PARP inhibitors Lord, Christopher J.; Ashworth, Alan
Science,
03/2017, Letnik:
355, Številka:
6330
Journal Article
Recenzirano
Odprti dostop
PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a ...century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
BRCAness revisited Lord, Christopher J; Ashworth, Alan
Nature reviews. Cancer,
02/2016, Letnik:
16, Številka:
2
Journal Article
Recenzirano
Over the past 20 years, there has been considerable progress in our understanding of the biological functions of the BRCA1 and BRCA2 cancer susceptibility genes. This has led to the development of ...new therapeutic approaches that target tumours with loss-of-function mutations in either BRCA1 or BRCA2. Tumours that share molecular features of BRCA-mutant tumours - that is, those with 'BRCAness' - may also respond to similar therapeutic approaches. Several paradigm shifts require a reassessment of the concept of BRCAness, how this property is assayed and its relevance to our understanding of tumour biology and the treatment of cancer.
The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in ...individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.
Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall ...the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical ...exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.
As cancer cell genomes are unveiled at a breathtaking pace, the genetic principles at play in cancer are emerging in all their complexity, prompting the assessment of classical genetic interaction ...models. Here, we discuss the implications of these findings for cancer progression and heterogeneity and for the development of new therapeutic approaches.
This article develops a standard for evaluating how parliaments can contribute to the legitimacy of the European semester. It then uses that standard to identify where national parliaments may be ...able to oversee the semester through their relationships to their own governments and where that solution may, conversely, be insufficient. The article uses that analysis to raise four questions. Firstly, what powers over the semester should be exericed by some parliament somewhere? Secondly, how should any parliamentary participation in the semester be distributed across European, national and even sub-national parliaments? Thirdly, how far should parliaments co-operate in their responses to the semester? Fourthly, how uniform across parliaments should participation in the semester be?
PARP inhibitor combination therapy Drean, Amy; Lord, Christopher J; Ashworth, Alan
Critical reviews in oncology/hematology,
12/2016, Letnik:
108
Journal Article
Recenzirano
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.
When is differentiated integration (DI) of the European Union a source of autonomy and when is it a source of domination? Much depends on what collective goods member state democracies seek through ...integration. Club goods often require member state democracies to form DIs of their choice. Public goods and common resource goods may, in contrast, require limits on DI if member state democracies are to meet their own obligations to their own publics to secure rights, justice, non‐domination and democracy itself. Those differences are important to understanding how European democracies should be ‘internationally ordered’ if they are to sustain internal forms of political autonomy. They also demonstrate the importance of DI to the autonomy of member state democracies in associating together beyond the state; in defining obligations within the state; and in securing the greatest autonomy of each European democracy compatible with the greatest possible autonomy of all European democracies.
Zusammenfassung
Wann ist die differenzierte Integration (DI) der Europäischen Union eine Quelle der Autonomie und wann eine Quelle der Herrschaft? Viel hängt davon ab, welche kollektiven Güter die Demokratien der Mitgliedsstaaten durch Integration anstreben. Clubgüter erfordern oft, dass die Demokratien der Mitgliedsstaaten DIs ihrer Wahl bilden. Öffentliche Güter und Gemeingüter können dagegen Beschränkungen für DI erfordern, wenn die Demokratien der Mitgliedstaaten ihren Verpflichtungen gegenüber ihrer eigenen Öffentlichkeit nachkommen sollen, um Rechte, Gerechtigkeit, Nichtherrschaft und Demokratie zu sichern. Diese Unterschiede sind wichtig, um zu verstehen, wie europäische Demokratien „international geordnet“ sein sollten, wenn sie interne Formen politischer Autonomie aufrechterhalten sollen. Sie zeigen auch die Bedeutung von DI für die Autonomie der Demokratien der Mitgliedstaaten bei der Zusammenarbeit über den Staat hinaus; bei der Definition von Verpflichtungen innerhalb des Staates; und bei der Sicherung der größtmöglichen Autonomie jeder europäischen Demokratie, die mit der größtmöglichen Autonomie aller europäischen Demokratien vereinbar ist.
Résumé
Quand l'intégration différenciée (ID) de l'Union européenne est‐elle une source d'autonomie et quand est‐elle une source de domination ? La réponse à cette question dépend beaucoup des biens collectifs que les démocraties des États membres recherchent à travers l'intégration. Les biens de club exigent souvent que les démocraties des États membres forment les IDs de leur choix. Les biens publics et les ressources communes peuvent, en revanche, nécessiter des limites à l'ID si les démocraties des États membres doivent remplir leurs propres obligations envers leurs publics pour garantir les droits, la justice, la non‐domination et la démocratie. Ces différences sont importantes pour comprendre comment les démocraties européennes devraient être « ordonnées au niveau international » si elles veulent maintenir des formes internes d'autonomie politique. Elles démontrent également l'importance de l’ID pour l’autonomie des démocraties des États membres lorsque ces derniers s'associent ; pour la définition des obligations au sein de l'État ; et pour le maintien de la plus grande autonomie de chaque démocratie européenne, compatible avec la plus grande autonomie possible de toutes les démocraties européennes.
The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to ...cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline
BRCA1
or
BRCA2
gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-
BRCA
-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.
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