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Cancer Chemotherapy and Pharmacology Jan 2022Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models....
PURPOSE
Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C.
METHODS
Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci.
RESULTS
Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC.
CONCLUSION
V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34669023
DOI: 10.1007/s00280-021-04350-x -
Lung Cancer (Amsterdam, Netherlands) Nov 2021Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have...
Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study.
OBJECTIVES
Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC.
MATERIALS AND METHODS
Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed.
RESULTS
Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80-240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%.
CONCLUSION
Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug-drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nivolumab; Platinum
PubMed: 34607210
DOI: 10.1016/j.lungcan.2021.09.004 -
Clinical Cancer Research : An Official... Dec 2021PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic...
PURPOSE
PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer.
PATIENTS AND METHODS
This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14-day cycles.
RESULTS
After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months ( = 0.05) and 10.1 versus 5.9 months ( = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months ( = 0.62) and 7.4 versus 5.1 months ( = 0.10), respectively, with veliparib plus mFOLFIRI.
CONCLUSIONS
Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Humans; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34580114
DOI: 10.1158/1078-0432.CCR-21-1789 -
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 -
Blood Advances Nov 2021Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The... (Review)
Review
Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first, PARP1 inhibitors (PARPis) were developed to target breast cancer mutated cancer cells. Currently, PARPis are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib, and the recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome and acute myeloid leukemia, we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of myelodysplastic syndrome/acute myeloid leukemia and we analyze the available data on the use of PARPis, highlighting their promising advances in clinical application.
Topics: Breast Neoplasms; DNA Repair; Female; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34529761
DOI: 10.1182/bloodadvances.2021004638 -
Frontiers in Oncology 2021Breast cancer type 1 susceptibility (BRCA) mutations not only increase breast cancer (BC) risk but also result in poor survival and prognosis for BC patients. This study...
PURPOSE
Breast cancer type 1 susceptibility (BRCA) mutations not only increase breast cancer (BC) risk but also result in poor survival and prognosis for BC patients. This study will analyze the effect and safety of therapeutic regimens for the treatment of BC patients with germline BRCA (gBRCA) mutations by network meta-analysis.
METHODS
Public databases were searched from inception to 29 April 2021. Frequentist network meta-analysis was conducted to analyze the benefit of chemotherapy and targeted drug-related strategies.
RESULTS
Seventeen articles were included in the analysis. For progression-free survival (PFS), olaparib (hazard ratio (HR): 0.58; 95% confidence interval (CI): 0.43 - 0.79), platinum (HR: 0.45; 95% CI: 0.22 - 0.89), and talazoparib (HR: 0.54; 95% CI: 0.41 - 0.71) were significantly better than platinum-free chemotherapy (Chemo). The results based on indirect comparisons showed that veliparib (Vel) + platinum + Chemo was also significantly better than Chemo (HR: 0.37; 95% CI: 0.20 - 0.69). For overall survival (OS), olaparib was significantly better than Chemo only in the population who did not receive prior chemotherapy. For pathologic complete response (pCR), bevacizumab+Chemo had a significant advantage over platinum agents (OR: 3.64; 95% CI: 1.07 - 12.39). Olaparib and talazoparib both showed significantly higher objective response rates (ORRs) than Chemo.
CONCLUSION
The PFS results suggested that olaparib, talazoparib, and Vel+platinum agent+Chemo were ideal regimens for overall, TNBC, and advanced BC patients with gBRCA mutations. Whether PARPis are suitable for patients with gBRCA mutations who have received prior platinum therapy still needs to be clarified.
PubMed: 34490117
DOI: 10.3389/fonc.2021.718761 -
JCO Precision Oncology 2021In pancreatic cancer (PC), the family alterations define a rare subset of patients that may predict response to inhibition of the signaling pathway. A comprehensive...
PURPOSE
In pancreatic cancer (PC), the family alterations define a rare subset of patients that may predict response to inhibition of the signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of -mutated PC may support future development of -directed strategies.
METHODS
Clinical outcomes were assessed across a multi-institutional case series of 81 patients with family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications.
RESULTS
The frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where V600E (Exon 15), (Exon 11), and fusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with or fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical variants and/or multiple oncogenic drivers. Clinical benefit from inhibitors was observed in 3 of 3 subjects within the V600 subgroup (two partial responses), 4 of 6 with fusions (two partial responses), 2 of 6 with Exon 11 mutations (one partial response), and 0 of 3 with confounding drivers. Outcomes analyses also suggested a trend favoring fluorouracil-based regimens over gemcitabine/nab-paclitaxel within the fusion subgroup ( = .027).
CONCLUSION
Prospective evaluation of -directed therapies is warranted in -mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials.
Topics: Aged; Exons; Female; Humans; MAP Kinase Signaling System; Male; Middle Aged; Mutation; Neoplasm Metastasis; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retrospective Studies; Survival Analysis
PubMed: 34476331
DOI: 10.1200/PO.20.00494 -
Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome.Computational and Structural... 2021Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to...
Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to expand the scale of patients who can benefit from PARPis, and overcome drug resistance associated with it. Genetic interactions (GIs) include SL and synthetic viability (SV) that participate in drug response in cancer cells. Based on the hypothesis that mutated genes with SL or SV interactions with PARP1/2/3 are potential sensitive or resistant PARPis biomarkers, respectively, we developed a novel computational method to identify them. We analyzed fitness variation of cell lines to identify PARP1/2/3-related GIs according to CRISPR/Cas9 and RNA interference functional screens. Potential resistant/sensitive mutated genes were identified using pharmacogenomic datasets. We identified 41 candidate resistant and 130 candidate sensitive PARPi-response related genes, and observed that with gain-of-function mutation induced PARPi resistance, and predicted a combination therapy with PARP inhibitor (veliparib) and EGFR inhibitor (erlotinib) for lung cancer. We also revealed that a resistant gene set (, , and ) in lower grade glioma and a sensitive gene set (, , and ) in ovarian cancer, which were associated with prognosis. Thus, cancer genome-derived GIs provide new insights for identifying PARPi biomarkers and a new avenue for precision therapeutics.
PubMed: 34471490
DOI: 10.1016/j.csbj.2021.08.007 -
International Journal of Molecular... Aug 2021DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if...
DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.
Topics: Benzimidazoles; DNA; G-Quadruplexes; Humans; Indazoles; Magnetic Resonance Spectroscopy; Models, Molecular; Phthalazines; Piperazines; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Promoter Regions, Genetic
PubMed: 34445442
DOI: 10.3390/ijms22168737 -
International Journal of Molecular... Aug 2021Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes or that result in...
Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes or that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of . In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
Topics: BRCA1 Protein; BRCA2 Protein; Cell Line, Tumor; Female; Humans; Models, Biological; Mutation; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34445211
DOI: 10.3390/ijms22168506