in many preclinical models. Several drugs designed to inhibit PARP are currently in clinical development, many following a development path different from that of typical anticancer agents. In this review we will focus on the early clinical data from PARP inhibitors that are entering clinical trials, the potential tumors they might target, their combination with other drugs and the different biomarkers that are being explored. Concepts such as ‘BRCAness’, synthetic lethality, Phase 0 trials and pharmacodynamic markers will be discussed in the context of the development of PARP inhibitors.     

PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anti-cancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.     

PARP inhibitors: New tools to protect from inflammation

Poly(ADP-ribosylation) consists in the conversion of β-NAD⁺ into ADP-ribose, which is then bound to acceptor proteins and further used to form polymers of variable length and structure. The correct turnover of poly(ADP-ribose) is ensured by the concerted action of poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) enzymes, which are responsible for polymer synthesis and degradation, respectively. Despite the positive role of poly(ADP-ribosylation) in sensing and repairing DNA damage, generated also by ROS, PARP over-activation could allow NAD depletion and consequent necrosis, thus leading to an inflammatory condition in many diseases. In this respect, inhibition of PARP enzymes could exert a protective role towards a number of pathological conditions; i.e. the combined treatment of tumors with PARP inhibitors/anticancer agents proved to have a beneficial effect in cancer therapy. Thus, pharmacological inactivation of poly(ADP-ribosylation) could represent a novel therapeutic strategy to limit cellular injury and to attenuate the inflammatory processes that characterize many disorders.     

A snapshot of chemoresistance to PARP inhibitors

The exploitation of synthetic lethality in BRCA-deficient tumor carriers using potent inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP)-1 has led to an enthusiastic response among basic scientists, oncologists and pharmaceutical companies. However, accumulating evidence demonstrates that resistance to these drugs develops in tumors in both preclinical and clinical settings. Here, I focus on literature dealing with resistance to these drugs and discuss the molecular mechanisms involved, such as restoration of BRCA function, upregulation of nonhomologous end-joining-dependent DNA repair, induction of P-glycoprotein expression and epigenetic deregulation. Clinical implications of resistance to PARP1 inhibitors are also discussed.     

聚腺苷二磷酸核糖聚合酶抑制剂在神经保护方面的研究进展

作者对聚腺苷二磷酸核糖聚合酶[poly（ADP—ribose）polymerase，PARP]的结构亚型和生物学功能做了简要介绍。归纳了近几年PARP抑制剂在神经保护方面的研究成果。并从结构分类的角度探讨了部分具有应用前景的化合物的构效关系。