The regulation of stem cell self-renewal must balance the regenerative needs of tissues that persist throughout life with the potential for cell overgrowth, transformation and cancer. Here, we ...attempt to deconstruct the relationship that exists between cell-cycle progression and the self-renewal versus commitment cell-fate decision in embryonic and adult stem cells. Recent genetic studies in mice have provided insights into the regulation of the cell cycle in stem cells, including its potential modulation by the stem cell niche. Although the dynamics of the embryonic and adult stem cell cycles are profoundly dissimilar, we suggest that shared principles underlie the governance of this important decision point in diverse stem cell types.
Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define ...the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.
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•An activity-based assay localizes degradation of DNA-bound proteins•Proteolysis is dominant at enhancers and at promoters of distinct gene ontologies•Steady expression of mitochondrial genes requires degradation of NCoR1•Ubiquitin ligase Siah2 mediates derepression especially at CREB target promoters
A genome-wide proteolysis map shows a correlation between DNA-bound protein degradation and active gene promoters. In particular, continual removal of the corepressor NCoR1 from nuclear-encoded mitochondrial genes is required for optimal mitochondrial function.
Summary
Aim
To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib ...under these conditions in patients with advanced solid tumours.
Methods
This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- B or a high-fat C meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal A.
Results
In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC
0–24
increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37–2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98–3.43). Lapatinib C
max
increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49–2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08–3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %).
Conclusions
Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.
Abstract
1. This study assessed the mass balance, metabolism and disposition of 14Ctrametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an ...open-label, single solution dose (2 mg, 2.9 MBq 79 µCi) in two male subjects with advanced cancer.
2. Trametinib absorption was rapid. Excretion was primarily via feces (∼81% of excreted dose); minor route was urinary (∼19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (∼10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK inhibitor with clinical activity in late stage clinical studies.
3. This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an anticancer agent, like trametinib, with both low exposure and a long elimination half-life.
To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).
A total of 43 patients ...with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.
Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.
The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.
Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) ...inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
Dose escalation by 3 + 3 design was followed by exploratory tumor-/biomarker-specific cohorts.
Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).
Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.
Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the ...mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).
Eligible patients with mRCC, previously treated with at least two prior lines of therapy including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI) were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; one-sided α <0.2).
Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE versus 1.9 months for PboE HR, 0.64; 95% confidence interval (CI), 0.34-1.20; one-sided P = 0.079. One TelaE patient had a partial response and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; grade 3 to 4 events occurred in 74% TelaE patients versus 61% PboE.
TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.
Purpose
To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.
Patients and methods
Eligibility criteria were ...advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed.
Results
Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule 1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1–10 every 28 days) was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response.
Conclusion
Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.
Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits ...modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).
mRCC patients received escalating doses of telaglenastat 400-800 mg per os (p.o.) twice daily in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.
Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% 20/21, including 1 partial response (PR) among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies 5/10 PRs as best response (3 confirmed) in clear cell.
TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.
Aims
The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an ...orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.
Methods
A microtracer study approach, in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.
Results
The least‐squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5 h and the geometric mean terminal half‐life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h−1 and 976 l, respectively, resulting in a terminal elimination half‐life of 11 days.
Conclusions
Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.
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