11 research outputs found
Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial
Background
Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.
Methods
In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0â2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.
Findings
Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6â13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7â46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.
Interpretation
Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations
Formation of Covalently Bonded Polycyclic Hydrocarbon Ions by Intracluster Polymerization of Ionized Ethynylbenzene Clusters
Here we report a detailed study aimed
at elucidating the mechanism
of intracluster ionic polymerization following the electron impact
ionization of van der Waals clusters of ethynylbenzene (C<sub>8</sub>H<sub>6</sub>)<sub><i>n</i></sub> generated by a supersonic
beam expansion. The structures of the C<sub>16</sub>H<sub>12</sub>, C<sub>24</sub>H<sub>18</sub>, C<sub>32</sub>H<sub>24</sub>, C<sub>40</sub>H<sub>30</sub>, and C<sub>48</sub>H<sub>36</sub> radical
cations resulting from the intracluster ionâmolecule addition
reactions have been investigated using a combination of mass-selected
ion dissociation and ion mobility measurements coupled with theoretical
calculations. Noncovalent structures can be totally excluded primarily
because the measured fragmentations cannot result from noncovalent
structures, and partially because of the large difference between
the measured collision cross sections and the calculated values corresponding
to noncovalent ionâneutral complexes. All the mass-selected
cluster ions show characteristic fragmentations of covalently bonded
molecular ions by the loss of stable neutral fragments such as CH<sub>3</sub>, C<sub>2</sub>H, C<sub>6</sub>H<sub>5</sub>, and C<sub>7</sub>H<sub>7</sub>. The population of the C<sub>16</sub>H<sub>12</sub> dimer ions is dominated by structural isomers of the type (C<sub>6</sub>H<sub>5</sub>)îžCîŒCîžCH<sup><b>âą+</b></sup>CHîž(C<sub>6</sub>H<sub>5</sub>), which can grow by the
sequential addition of ethynylbenzene molecules, in addition to some
contributions from cyclic isomers such as the 1,3- or 1,4-diphenyl
cyclobutadiene ions. Similarly, two major covalent isomers have been
identified for the C<sub>24</sub>H<sub>18</sub> trimer ions: one that
has a blocked cyclic structure assigned to 1,2,4- or 1,3,5-triphenylbenzene
cation, and a second isomer of the type (C<sub>6</sub>H<sub>5</sub>)îžCîŒCîžCÂ(C<sub>6</sub>H<sub>5</sub>)î»CHîžCH<sup><b>âą+</b></sup>CHîž(C<sub>6</sub>H<sub>5</sub>) where the covalent addition of further ethynylbenzene molecules
can occur. For the larger ions such as C<sub>32</sub>H<sub>24</sub>, C<sub>40</sub>H<sub>30</sub>, and C<sub>48</sub>H<sub>36</sub>,
the major isomers present involve the growing oligomer sequence (C<sub>6</sub>H<sub>5</sub>)îžCîŒCîž[CÂ(C<sub>6</sub>H<sub>5</sub>)î»CH]<sub><i>n</i></sub>îžCH<sup><b>âą+</b></sup>CHîž(C<sub>6</sub>H<sub>5</sub>) with
different locations and orientations of the phenyl groups along the
chain. In addition, the larger ions contain another family of structures
consisting of neutral ethynylbenzene molecules associated with the
blocked cyclic isomer ions such as the diphenylcyclobutadiene and
triphenylbenzene cations. Low-energy dissociation channels corresponding
to evaporation of ethynylbenzene molecules weakly associated with
the covalent ions are observed in the large clusters in addition to
the high-energy channels corresponding to fragmentation of the covalently
bonded ions. However, in small clusters only high-energy dissociation
channels are observed corresponding to the characteristic fragmentation
of the molecular ions, thus providing structural signatures to identify
the product ions and establish the mechanism of intracluster ionic
polymerization
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A Phospholipase C-Îł1âIndependent, RasGRP1-ERKâDependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T CellsâY136F Mutant Mice
Mice expressing a germline mutation in the phospholipase C-γ1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-Ξ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting
A Phospholipase C-Îł1âIndependent, RasGRP1-ERKâDependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T CellsâY136F Mutant Mice
Mice expressing a germline mutation in the phospholipase C-γ1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-Ξ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting