mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months,and conventional chemotherapeutics are the main treatment strategy.Poly(ADP-ribose)polymerase(PARP)inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer,opening a new era for targeted therapy for this disease.However,most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors.Here,we reported that mammalian target of rapamycin complex 2(mTORC2)kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion.Moreover,we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib.Mechanistically,we showed that mTORC2 positively regulates homologous recombination(HR)repair by modulating BRCA1 recruitment to DNA double-strand breaks(DSBs).In addition,we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo.Thus,this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials

Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

PhaseⅠdose-escalation and expansion study of PARP inhibitor,fluzoparib(SHR3162),in patients with advanced solid tumors

Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.

PARP inhibitor reduces proliferation and increases apoptosis in breast cancer cells

Objective： Apoptosis is a reliable marker of chemotherapeutic efficacy. Olaparib and paclitaxel inhibit proliferation and induce apoptosis in a variety of cancers. We investigated the effects of paclitaxel combined with olaparib on apoptosis in breast cancer Bcap37 cells. Methods： Proliferation and apoptosis were detected by MTT assay and PI staining. Degradation of procaspase-3 and poly（ADP-ribose） polymerase （PARP） was analyzed by Western blotting. Results： Compared with paclitaxel alone, paclitaxel combined with 100 mg olaparib significantly reduced survival in Bcap37 cells at all tested treatment durations （P〈0.05）; inhibition increased with increasing olaparib dose and treatment time （P〈0.01）. Combined treatment yielded significantly higher rates of apoptosis （P〈0.05）, which also increased with time （P〈0.01）. Fluorescence micrographs showed that early and late apoptotic cells increased with treatment time. Pro-caspase-3 and PARP degradation was induced by paclitaxel and enhanced by olaparib in a dose-dependent manner. Thus, combined treatment was substantially more effective than treatment with paclitaxel alone. Conclusions： Our findings suggest that paclitaxel and olaparib inhibit breast cancer Bcap37 cell proliferation and induce apoptosis. Combined treatment further reduced cell growth and enhanced apoptosis, suggesting that this combination therapy may be a promising treaunent for breast cancer.

PARP inhibitors: its role in treatment of cancer

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.

Mechanism of PARP inhibitor resistance and potential overcoming strategies

PARP inhibitors(PARPi)are a kind of cancer therapy that targets poly(ADP-ribose)polymerase.PARPi is the first clinically approved drug to exert synthetic lethality by obstruct-ing the DNA single-strand break repair process.Despite the significant therapeutic effect in pa-tients with homologous recombination(HR)repair deficiency,innate and acquired resistance to PARPi is a main challenge in the clinic.In this review,we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance,aiming at extending PARPi application and improving patient outcomes.

Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors

Background:The homologous recombination deficiency(HRD)score serves as a promising biomarker to iden-tify patients who are eligible for treatment with PARP inhibitors(PARPi).Previous studies have suggested a 3-biomarker Genomic Instability Score(GIS)threshold of≥42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer.However,the GIS threshold for prostate cancer(PCa)is still lacking.Here,we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients.Methods:A total of 181 patients with metastatic castration-resistant PCa were included in this study.Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair(HRR)genes and copy number variation(CNV)analysis.The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms(SNP)distributed across the human genome,incorporating three SNP-based as-says:loss of heterozygosity,telomeric allelic imbalance,and large-scale state transition.The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors.The relation-ship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed.Results:Genomic testing was succeeded in 162 patients.In our cohort,61 patients(37.7%)had HRR mutations(HRRm).BRCA mutations occurred in 15 patients(9.3%).The median HRD score was 4(ranged from 0 to 57)in the total cohort,which is much lower than that in breast and ovarian cancers.Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores.CNV occured more frequently in patients with HRRm.The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores≥43.In the 16 patients who received PARPi in our cohort,4 patients with a high HRD score achieved an objective response rate(ORR)of 100%while 12 patients with a low HRD score achieved an ORR of 8.3%.Progression-free survival(PFS)in HRD high patients was longer compared to HRD low patients,regardless of HRRm.Conclusions:A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study.Future studies are needed to further verify this threshold.

Cervical cancer:a tale from HPV infection to PARP inhibitors

Globally,cervical cancer(CxCa)ranks 4th common cancer among females and led to 569,847 incidences and 311,365 deaths in 2018.80%of CxCa cases occur due to persistent infection with a high-risk subtype of human papillomavirus(HPV-16 and 18).Smoking,high par-ity,and co-infection with type 2 herpes simplex or HIV are other known risk factors for CxCa.Major histological subtypes are squamous(70%)and adenocarcinoma(25%).Presently,concur-rent radiation plus cisplatin(CDDP)-based chemotherapy is the standard treatment for CxCa patients.However,CDDP resistance and toxic side effects limit its efficacy,leading to a poorer response rate and an expected overall survival ranging from 10 to 17.5 months.Reduced drug uptake,increased DNA damage repair,increased CDDP inactivation,and overexpressed Bcl-2 or caspase inhibition,are primarily accountable mechanisms for CDDP resistance and improving CDDP’s efficacy remains the major challenge.Poly(ADP-ribosyl)polymerase-1,an effective mediator of nucleotide excision repair pathway,is involved in DNA repair as well as maintaining genomic stability and is significantly expressed in malignant lymphomas,hepa-tocellular-,cervical-and colorectal carcinoma,which has been approved effective in mainte-nance therapy and may serve as an effective target to enhance CDDP sensitivity in CxCa.Here,we summarize the etiology and epidemiology of and treatment for CxCa,the mechanism responsible for chemotherapy resistance,PARP inhibitor as a possible therapy for CxCa,and other possible chemotherapeutic options for CxCa treatment.

Effects of the PARP inhibitor Niraparib on the radiosensitivity of human lung and cervical cancer cells

ObjectiveTo investigate the effect of Niraparib,a clinically approved PARP inhibitor on the radiosensitivity of human lung and cervical cancer cells,and preliminarily explore the underlying mechanism.MethodsThe human lung cancer cell line A549 and human cervical cancer cell line Siha were both treated with Niraparib for 1h,or X-ray irradiation with 4y,or Niraparib for 1h combined with X-ray irradiation with 4Gy.The effect was examined via measurements of cell proliferation by the cell counting kit-8 assay,and cell viability was detected by clone formation assays.Cell apoptosis and cell cycle distribution were investigated by flow cytometry.ResultsIn human lung and cervical cancer cell lines,Niraparib combined with radiation therapy significantly inhibited cell proliferation.The proportion of apoptotic cells in cell lines treated with Niraparib plus radiation(the combination group)was significantly higher compared with control,radiation,and Niraparib groups(P<0.05).Additionally,the proportion of A549 cells in the G_(2)/M phase was significantly increased in the combination group compared with the radiation group(P<0.05).ConclusionPARP inhibitor Niraparib increases the radiosensitivity of tumorcells,promotes their apoptosis,and induces cell cycle redistribution.The possible mechanism is associated with the inhibition of radiation-induced DNA damage repair.

New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers

The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP)ribose polymerase(PARP)inhibitors.However,the efficacy of these compounds is hampered by resistance,which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage.Here,we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance.We discuss the implications,with a particular focus on epigenetic modifications and H3K4 methylation.We also deliberate on the mechanisms responsible,the consequences for the refinement of PARP inhibitor use in the clinic,and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

互联网药学服务在卵巢癌患者口服PARP抑制剂中的应用

目的:探讨互联网药学服务在卵巢癌患者口服多腺苷二磷酸核糖聚合酶(PARP)抑制剂中的应用效果。方法:选取2021年9月~2022年3月某院收治的54例口服PARP抑制剂的卵巢癌患者作为研究对象,按照随机数字表法分为对照组和研究组,每组27例。对照组提供传统药学服务;研究组在传统药学服务基础上提供互联网药学服务。通过Morisky用药依从性问卷、自主设计的PARP抑制剂知识问卷和满意度问卷,了解患者用药依从性、用药知晓度和对互联网药学服务满意度,并比较两组患者不良反应发生情况。结果:研究组患者用药依从性和用药知晓度均优于对照组(P<0.05)。研究组因不良反应中止治疗者1例少于对照组3例(χ^(2)=1.067,P<0.05)。研究组27例患者中,对互联网药学服务满意17例,较满意9例,不满意1例。结论:在PARP抑制剂应用过程中,互联网药学服务可有效提高患者用药依从性、用药知晓度和用药安全性,且管理规范、操作简单、易被接受,可作为卵巢癌患者慢病管理的一种手段。

基于PARP-1/AIF信号通路分析针刺对急性缺血性卒中大鼠脑血流及行为学恢复的影响

目的基于PARP-1/AIF信号通路分析针刺对急性缺血性卒中大鼠脑血流及行为学恢复的影响。方法将40只健康成年雄性SPF级大鼠分为Sham组、模型组、针刺组及针刺+PJ34组,每组10只,除Sham组外均建立动物模型,针刺组及针刺+PJ34组大鼠均进行针刺治疗,针刺+PJ34组以10μmoL/g腹腔注射多聚腺苷二磷酸核糖转移酶-1(PARP-1)抑制剂PJ34,Sham组及模型组不进行针刺干预,均注射相同体积的0.9%生理盐水。11分制单盲评分评价建模后、干预第1、2、3天行为学评分;多普勒仪探头记录软脑膜微循环血流量;HE染色观察脑组织病理形态;TUNEL法检测各组神经细胞凋亡率;免疫组化检测Bax、Bcl-2阳性表达;免疫印迹检测PARP-1、凋亡诱导因子(AIF)蛋白含量。结果建模后,模型组、针刺组及针刺+PJ34组的行为学评分均升高,与Sham组比较差异有统计学意义(P<0.05),干预第1、2、3天时与模型组相比,针刺组行为学评分均降低(P<0.05),针刺+PJ34组上述时间行为学评分均降低,与针刺组比较差异有统计学意义(P<0.05);Sham组、模型组、针刺组及针刺+PJ34组的软脑膜微循环血流量分别为(756.35±102.33)、(233.06±45.17)、(416.40±63.55)、(560.80±72.04)AU,组间比较差异均有统计学意义(F=90.390,P<0.001);HE染色示Sham组大鼠脑组织及神经细胞排列整齐,模型组脑组织紊乱且神经细胞数目减少,针刺组及针刺+OJ34组神经细胞存活较多,排列整齐;Sham组、模型组、针刺组及针刺+PJ34组的神经细胞凋亡率分别为(3.30%±0.21%)、(30.04%±4.52%)、(16.30%±2.25%)、(11.69%±1.33%),组间比较差异均有统计学意义(F=90.390,P<0.001);与Sham组比较,模型组大鼠Bax阳性细胞数降低,Bcl-2阳性细胞数、PARP-1、AIF蛋白升高(均P<0.05),与模型组相比,针刺组及针刺+PJ34组的Bax阳性细胞数及Bcl-2阳性细胞数、PARP-1、AIF蛋白升高(均P<0.05),针刺组及针刺+PJ34组上述指标比较差异均有统计学意义(P<0.05)。结论急性缺血性卒中大鼠采用针刺干预后能够改善行为学,增加脑血流灌溉的同时可通过调节细胞凋亡因子而减少神经细胞凋亡,研究机制可能与抑制PARP-1、AIF活性相关。

张梅教授防治PARP抑制剂所致血小板减少经验介绍

张梅教授在防治PARP抑制剂致血小板减少相关疾病中经验丰富。张师认为PARP抑制剂引发的血小板减少属药毒侵犯,病位在髓,应以“补脾益肾,填精生髓”为治疗大法,并将女性卵巢癌生理特性与临床表现相结合,肝木旺盛,则脾土丰腴,肾水乃活,张教授善佐化瘀之药,活血与养血并用,巧思宣导之品鼓舞坎中之真阳,奏气血生长畅达之效。顾护了PARP抑制剂的应答持续性,提高了患者生存质量。附医案1则予佐证。

PARP抑制剂在乳腺癌应用中的现状及前景

PARP抑制剂可通过合成致死、PARP-DNA捕获等机制对恶性肿瘤产生抑制效果,在治疗包括乳腺癌在内的多种恶性肿瘤患者中取得巨大进展。通过对BRCA基因与乳腺癌、PARP抑制剂抗肿瘤分子机制及其在乳腺癌应用中的情况作一简单综述,以期提高人们对PARP抑制剂的认识,并且为未来临床应用提供参考。

Recent advancements in PARP inhibitors-based targeted cancer therapy

Poly(ADP-ribose)polymerase inhibitors(PARPi)are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers.Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers.This review highlights recent advancements in understanding the molecular mechanisms of PARP‘trapping’and synthetic lethality.Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds,and common characteristics of PARPi and non-homologous end-joining have been elucidated.The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome.This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity.Lastly,acquired chemoresistance is a crucial issue for clinical application of PARPi.The molecularmechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

Ovarian cancer recurrence:“is the definition of platinum resistance modified by PARP inhibitors and other intervening treatments?”

PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian cancer.Particularly in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to treatment.In this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.

二甲双胍通过抑制IL-6/NF-κB/P-gp改善卵巢癌PARP抑制剂耐药

目的:探讨二甲双胍对同源重组修复功能缺陷(HRD)阳性PARP抑制剂(PARPi)耐药卵巢癌的作用及相关机制。方法:逐步诱导法建立尼拉帕利耐药的HRD阳性SKOV3卵巢癌细胞系(SKOV3/PARPi)。白细胞介素-6(IL-6)、转染si-IL-6 RNA以及二甲双胍作用后,采用CCK-8法检测SKOV3或SKOV3/PARPi细胞增殖的变化,Western blot检测细胞内IL-6及P糖蛋白(P-gp)水平、AKT及NF-κB活性的变化,ELISA法检测细胞培养上清液中IL-6含量的变化。建立SKOV3/PARPi卵巢癌裸鼠荷瘤模型并验证二甲双胍、PARPi处理对瘤体的影响,免疫组化及Western blot检测瘤组织内P-gp蛋白的表达。结果:100μg/L IL-6作用SKOV3细胞后尼拉帕利的IC_(50)上调(P<0.001),细胞内P-gp表达增加(P<0.001)。SKOV3/PARPi细胞转染si-IL-6 RNA后尼拉帕利的IC_(50)下调(P=0.008),P-gp表达降低(P<0.001)。二甲双胍作用SKOV3/PARPi细胞后,尼拉帕利的IC_(50)下调(P<0.001);细胞内IL-6及P-gp蛋白水平、AKT及NF-κB活性均下降(P<0.001)。二甲双胍可改善SKOV3/PARPi荷瘤裸鼠尼拉帕利耐药,下调瘤组织内P-gp表达(P均<0.05)。结论:二甲双胍可通过抑制IL-6/NF-κB/P-gp改善卵巢癌PARPi耐药。

PARP抑制剂应用后的卵巢癌三级预防

当下卵巢癌第三级预防的主要任务:患者全生命周期的管理和关怀;患者的初诊教育和培训;合格外科手术医生的培训;PARPi使用后生物学行为的再认识。手术仍然是卵巢癌治疗的基石,PARPi使用后的复发卵巢癌手术需谨慎对待。美国FDA新近撤回了PARP抑制剂治疗L3+化疗后复发卵巢癌的适应证,因为这三种PARPi增加30%以上的卵巢癌患者死亡风险。现有情况下,我们需要重点关注PARPi后的生物学复发和PARPi导致的耐药,尤其是复发后生存时间的改变。

The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

PARP-1抑制剂Olaparib对MCF-7乳腺癌的放疗增敏作用及乏氧显像

目的探讨PARP抑制剂Olaparib对MCF-7乳腺癌模型的放疗增敏作用,并通过^(18)F-氟赤式硝基咪唑(^(18)F-FETNIM)PET/CT监测Olaparib的放疗增敏效应。方法建立MCF-7乳腺癌模型,按随机数字表法分为对照组、Olaparib组、放疗(IR)组、Olaparib+IR组;定期测量肿瘤大小,并统计荷瘤鼠生存时间;治疗前后进行^(18)F-FETNIM PET/CT显像,定量分析肿瘤/肌肉比值(TMR)。对HIF-1α、Ki67及p53蛋白进行免疫组织化学分析;分析TMR与HIF-1α、Ki67及p53的相关性。数据分析采用配对t检验、两独立样本t检验、单因素方差分析和Pearson相关分析。结果Olaparib单独应用时对肿瘤疗效甚微,当与放疗联合时,可减缓肿瘤生长速度,延长生存周期;治疗前,各组之间的TMR值差异无统计学意义;治疗后,与IR组相比,Olaparib+IR组的TMR值明显降低,差异有统计学意义;免疫组化结果显示,与IR组相比,HIF-1α、Ki67及p53在Olaparib+IR组中表达最低(P=0.004;P=0.002;P<0.001);TMR与HIF-1α、Ki67及p53呈正相关性(r=0.918;r=0.919;r=0.914)。结论Olaparib联合放疗能够抑制肿瘤生长,延长生存周期,下调HIF-1α、Ki67及p53等生物标志物,对MCF-7乳腺癌具有放疗增敏作用,同时,^(18)F-FETNIM PET/CT显像能够动态监测肿瘤乏氧情况,反映放疗增敏疗效。