卵巢癌是妇科3大肿瘤之一,发病率逐年上升。尽管目前对卵巢癌的治疗方法已取得长足进步,但是患者生存率仍较低,寻求更加高效低不良反应的治疗方法仍是临床医师及科研人员不懈努力的方向。近年来已在卵巢癌中进行了多种聚腺苷二磷酸核糖...卵巢癌是妇科3大肿瘤之一,发病率逐年上升。尽管目前对卵巢癌的治疗方法已取得长足进步,但是患者生存率仍较低,寻求更加高效低不良反应的治疗方法仍是临床医师及科研人员不懈努力的方向。近年来已在卵巢癌中进行了多种聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂的临床研究。niraparib为新型PARP抑制剂,也是首个应用于复发型卵巢上皮癌的靶向药物,对乳腺癌易感基因(breast cancer susceptibility gene,BRCA)野生型及突变型患者均有较好的治疗效果,与放疗及化疗联合应用也有良好效果。本文对niraparib在卵巢癌中的应用进行综述。展开更多
Background Immune checkpoint inhibitors combined with poly ADP-ribose polymerase(PARP)inhibitors and chemotherapy can enhance anti-tumor activity.This phase Ib clinical study was designed to evaluate the safety and ef...Background Immune checkpoint inhibitors combined with poly ADP-ribose polymerase(PARP)inhibitors and chemotherapy can enhance anti-tumor activity.This phase Ib clinical study was designed to evaluate the safety and efficacy of cisplatin in combination with sintilimab and niraparib in patients with advanced solid tumors.Methods Patients with advanced solid tumors who had progressed after one or more lines of standard therapy were enrolled in the study,and received cisplatin and sintilimab on day 1 and niraparib from days 1–21 every 3 weeks for up to 4 cycles,followed by maintenance therapy with sintilimab and niraparib(the same doses and schedules as before),until disease progression,death,or intolerable toxicities.During the dose-escalation phase,patients were divided into three dose groups on the basis of a 3+3 dose-escalation regimen,and a dose-expansion phase was conducted based on the determined maximum tolerated dose(MTD).The primary endpoint was safety,including treatment-related adverse events(TRAEs),dose-limiting toxicity(DLT),and the recommended phase 2 dose(RP2D),and the secondary endpoint was efficacy.In addition,exploratory endpoints were prespecified to analyze potential biomarkers.Results From July 31,2019,to July 1,2022,a total of 26 patients were enrolled,and no DLTs were observed in the dose-escalation phase.The recommended RP2Ds of cisplatin,sintilimab,and niraparib were 60 mg/m2,200 mg,and 100 mg every 3 weeks,respectively.All patients experienced TRAEs of varying severity,and a 19.23%(5 patients)incidence of immune-related adverse events(irAEs).With the median follow-up time of 47.9 months(95%confidence interval[CI]:38.8–NA),objective response rate(ORR)was 26.92%(7 patients,95%CI,11.57–47.79),disease control rate was 57.69%(15 patients,95%CI:36.92–76.65),the median progression-free survival(PFS)was 3.30 months(95%CI:2.14–4.46)and the median overall survival(OS)was 8.03 months(95%confidence interval[CI]:3.41–12.66),with PFS rates of 26.92%(seven patients)and 11.54%(three patients)at 6 and 12 months,and OS rates of 69.23%,34.62%and 11.54%at 6,12 and 24 months,respectively.Patients with programmed cell death ligand 1(PD-L1)expression≥1%showed significantly longer PFS(3.93 months,P=0.032)and OS(14.97 months,P=0.036)compared to those with PD-L1 expression<1%.Conclusion The combination of cisplatin with sintilimab and niraparib showed a manageable safety profile and modest anti-tumor activity in patients with advanced solid tumors.Further validation in larger,histology-specific patients is needed to confirm clinical benefit.展开更多
Poly(adenosine 5'-diphosphate-ribose)polymerase inhibitors(PARPi)are increasingly important in the treatment of ovarian cancer.However,more than 40%of BRCA1/2-deficient patients do not respond to PARPi,and BRCA wi...Poly(adenosine 5'-diphosphate-ribose)polymerase inhibitors(PARPi)are increasingly important in the treatment of ovarian cancer.However,more than 40%of BRCA1/2-deficient patients do not respond to PARPi,and BRCA wild-type cases do not show obvious benefit.In this study,we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status.This synergy was validated in an ovarian cancer organoid model and in vivo experiments.Furthermore,we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage.In clinical cohort,it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy,and high progesterone receptor expression combined with low glutathione peroxidase 4(GPX4)expression predicted better efficacy of PARPi in patients with ovarian cancer.These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.展开更多
PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair p...PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair pathways.However,as the case with other chemotherapeutic agents,their effectiveness is often compromised by the development of resistance.PARP inhibitors have consistently been reported to promote autophagy,a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.Autophagy can exhibit different functional properties,the most prominent being cytoprotective.In addition,both cytotoxic and non-protective functions forms have also been identified.In this review,we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors,highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.展开更多
文摘卵巢癌是妇科3大肿瘤之一,发病率逐年上升。尽管目前对卵巢癌的治疗方法已取得长足进步,但是患者生存率仍较低,寻求更加高效低不良反应的治疗方法仍是临床医师及科研人员不懈努力的方向。近年来已在卵巢癌中进行了多种聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂的临床研究。niraparib为新型PARP抑制剂,也是首个应用于复发型卵巢上皮癌的靶向药物,对乳腺癌易感基因(breast cancer susceptibility gene,BRCA)野生型及突变型患者均有较好的治疗效果,与放疗及化疗联合应用也有良好效果。本文对niraparib在卵巢癌中的应用进行综述。
文摘Background Immune checkpoint inhibitors combined with poly ADP-ribose polymerase(PARP)inhibitors and chemotherapy can enhance anti-tumor activity.This phase Ib clinical study was designed to evaluate the safety and efficacy of cisplatin in combination with sintilimab and niraparib in patients with advanced solid tumors.Methods Patients with advanced solid tumors who had progressed after one or more lines of standard therapy were enrolled in the study,and received cisplatin and sintilimab on day 1 and niraparib from days 1–21 every 3 weeks for up to 4 cycles,followed by maintenance therapy with sintilimab and niraparib(the same doses and schedules as before),until disease progression,death,or intolerable toxicities.During the dose-escalation phase,patients were divided into three dose groups on the basis of a 3+3 dose-escalation regimen,and a dose-expansion phase was conducted based on the determined maximum tolerated dose(MTD).The primary endpoint was safety,including treatment-related adverse events(TRAEs),dose-limiting toxicity(DLT),and the recommended phase 2 dose(RP2D),and the secondary endpoint was efficacy.In addition,exploratory endpoints were prespecified to analyze potential biomarkers.Results From July 31,2019,to July 1,2022,a total of 26 patients were enrolled,and no DLTs were observed in the dose-escalation phase.The recommended RP2Ds of cisplatin,sintilimab,and niraparib were 60 mg/m2,200 mg,and 100 mg every 3 weeks,respectively.All patients experienced TRAEs of varying severity,and a 19.23%(5 patients)incidence of immune-related adverse events(irAEs).With the median follow-up time of 47.9 months(95%confidence interval[CI]:38.8–NA),objective response rate(ORR)was 26.92%(7 patients,95%CI,11.57–47.79),disease control rate was 57.69%(15 patients,95%CI:36.92–76.65),the median progression-free survival(PFS)was 3.30 months(95%CI:2.14–4.46)and the median overall survival(OS)was 8.03 months(95%confidence interval[CI]:3.41–12.66),with PFS rates of 26.92%(seven patients)and 11.54%(three patients)at 6 and 12 months,and OS rates of 69.23%,34.62%and 11.54%at 6,12 and 24 months,respectively.Patients with programmed cell death ligand 1(PD-L1)expression≥1%showed significantly longer PFS(3.93 months,P=0.032)and OS(14.97 months,P=0.036)compared to those with PD-L1 expression<1%.Conclusion The combination of cisplatin with sintilimab and niraparib showed a manageable safety profile and modest anti-tumor activity in patients with advanced solid tumors.Further validation in larger,histology-specific patients is needed to confirm clinical benefit.
基金supported by the National Natural Science Foundation of China(82003050 and 82173142)Hunan Provincial Natural Science Foundation(2023JJ30375 and 2023JJ60016)+2 种基金Hunan Cancer Hospital Climb Plan(2023NSFC-A004 and 2023NSFC-A003)Changsha Science and Technology Board(kh2201054)Hunan Provincial Health Commission(B2023047708).
文摘Poly(adenosine 5'-diphosphate-ribose)polymerase inhibitors(PARPi)are increasingly important in the treatment of ovarian cancer.However,more than 40%of BRCA1/2-deficient patients do not respond to PARPi,and BRCA wild-type cases do not show obvious benefit.In this study,we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status.This synergy was validated in an ovarian cancer organoid model and in vivo experiments.Furthermore,we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage.In clinical cohort,it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy,and high progesterone receptor expression combined with low glutathione peroxidase 4(GPX4)expression predicted better efficacy of PARPi in patients with ovarian cancer.These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.
基金Research in Dr.Gewirtz’s laboratory is supported by Grants#CA268819 and CA239706 from the National Cancer InstituteNational Institutes of Health and Grant#W81XWH 19-1-0490 from the Department of Defense Congressionally Directed Breast Cancer Research Program.
文摘PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deficient in DNA repair pathways.However,as the case with other chemotherapeutic agents,their effectiveness is often compromised by the development of resistance.PARP inhibitors have consistently been reported to promote autophagy,a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.Autophagy can exhibit different functional properties,the most prominent being cytoprotective.In addition,both cytotoxic and non-protective functions forms have also been identified.In this review,we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors,highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.
