A5079266225- PARP inhibition in cancer therapy
- BRCA gene mutations in cancer
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Ovarian cancer diagnosis and treatment
- Lung Cancer Treatments and Mutations
- DNA Repair Mechanisms
- Cancer Genomics and Diagnostics
- Cancer Treatment and Pharmacology
- Cancer Immunotherapy and Biomarkers
- Biochemical and Molecular Research
- Advanced Breast Cancer Therapies
- Global Cancer Incidence and Screening
- Bladder and Urothelial Cancer Treatments
- Colorectal Cancer Treatments and Studies
- Cancer, Lipids, and Metabolism
- Cell death mechanisms and regulation
- Prostate Cancer Treatment and Research
- Cancer Research and Treatments
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Endometriosis Research and Treatment
- Lung Cancer Diagnosis and Treatment
- Ferroptosis and cancer prognosis
- Genetic factors in colorectal cancer
Mediclinic City Hospital
2024
Dubai Hospital
2022-2023
Sarah Cannon Research Institute
2016-2019
Roche (United Kingdom)
2017-2019
Ludwig-Maximilians-Universität München
2018
The University of Texas MD Anderson Cancer Center
2018
Fukushima Medical University
2018
Pontifícia Universidade Católica do Rio Grande do Sul
2018
Roche (United States)
2018
Roche (Switzerland)
2018
To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), role PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).
Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy this two-part, phase I, first-in-human trial. Antitumor MTD, pharmacokinetics, pharmacodynamics of once-daily were determined an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with elimination half-life 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) anemia (25/71...
An acquired genetic instability, resulting from the loss of some types DNA repair, is an early event in development a subset human cancers. The involvement BRCA1 and BRCA2 homologous recombination repair (HRR) double-strand breaks implicates this pathway suppression breast cancer. A family proteins related to RAD51, including XRCC2, are essential components pathway. Using site-directed mutagenesis XRCC2 , we show that non-conservative substitution or deletion amino acid 188 can significantly...
Abstract Background Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics antitumour activity daily oral epertinib combined with trastuzumab (arm A), plus vinorelbine B) or capecitabine C), in patients HER2-positive metastatic breast cancer (MBC). Methods Eligible patients, without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined tolerability each combination...
Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 cases controls, primarily of European descent, from 30 Breast Cancer Association Consortium. We calculated odds ratios (OR) 95% confidence intervals (95% CI) as a measure association. found these...
7522 Background: BMN 673 is the most potent inhibitor of PARP1/2 in clinical development (IC50<1nM), inducing synthetic lethality tumors deficient homologous recombination. Based on preclinical data showing high PARP expression SCLC models and significant antitumor activity 673, an expansion cohort patients was also studied. Methods: Safety, pharmacokinetics (PK), pharmacodynamics (PD), were evaluated a 2-stage study. In dose escalation (Stage 1), cycle 1 6 wks, with drug taken days 8-35,...
Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy other targeted therapies. Although these not known be myelosuppressive, an increased risk of infection has been reported rapamycin analogues. However, new inhibitors this such PI3K, AKT, mTORC 1/2, multikinase is unknown.
PI3K–AKT–mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and becoming increasingly important with their use in larger numbers patients. Retrospective case-control study comparing incidence severity hyperglycaemia (all grades) between case group 387 patients treated on 18 phase I clinical trials PAMi (78 PI3Ki, 138 mTORi, 144 AKTi 27 PI3K/mTORi) control 109 10 not directly targeting the PAM pathway. Diabetic were...
The XRCC3 variant T241M, but not D213N, has been reported to be associated with an increased risk of some cancers. is one out five RAD51 paralogues and involved in homologous recombination, as are the BRCA1 BRCA2 proteins. However, contrast mutations BRCA2, XRCC3(T241M) protein proficient recombination reverts sensitivity mitomycin C found XRCC3-deficient cells, whereas XRCC3(D213N) defective recombination. Here, we report that both D213N T241M alleles increase centrosome number binucleated...
The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed only approximately 40% of the impact baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker inhibitors, platinum-resistant disease still respond olaparib.108 cancers were included. interval between end most recent...
4502 Background: A Phase 1/2 dose escalation and expansion study is evaluating the safety efficacy of durvalumab, a modified human IgG1 mAb that blocks PD-L1 binding to PD-1 CD80, in solid tumors including urothelial bladder cancer (UBC). Methods: Eligible patients (pts) have inoperable or metastatic UBC, ECOG PS 0-1, with no prior anti-PD-1/PD-L1 exposure. Durvalumab 10 mg/kg administered IV q2w for up 12 mos. expression on tumor cells (TC) tumor-associated immune (IC) assessed Ventana...
TPS11614 Background: Molecular stratification of patients to early phase trials targeted therapies is a rational approach drug development help maximise benefit for individuals and provide an indication efficacy. Tumour characterisation often performed on archival biopsies which may not reflect the current complete genetic profile disease there be practical issues delays with obtaining specimens. Analysis circulating tumour DNA (ctDNA) will rapid contemporaneous profile, perhaps representing...
Inherited mutations of the BRCA1 and BRCA2 genes, whose protein products are necessary for homology-directed DNA repair pathway, confer a dominant susceptibility to cancer. We have investigated whether genes encoding other components same pathway can also affect cancer susceptibility. identified three novel non-synonymous substitutions in one such gene, RAD51-related XRCC3. One these variants, D213N, occurs highly conserved ATP-binding domain completely abrogates ability transfected gene...
Abstract Background Atezolizumab is an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the binding of PD-L1 to PD-1 and B7.1 receptors, thereby restoring tumor-specific immunity. TNBC characterized by expression on tumor-infiltrating immune cells (IC), high levels lymphocytes (TILs), a higher mutation rate compared with other breast cancers suggesting therapeutic opportunity for atezolizumab. alone in combination nab-paclitaxel well tolerated, promising clinical...
e14098 Background: Osimertinib is a potent, oral, irreversible EGFR-TKI with efficacy in pts sensitizing (EGFRm) and T790M mutation positive advanced NSCLC. In vitro data show osimertinib induces and/or inhibits cytochrome P450 (CYP)3A breast cancer resistance protein (BCRP) transporters. We report results (Part A) from 2 Phase I open-label, 2-part clinical studies designed to evaluate the effects of on simvastatin (sensitive CYP3A4 substrate; Study 14; NCT02197234) or rosuvastatin (BCRP 19;...