BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breas...BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.展开更多
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 w...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.展开更多
Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to p...Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.展开更多
A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma w...A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma with the mutation of breast cancer susceptibility gene 1 and liver metastasis.The primary lung lesions and local liver metastases were well controlled through combined immunotherapy,antiangiogenic medications and Poly ADP-ribose polymerase inhibitors.Considering the high tumor load and the generally poor condition of the patient,transarterial chemoembolization,in place of the conventional chemotherapy treatment mode was chosed for liver metastasis in the current case.We discussed selecting a tailored program and outlined the patient’s diagnosis and treatment process.Additionally mentioned multiple drug combination strategies for squamous lung cancer.展开更多
A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarograph...A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarographic method. The detection limit of NIC was 0.03μmol/L, the calibration graph was linear up to 5μmol/L ( r = 0.999). The recoveries were approximately in the range of 92% to 98% and the relative standard deviations were less展开更多
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 pr...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.展开更多
gallbladder cancer(gbc), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. the late diagnosis and abysmal prognosis present challenges to treatment. the over...gallbladder cancer(gbc), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. the late diagnosis and abysmal prognosis present challenges to treatment. the overall 5-year survival rate for metastatic gbc patients is extremely low. BRC A1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European commission for the treatment of ovarian cancer with any BRCA1/2 mutations. the first case of BRCA1-mutated gbc patient who responded to olaparib treatment is reported here.展开更多
Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in t...Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors.Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8%of patients with sporadic pancreatic cancer.In patients with germline BRCA mutations,platinum-based chemotherapies and poly(ADP-ribose)polymerase inhibitors are effective treatment options which may offer survival benefits.This review will focus on the molecular biology,epidemiology,and management of BRCA-mutated pancreatic cancer.Further-more,we will discuss future directions for this area of research and promising active areas of research.展开更多
In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens ...In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens have little impact,and surgical resection remains the only reliable curative approach.We address current treatment options for these patients,focusing on the usefulness of breast cancer(BRCA)gene mutation as a prognostic biomarker and predictor of response to chemotherapy.Superior survival outcomes have been reported in patients with PC and mutant BRCA gene treated with first-line platinum-based chemotherapy.Therefore,it appears appropriate to include BRCA gene status among clinical criteria used to select the chemotherapy regimen.In addition,maintenance treatment with poly(ADP-ribose)polymerase inhibitors has been found to improve progression-free survival in patients with PC and mutated BRCA whose disease does not progress after first-line platinum-based chemotherapy.This combination has therefore been proposed as the optimal treatment regimen for these patients.展开更多
文摘BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.
文摘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.
基金Supported by The Ministry of Science and Higher Education of the Russian Federation,No.075-15-2020-789.
文摘Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.
文摘A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma with the mutation of breast cancer susceptibility gene 1 and liver metastasis.The primary lung lesions and local liver metastases were well controlled through combined immunotherapy,antiangiogenic medications and Poly ADP-ribose polymerase inhibitors.Considering the high tumor load and the generally poor condition of the patient,transarterial chemoembolization,in place of the conventional chemotherapy treatment mode was chosed for liver metastasis in the current case.We discussed selecting a tailored program and outlined the patient’s diagnosis and treatment process.Additionally mentioned multiple drug combination strategies for squamous lung cancer.
文摘A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarographic method. The detection limit of NIC was 0.03μmol/L, the calibration graph was linear up to 5μmol/L ( r = 0.999). The recoveries were approximately in the range of 92% to 98% and the relative standard deviations were less
文摘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.
基金supported by International Science and Technology Cooperation Projects,No.2015DFA30650 and No.2010DFB33720Capital Special Research Project for Health Development,No.2014-2-4012Capital Research Project for the Characteristics Clinical Application,No.Z151100004015170
文摘gallbladder cancer(gbc), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. the late diagnosis and abysmal prognosis present challenges to treatment. the overall 5-year survival rate for metastatic gbc patients is extremely low. BRC A1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European commission for the treatment of ovarian cancer with any BRCA1/2 mutations. the first case of BRCA1-mutated gbc patient who responded to olaparib treatment is reported here.
文摘Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors.Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8%of patients with sporadic pancreatic cancer.In patients with germline BRCA mutations,platinum-based chemotherapies and poly(ADP-ribose)polymerase inhibitors are effective treatment options which may offer survival benefits.This review will focus on the molecular biology,epidemiology,and management of BRCA-mutated pancreatic cancer.Further-more,we will discuss future directions for this area of research and promising active areas of research.
基金by Junta de Andalucía,No.PC-0498-2017 and No.PC-0549-2017.
文摘In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens have little impact,and surgical resection remains the only reliable curative approach.We address current treatment options for these patients,focusing on the usefulness of breast cancer(BRCA)gene mutation as a prognostic biomarker and predictor of response to chemotherapy.Superior survival outcomes have been reported in patients with PC and mutant BRCA gene treated with first-line platinum-based chemotherapy.Therefore,it appears appropriate to include BRCA gene status among clinical criteria used to select the chemotherapy regimen.In addition,maintenance treatment with poly(ADP-ribose)polymerase inhibitors has been found to improve progression-free survival in patients with PC and mutated BRCA whose disease does not progress after first-line platinum-based chemotherapy.This combination has therefore been proposed as the optimal treatment regimen for these patients.
