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Journal of Pharmaceutical and... Sep 2021We developed a generic high-performance liquid chromatography mass spectrometry approach for quantitation of small molecule compounds without availability of...
AIM
We developed a generic high-performance liquid chromatography mass spectrometry approach for quantitation of small molecule compounds without availability of isotopically labelled standard.
METHODS
The assay utilized 50 μL of plasma and offers 8 potential internal standards (IS): acetaminophen, veliparib, busulfan, neratinib, erlotinib, abiraterone, bicalutamide, and paclitaxel. Preparation consisted of acetonitrile protein precipitation and aqueous dilution in a 96 well-plate format. Chromatographic separation was achieved with a Kinetex C18 reverse phase (2.6 μm, 2 mm x 50 mm) column and a gradient of 0.1 % formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an AB SCIEX4000QTRAP with electrospray, positive-mode ionization. Performance of the generic approach was evaluated with seven drugs (LMP744, olaparib, cabozantinib, triapine, ixabepilone, berzosertib, eribulin) for which validated assays were available.
RESULTS
The 8 IS covered a range of polarity, size, and ionization; eluted over the range of chromatographic retention times; were quantitatively extracted; and suffered limited matrix effects. The generic approach proved to be linear for test drugs evaluated over at least 3 orders of magnitude starting at 1-10 ng/mL, with extension of assay ranges with analyte isotopologue MRM channels. At a bias of less than 16 % and precision within 15 %, the assay performance was acceptable.
CONCLUSION
The generic approach has become a useful tool to further define the pharmacology of drugs studied in our laboratory and may be utilized as described, or as starting point to develop drug-specific assays with more extensive performance characterization.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Indicator Dilution Techniques; Pharmaceutical Preparations; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 34111734
DOI: 10.1016/j.jpba.2021.114185 -
Gynecologic Oncology Aug 2021Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have... (Review)
Review
Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have aimed to establish whether combination therapy can augment the response seen with PARP inhibitors or antiangiogenic agents alone. This review provides an overview of PARP inhibitors and antiangiogenics as monotherapy in women with advanced ovarian cancer, explores potential mechanisms of action of PARP inhibitor and antiangiogenic combination treatments, reviews efficacy and safety data from trials evaluating this combination, and outlines ongoing and future trials evaluating this combination, discussing these in the context of the current and future treatment landscape for women with advanced ovarian cancer. Sentinel studies evaluating PARP inhibitor (n = 8), antiangiogenic (n = 4), and combination (n = 7) therapy were identified in women with newly diagnosed (n = 7) and recurrent (n = 12) ovarian cancer. PARP inhibitors included olaparib (n = 9), niraparib (n = 4), rucaparib (n = 1), and veliparib (n = 1). Antiangiogenic agents included bevacizumab (n = 7) and cediranib (n = 4). PARP inhibitors combined with antiangiogenics demonstrated efficacy based on objective response rates and progression-free survival (PFS) in the relapsed disease setting. Maintenance therapy with the PARP inhibitor, olaparib, plus antiangiogenic therapy offered a significant PFS benefit versus the antiangiogenic alone in women with newly diagnosed advanced ovarian cancer who tested positive for homologous recombination deficiency. Combination therapy was tolerated, with no new safety signals reported compared with monotherapy trials. PARP inhibitors and antiangiogenics have changed the landscape of ovarian cancer treatment. The PARP inhibitor plus antiangiogenic combination is a novel treatment option that appears promising in the first-line advanced and recurrent ovarian cancer settings, although the role of this combination in recurrent disease requires further elucidation. Defining which patients are candidates for monotherapy or combination therapy is critical, taking into consideration safety profiles of therapies alone or in combination, and how these treatments should be sequenced in clinical practice.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Drug Administration Schedule; Female; Humans; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Patient Selection; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Recombinational DNA Repair
PubMed: 34090705
DOI: 10.1016/j.ygyno.2021.05.018 -
Therapeutic Advances in Gastroenterology 2021Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic mutations, some trials are enrolling patients with defects in other DDR genes such as , , and . With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.
PubMed: 34025781
DOI: 10.1177/17562848211014818 -
Frontiers in Molecular Biosciences 2021Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new...
Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan-Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.
PubMed: 33996894
DOI: 10.3389/fmolb.2021.633344 -
Neuro-oncology Oct 2021Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.
METHODS
VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.
RESULTS
A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.
CONCLUSION
The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.
Topics: Antineoplastic Agents, Alkylating; Benzimidazoles; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Humans; Male; Middle Aged; Radiation Oncology; Temozolomide; Tumor Suppressor Proteins
PubMed: 33984151
DOI: 10.1093/neuonc/noab111 -
JCO Precision Oncology 2021This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of...
UNLABELLED
This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm).
MATERIALS AND METHODS
Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway.
RESULTS
Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm.
CONCLUSION
Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Carboplatin; DNA, Neoplasm; Double-Blind Method; Everolimus; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Neoplasms; Pyrazoles; Pyridones; Pyrimidinones; Temozolomide; Young Adult
PubMed: 33928209
DOI: 10.1200/PO.20.00372 -
Cancers Apr 2021Cancer spheroids are very effective preclinical models to improve anticancer drug screening. In order to optimize and extend the use of spheroid models, these works were...
The New Serum-Free OptiPASS Medium in Cold and Oxygen-Free Conditions: An Innovative Conservation Method for the Preservation of MDA-MB-231 Triple Negative Breast Cancer Spheroids.
Cancer spheroids are very effective preclinical models to improve anticancer drug screening. In order to optimize and extend the use of spheroid models, these works were focused on the development of a new storage concept to maintain these models in the longer term using the Triple-Negative Breast Cancer MDA-MB-231 spheroid models. The results highlight that the combination of a temperature of 4 °C and oxygen-free conditions allowed the spheroid characteristics of OptiPASS serum-free culture medium to preserve the spheroid characteristics during 3-, 5- or 7-day-long storage. Indeed, after storage they were returned to normal culture conditions, with recovered spheroids presenting similar growth rates (recovery = 96.2%), viability (Live/Dead profiles) and metabolic activities (recovery = 90.4%) compared to nonstored control spheroids. Likewise, both recovered spheroids (after storage) and nonstored controls presented the same response profiles as two conventional drugs, i.e., epirubicin and cisplatin, and two anti-PARP1 targeted drugs-i.e., olaparib and veliparib. This new original storage concept seems to induce a temporary stop in spheroid growth while maintaining their principal characteristics for further use. In this way, this innovative and simple storage concept may instigate future biological sample preservation strategies.
PubMed: 33919619
DOI: 10.3390/cancers13081945 -
Journal of Clinical Pharmacology Sep 2021Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination... (Meta-Analysis)
Meta-Analysis
Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (V /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on V /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUC ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUC compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Benzimidazoles; Body Weight; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Creatinine; Cytochrome P-450 CYP2D6 Inhibitors; Dose-Response Relationship, Drug; Humans; Membrane Transport Proteins; Metabolic Clearance Rate; Models, Biological; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Serum Albumin; Sex Factors
PubMed: 33894017
DOI: 10.1002/jcph.1875 -
The Cochrane Database of Systematic... Apr 2021Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established.
OBJECTIVES
To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events.
SEARCH METHODS
On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed.
SELECTION CRITERIA
We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity.
MAIN RESULTS
We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes.
AUTHORS' CONCLUSIONS
In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.
Topics: Bias; Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; Randomized Controlled Trials as Topic; Triple Negative Breast Neoplasms
PubMed: 33886122
DOI: 10.1002/14651858.CD011395.pub2 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2021Electrophilic C-labelled aroyl dimethylaminopyridinium salts, obtained by carbonylative cross-coupling of aryl halides with [ C]carbon monoxide, were prepared for the...
Electrophilic C-labelled aroyl dimethylaminopyridinium salts, obtained by carbonylative cross-coupling of aryl halides with [ C]carbon monoxide, were prepared for the first time and shown to be valuable intermediates in the synthesis of primary [ C]benzamides. The methodology furnished a set of benzamide model compounds, including the two poly (ADP-ribose) polymerase (PARP) inhibitors niraparib and veliparib, in moderate to excellent radiochemical yields. In addition to providing a convenient and practical route to primary [ C]benzamides, the current method paves the way for future application of [ C]aroyl dimethylaminopyridinium halide salts in positron emission tomography (PET) tracer synthesis.
Topics: Benzamides; Carbon Monoxide; Positron-Emission Tomography; Radiopharmaceuticals; Salts
PubMed: 33885193
DOI: 10.1002/chem.202100544