Patients with a germline
or
mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor ...activity in this population.
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline
or
mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review.
Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval CI, 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.
Among patients with a germline
mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).
Objective
To analyze whether a combination of quercetin (Q) and resveratrol (RSV) would induce a white adipose tissue (WAT) browning effect.
Methods
Thirty‐six rats were fed an obesogenic diet and ...divided into four groups: control, treated with RSV (15 mg/kg body weight/day; RSV group), treated with Q (30 mg/kg body weight/day; Q group), or treated with both polyphenols (RSV + Q group).
Results
After 6 weeks, body and WAT weights were significantly reduced in the RSV + Q group. In perirenal WAT of the control, RSV, and Q groups, white unilocular adipocytes appeared in the majority of cells, while in the RSV + Q group numerous multilocular adipocytes with positive immunostaining for UCP1 were observed. The presence of UCP1 was confirmed by Western blot. This group also revealed increased mRNA levels of Cidea, Hocx9, Bmp4, Slc27a1, Pat2, Atgl, and Atp5d. Interscapular brown adipose tissue weight showed no differences between groups, but the Cidea mRNA level was increased in the RSV group, the Cox‐2 mRNA level in the RSV + Q group, and UCP1 protein expression in the RSV and the RSV + Q groups.
Conclusions
This study demonstrated that the RSV + Q combination produces a brown‐like remodeling effect in perirenal WAT, as well as increased UCP1 protein expression in interscapular brown adipose tissue.
Abstract Objective The scientific community is on the look-out for safe biomolecules useful in the prevention of obesity and related aberrations such as fatty liver. This study analyzed the influence ...of resveratrol on hepatic triacylglycerol metabolism. Methods Male Sprague-Dawley rats were divided into control and resveratrol-treated groups (30 mg/kg of body weight per day) and fed a commercial obesogenic diet for 6 wk. Liver triacylglycerol content and the activity of carnitine palmitoyl transferase-Ia (CPT-Ia), acyl-coenzyme A oxydase (ACO), fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), acetyl-coenzyme A carboxylase (ACC), adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) activation were measured. Mitochondrial protein cytochrome C oxidase subunit 2 (COXII), mitochondrial transcription factor A (TFAM), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-α (PPAR-α), sirtuin-1 (SIRT1), hepatocyte nuclear factor receptor-4α (HNF-4α), and PGC-1α mRNA levels were also analyzed. Serum insulin was quantified. Results Resveratrol decreased liver fat accumulation, increased CPT-Ia and ACO, and decreased ACC activities. Other lipogenic enzymes, FAS, ME, and G6PDH were not modified. The polyphenol activated AMPK and PGC-1α. The expression of SRBP-1c, PPAR-α, SIRT1, PGC-1α, HNF-4α, TFAM, and COXII was not modified. No changes in serum insulin levels were observed. Conclusion Resveratrol partly prevents the increase in liver fat accumulation induced by high-fat high-sucrose feeding by increasing fatty acid oxidation and decreasing lipogenesis. These effects are mediated by the activation of the AMPK/SIRT1 axis.
Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) ...blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8
effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with ...advanced solid tumors.
Seventy-one patients received oral TAK-117 once daily 100-300 mg (
= 24) or 3 days per week Monday-Wednesday-Friday (MWF), 200-1,200 mg (
= 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (
= 20), in 21-day cycles. Dose escalation proceeded via a 3 + 3 design.
TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all
mutated).
Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.
.
Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or ...fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab.
Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival.
Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio HR, 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti-vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities.
Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.
Colorectal cancer is the third most frequent cancer worldwide. Overall survival rates have improved greatly over the last few years due, at least in part, to the addition of targeted therapies to ...standard of care chemotherapy. Angiogenesis plays an important role in colorectal cancer, and therapies directed against the vascular endothelial growth factor (VEGF) axis have contributed significantly to improving the outcome of patients with metastatic colorectal cancer. Over the past few years, several new targeted antiangiogenic agents have been approved for this patient population, confirming the value of inhibiting tumour angiogenesis. The most recent among them is ramucirumab, a fully humanized monoclonal antibody that targets the extracellular domain of VEGF receptor 2. It has proven valuable in multiple tumour types including colorectal cancer. Several phase I and II clinical trials showed a favourable toxicity profile and promising clinical antitumour efficacy in colorectal cancer patients. In the phase III RAISE clinical trial, the addition of ramucirumab to FOLFIRI-based chemotherapy resulted in an improvement of overall survival in patients with metastatic colorectal cancer who had been previously treated with bevacizumab, oxaliplatin and a fluoropyrimidine. On the basis of these results, ramucirumab was approved by the US Food and Drug Administration for this setting. We present an overview of the key preclinical and clinical studies in the development of ramucirumab in the context of metastatic colorectal cancer.
•Proposals for the thermogenic pathways of resveratrol.•Resveratrol increased gene expression of mitochondriogenic markers, COX2 and TFAM.•Resveratrol increased expression of UCP1 and UCP3 in two ...important thermogenic tissues.•Thermogenic effects may contribute to the body-fat lowering effect of resveratrol.
The effect of resveratrol on thermogenesis in skeletal muscle and interscapular brown adipose tissue (IBAT) was investigated. Rats were fed an obesogenic diet supplemented with resveratrol (30mg/kg/day) or not supplemented for 6weeks. Resveratrol intake led to increased gene expression of mitochondrial-transcription-factor-A (TFAM), mitochondrial-protein-cytochrome-C-oxidase subunit-2 (COX2), sirtuin-1 (SIRT1), peroxisome-proliferator-activated-receptor-β/δ (PPARβ/δ) and proliferator-activated-receptor-gamma-coactivator1-α (PGC-1α) in IBAT and increased UCP1protein expression; however, peroxisome-proliferator-activated-receptor-α (PPARα) expression remained unchanged. In gastrocnemius muscle, resveratrol increased the gene expression of TFAM and COX2; however, no changes were observed in levels of SIRT1, PGC-1α and PPARβ/δ. Acetylated-PGC-1α was decreased in the resveratrol-treated group, indicating a higher level of activation, and a significant increase of UCP3 protein expression was observed in this group. The increases in UCP protein expression in two important thermogenic tissues after resveratrol treatment may contribute to increased whole-body energy dissipation, which may help to better understand the body-fat lowering effect of this polyphenol.
In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. ...Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I–IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A‐, B‐ and C‐type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial‐to‐mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A‐type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C‐type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A‐type and B‐type tumors have a more proliferative and epithelial phenotype and B‐types benefit from adjuvant chemotherapy. B‐type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.
What's new?
Even when tumors look the same, they may behave differently. But patients can be treated more effectively if clinicians know how aggressively a cancer will progress or how well it will respond to treatment. That's why this study investigated molecular and genetic differences in colorectal cancer to find out how to distinguish different subtypes. They classified tumors into three categories based on three biological hallmarks: epithelial to mesenchymal transition, high mutation frequency, and proliferation. Each of the tumor types has a different prognosis and response to chemotherapy, and a patient's tumor type can help determine what treatment should be attempted.
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