A5020575293- PARP inhibition in cancer therapy
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
- Neutropenia and Cancer Infections
- Ovarian cancer diagnosis and treatment
- Cancer Treatment and Pharmacology
- BRCA gene mutations in cancer
- Cancer, Hypoxia, and Metabolism
- Chronic Lymphocytic Leukemia Research
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- Integrated Circuits and Semiconductor Failure Analysis
- Acute Lymphoblastic Leukemia research
- Molecular Biology Techniques and Applications
- Lung Cancer Research Studies
- Sirtuins and Resveratrol in Medicine
- Cell death mechanisms and regulation
- Statistical Methods in Clinical Trials
- Renal and related cancers
- Cancer Research and Treatments
- Biosimilars and Bioanalytical Methods
- Acute Myeloid Leukemia Research
- Lung Cancer Treatments and Mutations
- Cancer-related molecular mechanisms research
- CRISPR and Genetic Engineering
Frederick National Laboratory for Cancer Research
2012-2024
National Cancer Institute
2011-2023
National Institutes of Health
2012-2023
Center for Cancer Research
2009-2020
Target (United States)
2011-2020
Leidos (United States)
2010-2018
Leidos Biomedical Research Inc. (United States)
2014-2018
The Ohio State University
2016
Georgetown University Medical Center
2016
Georgetown University
2016
Abstract Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic that block repair DNA single-strand breaks (SSB). However, the mechanism action with regard in cancer cells is not fully understood. In this study, we show trap PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP–DNA complexes were more cytotoxic than unrepaired SSBs caused by inactivation, arguing act part poisons enzyme on Moreover, potency trapping differed markedly among niraparib...
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and both olaparib niraparib act poisons at pharmacologic concentrations. Therefore, we proposed should be evaluated based on inhibition trapping. Here, novel inhibitor, BMN 673, compared its effects PARP1 PARP2 with two other clinical inhibitors, rucaparib, using...
Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical inhibitor (PARPi) olaparib through activation P-glycoprotein drug efflux transporter. Here, we show tumor-specific genetic inactivation increases long-term response olaparib, but these eventually developed PARPi resistance. In fraction cases, this caused...
Purpose We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under Exploratory Investigational New Drug Guidance US Food and Administration. It was first-in-human study poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 patients with advanced malignancies. Patients Methods administered as single oral dose 10, 25, or 50 mg to determine range time course over which inhibits PARP activity tumor samples peripheral blood mononuclear cells, evaluate pharmacokinetics....
Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of with single-agent antitumor activity preclinical models. We conducted phase I study adult patients refractory solid tumors determine its maximum-tolerated dose (MTD), pharmacokinetics, modulation phosphorylated Tyr15-Cdk (pY15-Cdk) histone H2AX (γH2AX) levels paired tumor biopsies.
We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to NAD<sup>+</sup>-competitive catalytic inhibitory mechanism. PARP is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent inhibitors. Here, we evaluated the combination of or veliparib therapeutically relevant DNA-targeted drugs, including topoisomerase I inhibitor camptothecin, alkylating...
Abstract A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, topoisomerase I–targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics the patients refractory solid tumors lymphomas. Varying schedules doses intravenous topotecan (10 mg) administered orally twice day (BID) were evaluated. Plasma urine pharmacokinetics assessed levels poly(ADP-ribose) (PAR) DNA damage marker γH2AX measured...
Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects preclinical models. We conducted a phase I trial inhibitor veliparib and patients refractory solid tumors lymphoid malignancies.
BackgroundOlaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
To determine the safety and tolerability of olaparib with cisplatin gemcitabine, establish maximum tolerated dose (MTD), evaluate pharmacodynamic pharmacokinetic profile combination.We conducted a phase I study gemcitabine in patients advanced solid tumors. Treatment at level 1 (DL1) consisted 100 mg orally every 12 hours on days to 4, 500 mg/m(2) 3 10, 60 day 3. PAR levels were measured peripheral blood mononuclear cells (PBMC).Dose-limiting toxicities (DLT) two three DL1 included...
Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized combination selective M6620 (previously VX-970) topotecan, inhibitor, would be tolerable active, particularly in with high replicative stress. Patients Methods This phase I study tested the topotecan 3-week cycles using 3 + dose escalation. The primary end point was identification...
Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide patients BRCA-mutant solid tumors phase I trial. To define the relative contribution of inhibition to observed activity, we conducted randomized II trial determine response rate veliparib compared alone pretreated ovarian cancer or primary peritoneal, fallopian tube, high-grade serous cancers (HGSOC).
PARP is essential for recognition and repair of DNA damage. In preclinical models, inhibitors modulate topoisomerase I inhibitor-mediated This phase study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), pharmacodynamics (PD) veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan.
Abstract Phase 0 trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents before initiating more traditional phase I testing. One major objectives is interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed validated preclinical models. Thus, close collaboration between laboratory scientists clinical investigators essential design conduct trials. Given...
Phosphorylated H2AX (γ-H2AX) is a sensitive marker for DNA double-strand breaks (DSBs), but the variability of expression in different cell and tissue types makes it difficult to interpret meaning γ-H2AX level. Furthermore, assays commonly used detection utilize laborious low-throughput microscopy-based methods. We describe here an ELISA assay that measures both phosphorylated total absolute amounts determine percentage γ-H2AX, providing normalized value representative amount damage....
Abstract Purpose: The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib. Patients and Methods: A 3 + dose-escalation design was used, given once daily on days 1 5 8 12 21-day cycles. Molecular biomarkers activity, including tyrosine 15–phosphorylated Cdk1/2 (pY15-Cdk), were assessed paired...
Phosphorylated histone H2AX (γH2AX) serves as a biomarker for formation of DNA double-strand break repair complexes. A quantitative pharmacodynamic immunofluorescence assay γH2AX was developed, validated, and tested in human tumor xenograft models with the use clinically relevant procedures.The uses novel data quantitation image processing algorithm to determine extent nuclear-specific staining needle biopsies hair follicles collected from mice bearing topotecan-responsive A375 xenografts....
Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored in vitro response of sarcoma cell lines against a large collection investigational and approved drugs identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated combinatorial (matrix) format highly active, synergistic drug combinations,...
Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) of veliparib in combination with weekly topotecan patients solid tumors. Correlative studies were included to assess impact on poly(ADP-ribose) levels peripheral blood mononuclear cells, serum pharmacokinetics both agents, potential association germline repair gene mutations outcome. Experimental Design: Eligible had metastatic nonhematologic malignancies measurable...
Background Poly(ADP-ribose) polymerase (PARP)facilitates DNA repair and PARP inhibitors may potentiate the effect of DNA-damaging chemotherapeutic agents in patients with cancer. Collection peripheral blood mononuclear cells (PBMCs)as a surrogate tissue to monitor inhibitor pharmacodynamic effects has several advantages over tumor biopsy collection, including minimally invasive sample collection ability collect multiple samples for longitudinal assessment drug effect. Methodology/Principal...
Abstract Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes chemotherapy drugs, including topoisomerase I inhibitors platinating agents. This study evaluated incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing 3+3 trial design, we administered escalating doses combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive...
Abstract Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because their limitations (chemical instability, drug efflux-mediated resistance, diarrhea), novel TOP1 are warranted. Indenoisoquinoline non-camptothecin overcome instability resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), LMP744, were examined in a phase study for...
To investigate the safety, activity, and potential biomarkers of response to olaparib carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation BRCAPro scores <10% a family history were eligible. A 3+3 dose escalation tested capsules (400mg bid, days1-7) AUC3-5 on day1 2 every 21 days, ≤ 8 cycles, 400mg bid maintenance. Peripheral blood mononuclear cells collected for polymorphisms PAR...