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International Journal of Gynecological... Jul 2020Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance... (Review)
Review
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the genes or have alterations in the homologous recombination deficiency (HRD) pathway. Contemporary studies are looking into potentially synergistic combination strategies with anti-angiogenics and immune checkpoint inhibitors, among others. The expansion of PARPi treatment has not been limited to ovarian cancer; talazoparib is licensed in patients with HER2-negative breast cancer with germline mutations (m), and front-line olaparib maintenance in patients with pancreatic cancer with germline m. Numerous studies assessing PARPi either in monotherapy or in combination with other agents are ongoing in multiple tumors, including prostate, endometrial, brain, and gastric cancers. Many patients are being treated with PARPi, some for prolonged periods of time. As a result, a thorough knowledge of the potential short- and long-term adverse events and their management is warranted to improve patient safety, treatment efficacy, and towards maintaining an appropriate dose intensity.
Topics: Clinical Trials, Phase III as Topic; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 32276934
DOI: 10.1136/ijgc-2020-001288 -
Translational Cancer Research Jan 2024
PubMed: 38410223
DOI: 10.21037/tcr-23-577 -
Cancers Feb 2022Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. As patients typically present with advanced disease and show poor... (Review)
Review
Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. As patients typically present with advanced disease and show poor responses to broad-spectrum chemotherapy, overall survival remains a dismal 10%. This underscores an urgent clinical need to identify new therapeutic approaches for PDAC patients. Precision medicine is now the standard of care for several difficult-to-treat cancer histologies. Such approaches involve the identification of a clinically actionable molecular feature, which is matched to an appropriate targeted therapy. Selective poly (ADP-ribose) polymerase (PARP) inhibitors such as Niraparib, Olaparib, Talazoparib, Rucaparib, and Veliparib are now approved for several cancers with loss of high-fidelity double-strand break homologous recombination (HR), namely those with deleterious mutations to , , and other functionally related genes. Recent evidence suggests that the presence of such mutations in pancreatic ductal adenocarcinoma (PDAC), the most common and lethal pancreatic cancer histotype, significantly alters drug responses both with respect to first-line chemotherapy and maintenance therapy. In this review, we discuss the current treatment paradigm for PDAC tumors with confirmed deficits in double-strand break HR, as well as emerging strategies to both improve responses to PARP inhibition in HR-deficient PDAC and confer sensitivity to tumors proficient in HR repair.
PubMed: 35205643
DOI: 10.3390/cancers14040897 -
BioMed Research International 2023The inhibition of poly(ADP-ribose) polymerases (PARPs) and ataxia telangiectasia and Rad3-related (ATR) would be an alternative approach for cancer treatments. The aim...
The inhibition of poly(ADP-ribose) polymerases (PARPs) and ataxia telangiectasia and Rad3-related (ATR) would be an alternative approach for cancer treatments. The aim of this study is to investigate the synergy of the different combinations of PARP inhibitors (olaparib, talazoparib, or veliparib) and ATR inhibitor AZD6738. A drug combinational synergy screen that combines olaparib, talazoparib, or veliparib with AZD6738 was performed to identify the synergistic interaction, and the combination index was calculated to verify synergy. TK6 isogenic cell lines with defects in different DNA repair genes were used as a model. Cell cycle analysis, micronucleus induction, and focus formation assays of serine-139 phosphorylation of the histone variant H2AX demonstrated that AZD6738 diminished G2/M checkpoint activation induced by PARP inhibitors and allowed DNA damage-containing cells to continue dividing, leading to greater increases in micronuclei as well as double-strand DNA breaks in mitotic cells. We also found that AZD6738 was likely to potentiate cytotoxicity of PARP inhibitors in homologous recombination repair deficiency cell lines. AZD6738 sensitized more genotypes of DNA repair-deficient cell lines to talazoparib than to olaparib and veliparib, respectively. The combinational approach of PARP and ATR inhibition to enhance response to PARP inhibitors could expand the utility of PARP inhibitors to cancer patients without BRCA1/2 mutations.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Cell Line, Tumor; Recombinational DNA Repair; Antineoplastic Agents; Poly(ADP-ribose) Polymerases; Homologous Recombination; Phthalazines; Ataxia Telangiectasia Mutated Proteins
PubMed: 36794257
DOI: 10.1155/2023/7891753 -
Gynecologic Oncology Reports Feb 2021The objective of this study was to describe the treatment experience of patients with recurrent epithelial ovarian cancer who are retreated with an inhibitor of...
The objective of this study was to describe the treatment experience of patients with recurrent epithelial ovarian cancer who are retreated with an inhibitor of poly(ADP-ribose)-polymerase (PARPi). We conducted a multi-institutional, retrospective review of ovarian cancer patients who received ≥2 lines of therapy containing a PARPi. Demographic, clinical, and pathological data were analyzed with descriptive statistics. Twenty-two patients were identified. For initial PARPi (PARPi1), 12 patients (54.5%) received veliparib, 7 (31.8%) olaparib and 3 (13.6%) rucaparib resulting in 10 patients who had no evidence of disease at the completion of therapy (NED), 3 partial responses (PR), 4 stable disease (SD), and 3 progressive disease (PD). (All 10 CRs involved veliparib given in conjunction with cytotoxic chemotherapy). PARPi1 was used as maintenance in 2 patients. PARPi1 was discontinued because planned number of cycles was reached (n = 10), progression (n = 8), toxicity (n = 2), other (n = 2). For second PARPi (PARPi2), 10 patients (45.4%) received niraparib, 6 (27.3%) olaparib, and 6 (27.3%) rucaparib resulting in 3 PR, 13 SD, and 3 PD. PARPi2 was used as maintenance in 3 patients. The 3 patients who experienced a PR to PARPi2 had a BRCA mutation and were NED following PARPi1. PARPi2 was discontinued because of progression (n = 13), toxicity (n = 6), other (n = 2). One patient currently remains on PARPi2. Toxicity after PARPi1 was not associated with toxicity from PARPi2 (p > 0.05). With 3 approved PARPi for different indications including frontline and recurrence, the opportunity to reuse PARPi has increased. Characterizing those who should be re-challenged is an important initiative moving forward.
PubMed: 33537389
DOI: 10.1016/j.gore.2021.100699 -
Development of a novel transcription factors-related prognostic signature for serous ovarian cancer.Scientific Reports Mar 2021Growing evidence suggest that transcription factors (TFs) play vital roles in serous ovarian cancer (SOC). In the present study, TFs mRNA expression profiles of 564 SOC...
Growing evidence suggest that transcription factors (TFs) play vital roles in serous ovarian cancer (SOC). In the present study, TFs mRNA expression profiles of 564 SOC subjects in the TCGA database, and 70 SOC subjects in the GEO database were screened. A 17-TFs related prognostic signature was constructed using lasso cox regression and validated in the TCGA and GEO cohorts. Consensus clustering analysis was applied to establish a cluster model. The 17-TFs related prognostic signature, risk score and cluster models were effective at accurately distinguishing the overall survival of SOC. Analysis of genomic alterations were used to elaborate on the association between the 17-TFs related prognostic signature and genomic aberrations. The GSEA assay results suggested that there was a significant difference in the inflammatory and immune response pathways between the high-risk and low-risk score groups. The potential immune infiltration, immunotherapy, and chemotherapy responses were analyzed due to the significant difference in the regulation of lymphocyte migration and T cell-mediated cytotoxicity between the two groups. The results indicated that patients with low-risk score were more likely to respond anti-PD-1, etoposide, paclitaxel, and veliparib but not to gemcitabine, doxorubicin, docetaxel, and cisplatin. Also, the prognostic nomogram model revealed that the risk score was a good prognostic indicator for SOC patients. In conclusion, we explored the prognostic values of TFs in SOC and developed a 17-TFs related prognostic signature to predict the survival of SOC patients.
Topics: Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Ovarian Neoplasms; Prognosis; RNA, Messenger; Transcription Factors
PubMed: 33785763
DOI: 10.1038/s41598-021-86294-z -
Cancers Nov 2022BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to... (Review)
Review
BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.
PubMed: 36428712
DOI: 10.3390/cancers14225619 -
Cancer Medicine Oct 2020The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.
OBJECTIVES
The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared.
MATERIALS AND METHODS
Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms.
RESULTS AND CONCLUSION
No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS.
GOV IDENTIFIER
NCT01642251.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Etoposide; Female; Humans; Lung Neoplasms; Male; Medication Adherence; Middle Aged; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Small Cell Lung Carcinoma
PubMed: 32860331
DOI: 10.1002/cam4.3416 -
Nucleic Acids Research Oct 2021The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has been ascribed to PARP trapping, which consists in tight DNA-protein complexes. Here we...
The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has been ascribed to PARP trapping, which consists in tight DNA-protein complexes. Here we demonstrate that the cytotoxicity of talazoparib and olaparib results from DNA replication. To elucidate the repair of PARP1-DNA complexes associated with replication in human TK6 and chicken DT40 lymphoblastoid cells, we explored the role of Spartan (SPRTN), a metalloprotease associated with DNA replication, which removes proteins forming DPCs. We find that SPRTN-deficient cells are hypersensitive to talazoparib and olaparib, but not to veliparib, a weak PARP trapper. SPRTN-deficient cells exhibit delayed clearance of trapped PARP1 and increased replication fork stalling upon talazoparib and olaparib treatment. We also show that SPRTN interacts with PARP1 and forms nuclear foci that colocalize with the replicative cell division cycle 45 protein (CDC45) in response to talazoparib. Additionally, SPRTN is deubiquitinated and epistatic with translesion synthesis (TLS) in response to talazoparib. Our results demonstrate that SPRTN is recruited to trapped PARP1 in S-phase to assist in the excision and replication bypass of PARP1-DNA complexes.
Topics: Animals; Cell Line; Chickens; DNA; DNA Repair; DNA Replication; DNA-Binding Proteins; Humans; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34551432
DOI: 10.1093/nar/gkab777 -
Cancers Dec 2021Ovarian cancer is the gynecological cancer with the worst prognosis and the highest mortality rate because 75% of patients are diagnosed with advanced stage III-IV... (Review)
Review
The Increasing Prognostic and Predictive Roles of the Tumor Primary Chemosensitivity Assessed by CA-125 Elimination Rate Constant K (KELIM) in Ovarian Cancer: A Narrative Review.
Ovarian cancer is the gynecological cancer with the worst prognosis and the highest mortality rate because 75% of patients are diagnosed with advanced stage III-IV disease. About 50% of patients are now treated with neoadjuvant chemotherapy followed by interval debulking surgery (IDS). In that context, there is a need for accurate predictors of tumor primary chemosensitivity, as it may impact the feasibility of subsequent IDS. Across seven studies with more than 12,000 patients, including six large randomized clinical trials and a national cancer registry, along with a mega-analysis database with 5842 patients, the modeled CA-125 ELIMination rate constant K (KELIM), the calculation of which is based on the longitudinal kinetics during the first three cycles of platinum-based chemotherapy, was shown to be a reproducible indicator of tumor intrinsic chemosensitivity. Indeed, KELIM is strongly associated with the likelihood of complete IDS, subsequent platinum-free interval, progression-free survival, and overall survival, along with the efficacy of maintenance treatment with bevacizumab or veliparib. As a consequence, KELIM might be used to guide more subtly the medical and surgical treatments in a first-line setting. Moreover, it could be used to identify the patients with poorly chemosensitive disease, who will be the best candidates for innovative treatments meant to reverse the chemoresistance, such as cell cycle inhibitors or immunotherapy.
PubMed: 35008262
DOI: 10.3390/cancers14010098